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Bjørnerud B, Wesche J, Haugsten EM. A rhabdomyosarcoma cell migration inhibitor screen using phase-contrast microscopy. Exp Cell Res 2025; 449:114582. [PMID: 40320199 DOI: 10.1016/j.yexcr.2025.114582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2025] [Accepted: 04/29/2025] [Indexed: 05/14/2025]
Abstract
Rhabdomyosarcoma (RMS) is a malignant soft tissue tumour occurring in young children. Alterations in fibroblast growth factor receptor 4 (FGFR4) signalling pathways are linked to metastasis and poor prognosis in RMS. A critical trait of metastatic disease is the ability of cancer cells to migrate and invade nearby and distant tissues. To study cell migration, we have developed a computational tool that automatically tracks and measures the velocity of migrating cells in phase contrast images. This tool facilitated an inhibitor screen comprising 462 compounds, analysing nearly 2000 videos and tracking approximately 700 000 RMS-derived cells harbouring a constitutively active FGFR4 (RMS559). The highly selective inhibitor screen targeted various signalling pathways, including receptor tyrosine kinases (RTKs), mitogen-activated protein kinases (MAPK), and phosphoinositide 3-kinases (PI3K). Validation of screen hits revealed that inhibiting proteins in the MAPK and PI3K pathway decreased cell migration and, in some cases, cell viability. Inhibiting FGFR4 resulted in decreased RMS559 cell migration, while, surprisingly, inhibitors targeting Rho-associated protein kinase (ROCK) and focal adhesion kinase (FAK) resulted in increased RMS559 cell migration. Mechanistically, the inhibition of ROCK and FAK resulted in fewer focal adhesions, thereby facilitating increased cell velocity. These findings suggest that targeting specific signalling pathways can effectively modulate migration and survival of metastatic RMS559 cells.
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Affiliation(s)
- Birgitte Bjørnerud
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Jørgen Wesche
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Ellen Margrethe Haugsten
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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Zhang R, Danshiitsoodol N, Noda M, Yonezawa S, Kanno K, Sugiyama M. Stevia Leaf Extract Fermented with Plant-Derived Lactobacillus plantarum SN13T Displays Anticancer Activity to Pancreatic Cancer PANC-1 Cell Line. Int J Mol Sci 2025; 26:4186. [PMID: 40362423 PMCID: PMC12071683 DOI: 10.3390/ijms26094186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/24/2025] [Accepted: 04/24/2025] [Indexed: 05/15/2025] Open
Abstract
Pancreatic cancer is a highly malignant tumor that remains a significant global health burden. In this study, we demonstrated the anticancer potential of stevia leaf extract fermented with plant-derived Lactobacillus (L.) plantarum SN13T strain. Evaluation of antioxidant capacity (including DPPH and ABTS radical scavenging activities and H2O2-induced oxidative damage repair in HEK-293 cells), as well as cytotoxicity against pancreatic cancer cells (PANC-1) and non-cancerous human embryonic kidney (HEK-293), revealed that the fermented extract exhibited significantly enhanced antioxidant activity and cytotoxicity against PANC-1 cells while showing minimal toxicity to HEK-293 cells compared to the unfermented extract. Further, validation through clonogenic, migration, and wound-healing assays demonstrated that the fermented extract effectively inhibited the proliferation and migration of PANC-1 cells. The active compound in the fermented extract has been identified as chlorogenic acid methyl ester (CAME), with a concentration of 374.4 μg/mL. Flow cytometry analysis indicated that CAME significantly arrested PANC-1 cells in the G0/G1 phase and induced apoptosis. Furthermore, CAME upregulated the expression of pro-apoptotic genes Bax, Bad, Caspase-3/9, Cytochrome c, and E-cadherin, while downregulating the anti-apoptotic gene Bcl-2. These findings suggest that CAME exerts potent cytotoxic effects on PANC-1 cells by inhibiting cell proliferation and migration, arresting the cell cycle, and regulating apoptosis-related gene expression. In conclusion, stevia leaf extract fermented with L. plantarum SN13T, which contains CAME, may serve as a promising candidate for pancreatic cancer treatment.
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Affiliation(s)
- Rentao Zhang
- Department of Probiotic Science for Preventive Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (R.Z.); (N.D.); (M.N.)
| | - Narandalai Danshiitsoodol
- Department of Probiotic Science for Preventive Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (R.Z.); (N.D.); (M.N.)
| | - Masafumi Noda
- Department of Probiotic Science for Preventive Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (R.Z.); (N.D.); (M.N.)
| | - Sayaka Yonezawa
- Department of General Internal Medicine, Hiroshima University Hospital, Hiroshima University, Hiroshima 734-8551, Japan; (S.Y.); (K.K.)
| | - Keishi Kanno
- Department of General Internal Medicine, Hiroshima University Hospital, Hiroshima University, Hiroshima 734-8551, Japan; (S.Y.); (K.K.)
| | - Masanori Sugiyama
- Department of Probiotic Science for Preventive Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan; (R.Z.); (N.D.); (M.N.)
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Xu M, Zhang Z, He X, Zhang P, Zhang H, Xia Y, Zhou J, Liu J, Ye X, Liu J. Mechanistic insights into proteasome inhibitor MG132 induced apoptosis in melanoma A375 cells. Sci Rep 2025; 15:14731. [PMID: 40289224 PMCID: PMC12034790 DOI: 10.1038/s41598-025-99151-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 04/17/2025] [Indexed: 04/30/2025] Open
Abstract
Despite advancements in melanoma therapy, the prognosis remains unfavorable for many patients. The proteasome inhibitor MG132 has shown therapeutic potential through pathway regulation, yet its precise mechanisms in melanoma require systematic elucidation. Using A375 melanoma cells, we conducted multi-modal investigations combining cytotoxicity assessment (CCK8), migration analysis (wound healing), apoptosis quantification (flow cytometry), and proteomic profiling (western blot) to dissect MG132's molecular mechanisms. Our findings revealed MG132's potent anti-tumor activity with an IC50 of 1.258 ± 0.06 µM, significantly suppressing cellular migration at therapeutic concentrations. Apoptosis assays demonstrated concentration-dependent effects, with 2 µM treatment inducing early apoptosis in 46.5% and total apoptotic response in 85.5% of cells within 24 h. Mechanistic studies uncovered MG132's dual regulatory capacity: (1) Through MDM2 inhibition, it activated p53/p21/caspase-3 axis while suppressing CDK2/Bcl2, triggering cell cycle arrest and DNA damage cascades; (2) MAPK pathway activation emerged as a critical apoptosis driver. Notably, western blot analysis established dose-responsive modulation of these molecular targets, confirming pathway specificity. Our results position MG132 as a multi-target agent capable of simultaneously disrupting proliferative signaling and activating apoptotic machinery. The observed MAPK-mediated apoptosis mechanism provides novel insights for melanoma therapeutics, suggesting that combinatorial targeting of proteasomal and MAPK pathways may enhance treatment efficacy.
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Affiliation(s)
- Meng Xu
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Ziqing Zhang
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Xinyi He
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Peixi Zhang
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Hengyuan Zhang
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Yuanxi Xia
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Jiaming Zhou
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Jia Liu
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Xiaotong Ye
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China
| | - Jieqing Liu
- School of Medicine, Huaqiao University, Quanzhou, 362021, People's Republic of China.
- Engineering Research Centre of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key Laboratory of Precision Medicine and Molecular Diagnosis of Fujian Universities, Key Laboratory of Xiamen Marine and Gene Drugs, Huaqiao University, Quanzhou, 362021, People's Republic of China.
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Shen X, Zhou Q, Peng Y, Ma H, Bu X, Xu T, Yang C, Yan F. Miniaturized High-Throughput and High-Resolution Platform for Continuous Live-Cell Monitoring via Lens-Free Imaging and Deep Learning. SMALL METHODS 2025:e2401855. [PMID: 40091386 DOI: 10.1002/smtd.202401855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 03/03/2025] [Indexed: 03/19/2025]
Abstract
Monitoring the morphology and dynamics of both individual and collective cells is crucial for understanding the complexities of biological systems, investigating disease mechanisms, and advancing therapeutic strategies. However, traditional live-cell workstations that rely on microscopy often face inherent trade-offs between field of view (FOV) and resolution, making it difficult to achieve both high-throughput and high-resolution monitoring simultaneously. While existing lens-free imaging technologies enable high-throughput cell monitoring, they are often hindered by algorithmic complexity, long processing times that prevent real-time imaging, or insufficient resolution due to large sensor pixel sizes. To overcome these limitations, here an imaging platform is presented that integrates a custom-developed 500 nm pixel-size, 400-megapixel sensor with lens-free shadow imaging technology. This platform is capable of achieving imaging at a speed of up to 40s per frame, with a large FOV of 1 cm2 and an imaging signal-to-noise ratio (SNR) of 42 dB, enabling continuous tracking of individual and cell populations throughout their entire lifecycle. By leveraging deep learning algorithms, the system accurately analyzes cell movement trajectories, while the integration of a K-means unsupervised clustering algorithm ensures precise evaluation of cellular activity. This platform provides an effective solution for high-throughput live-cell morphology monitoring and dynamic analysis.
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Affiliation(s)
- Xinyu Shen
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
| | - Qianwei Zhou
- College of Engineering and Applied Sciences, Nanjing University, Nanjing, 210093, China
| | - Yao Peng
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
| | - Haowen Ma
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
| | - Xiaofeng Bu
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
| | - Ting Xu
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
- College of Engineering and Applied Sciences, Nanjing University, Nanjing, 210093, China
| | - Cheng Yang
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
| | - Feng Yan
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
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Nguedia MY, Rebe RN, Bakam BY, Njamen D, Mendimi JMN, Zingue S. Anticancer Potential of Ethanolic Extract of Xylopia aethiopica (Dunal) A. Rich (Annonaceae) Dried Fruits on Breast Adenocarcinoma: In Vitro and In Vivo Evidences. ENVIRONMENTAL TOXICOLOGY 2025; 40:245-263. [PMID: 39400944 DOI: 10.1002/tox.24428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 08/13/2024] [Accepted: 09/29/2024] [Indexed: 10/15/2024]
Abstract
Breast cancer incidence and mortality rate in Cameroonian women is incredibly high, thus there is need for more effective therapy. Xylopia aethiopica dry fruits are traditionally used for both nutritional and medicinal purposes, including the management of diverse ailments such as cancer. This study evaluated the in vitro and in vivo anti-mammary cancer potential of X. aethiopica. The cytotoxic activity of the ethanolic extract of X. aethiopica dry fruits was assessed at different concentrations against MDA-MB 231 and MCF-7 cells using the MTT assay. Additionally, clone formation, apoptosis/necrosis, cell adhesion, cell migration, and chemotaxis were examined. Furthermore, the chemo-preventive potential of X. aethiopica dry fruit extract (XAE) was evaluated on breast tumors induced by DMBA in 42 female rats of age 45-55 days (~80 g). The normal (NOR) and negative (DMBA) control groups were daily treated with the vehicle, while the positive (Tamox) and test (XAE) groups were administered tamoxifen (3.3 mg/kg) and X. aethiopica extract (75, 150, and 300 mg/kg BW), respectively for 20 weeks. Parameters such as tumor volume and burden, tumor incidence, CA 15-3 serum level, inflammatory status, antioxidant and histopathology were evaluated. X. aethiopica significantly (p < 0.05) decreased ER+ (MCF-7) and ER- (MDA-MB 231) breast adenocarcinoma cell growth from 12.5 to 100 μg/mL after 72 h. At the 100 μg/mL concentration, clone formation, cell proliferation, and migration were notably decreased in MDA-MB 231 cells after 48 h, while there was an observed rise in cell adhesion to the collagen extracellular matrix. Additionally, there was a rise in apoptotic cell count (p < 0.01) and caspase-3 activity (p < 0.05) observed in MDA-MB 231 cells following exposure to XAE at 100 μg/mL. XAE, across all tested doses, demonstrated significant reductions in tumor incidence, burden, and volume, akin to tamoxifen, compared to untreated rats (DMBA). Furthermore, there was an elevation in antioxidants (SOD, CAT, and GSH) and a decrease in pro-inflammatory cytokines (INF-γ, TNF-α, IL-12, and IL-6) observed at all tested doses. Overall, X. aethiopica dry fruit displays anticancer potential through caspase-3-dependent apoptosis pathways, alongside antioxidant and anti-inflammatory activities.
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Affiliation(s)
- Merline Ymele Nguedia
- Faculty of Science, Department of Biological Sciences, University of Maroua, Maroua, Cameroon
| | - Roland Nhouma Rebe
- Faculty of Science, Department of Biological Sciences, University of Maroua, Maroua, Cameroon
| | - Berlise Yengwa Bakam
- Faculty of Science, Department of Animal Biology and Physiology, University of Yaoundé 1, Yaoundé, Cameroon
| | - Dieudonné Njamen
- Faculty of Science, Department of Animal Biology and Physiology, University of Yaoundé 1, Yaoundé, Cameroon
| | - Joseph Marie Nkodo Mendimi
- Faculty of Medicine and Biomedical Sciences, Department of Morphological Sciences and Pathological Anatomy, University of Yaounde 1, Yaounde, Cameroon
| | - Stéphane Zingue
- Faculty of Medicine and Biomedical Sciences, Department of Pharmacotoxicology and Pharmacokinetics, University of Yaounde 1, Yaounde, Cameroon
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Șerban RE, Boldeanu MV, Florescu DN, Ionescu M, Șerbănescu MS, Boldeanu L, Florescu MM, Stepan MD, Obleagă VC, Constantin C, Popescu DM, Streba CT, Vere CC. Comparison between Substance P and Calcitonin Gene-Related Peptide and Their Receptors in Colorectal Adenocarcinoma. J Clin Med 2024; 13:5616. [PMID: 39337103 PMCID: PMC11432560 DOI: 10.3390/jcm13185616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
Background: Colorectal cancer is a major health problem that still causes many deaths worldwide. Neuropeptides, such as substance P and calcitonin gene-related peptide, play the neurotransmitter and neurohormone roles that increase tumor invasiveness and metastasis potential. This study aimed to see whether these neuropeptides and their receptors-neurokinin 1 receptor and calcitonin receptor-like receptor-correlate with the diagnosis stage, tumor differentiation grade, and different patient characteristics in colorectal cancer and also to compare them. Methods: We performed serum analyses of substance P and CGRP levels in patients with colorectal cancer and also the immunohistochemical analysis of their receptors in colorectal tumors and then correlated them with the disease stage and with different tumor characteristics. Results: We demonstrated that both substance P and calcitonin gene-related peptide had increased levels in colorectal cancer and that their levels correlated with the stage of the disease and with the tumor differentiation grade. We also demonstrated the correlation of NK-1R and CRLR higher immunohistochemical scores with advanced and poorly differentiated tumors. Conclusions: This study demonstrates that the neuropeptides SP and CGRP and their receptors NK-1R and CRLR could play a role in the pathogenesis of colorectal cancer, and they could be used as diagnostic and prognostic markers and could represent potential therapeutic targets.
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Affiliation(s)
- Robert-Emmanuel Șerban
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.-E.Ș.); (C.C.V.)
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania
| | - Mihail Virgil Boldeanu
- Department of Immunology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dan Nicolae Florescu
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.-E.Ș.); (C.C.V.)
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania
| | - Mihaela Ionescu
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mircea-Sebastian Șerbănescu
- Department of Medical Informatics and Biostatistics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Lidia Boldeanu
- Department of Microbiology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mirela-Marinela Florescu
- Department of Pathology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Mioara-Desdemona Stepan
- Department of Infant Care-Pediatrics-Neonatology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Vasile-Cosmin Obleagă
- Department of Surgery, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cristian Constantin
- Department of Radiology and Medical Imaging, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Dragoş-Marian Popescu
- Department of Extreme Conditions Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Costin Teodor Streba
- Department of Scientific Research Methodology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
- Department of Pulmonology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Cristin Constantin Vere
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (R.-E.Ș.); (C.C.V.)
- Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, 200638 Craiova, Romania
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Luo D, He F, Liu J, Dong X, Fang M, Liang Y, Chen M, Gui X, Wang W, Zeng L, Fan X, Wu Q. Pseudolaric acid B suppresses NSCLC progression through the ROS/AMPK/mTOR/autophagy signalling pathway. Biomed Pharmacother 2024; 175:116614. [PMID: 38670047 DOI: 10.1016/j.biopha.2024.116614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/08/2024] [Accepted: 04/17/2024] [Indexed: 04/28/2024] Open
Abstract
Pseudolaric acid B (PAB), an acid isolated from the roots of Pseudolarix kaempferi gorden, has shown antitumour effects through multiple mechanisms of action. The objective of this study was to investigate the anticancer effect of PAB on non-small cell lung cancer (NSCLC) and its underlying mechanism. In our experiments, we observed that PAB decreased cell viability, inhibited colony formation, induced cell cycle arrest, impeded scratch healing, and increased apoptosis in H1975 and H1650 cells. Additionally, PAB treatment enhanced the fluorescence intensity of MDC staining in NSCLC cells, upregulated the protein expression of microtubule-associated protein light chain 3 II (LC3 II), and downregulated the expression of sequestosome 1 (SQSTM1/P62). Combined treatment with PAB and chloroquine (CQ) increased the protein expression levels of LC3 II and P62 while decreasing the apoptosis of H1975 and H1650 cells. Moreover, treatment with PAB led to significant mTOR inhibition and AMPK activation. PAB combined with compound C (CC) inhibited autophagy and apoptosis. Furthermore, PAB treatment increased intracellular reactive oxygen species (ROS) levels in NSCLC cells, which correlated with the modulation of the AMPK/mTOR signalling pathway and was associated with autophagy and apoptosis. Finally, we validated the antitumour growth activity and mechanism of PAB in vivo using athymic nude mice bearing H1975 tumour cells. In conclusion, our findings suggest that PAB can induce apoptosis and autophagic cell death in NSCLC through the ROS-triggered AMPK/mTOR signalling pathway, making it a promising candidate for future NSCLC treatment.
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Affiliation(s)
- Dan Luo
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Fang He
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Jingyun Liu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Xueting Dong
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Mengying Fang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Yuling Liang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Mengqin Chen
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Xuemei Gui
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Wenjun Wang
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China
| | - Li Zeng
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China.
| | - Xianming Fan
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China; Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646099, China.
| | - Qibiao Wu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China; Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong University of Technology, Guangdong, Guangzhou 510520, China; Zhuhai MUST Science and Technology Research Institute, Guangdong, Zhuhai 51900, China.
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Wang Y, Zhang Y, Ouyang J, Yi H, Wang S, Liu D, Dai Y, Song K, Pei W, Hong Z, Chen L, Zhang W, Liu Z, Mcleod HL, He Y. TRPV1 inhibition suppresses non-small cell lung cancer progression by inhibiting tumour growth and enhancing the immune response. Cell Oncol (Dordr) 2024; 47:779-791. [PMID: 37902941 DOI: 10.1007/s13402-023-00894-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/20/2023] [Indexed: 11/01/2023] Open
Abstract
PURPOSE TRPV1 is a nonselective Ca2+ channel protein that is widely expressed and plays an important role during the occurrence and development of many cancers. Activation of TRPV1 channels can affect tumour progression by regulating proliferation, apoptosis and migration. Some studies have also shown that activating TRPV1 can affect tumour progression by modulating tumour immunity. However, the effects of TRPV1 on the development of non-small cell lung cancer (NSCLC) have not been explored clearly. METHOD The Cancer Genome Atlas (TCGA) database and spatial transcriptomics datasets from 10 × Genomics were used to analyze TRPV1 expression in various tumour tissues. Cell proliferation and apoptosis were examined by cell counting kit 8 (CCK8), colony formation, and flow cytometry. Immunohistochemistry, qPCR, and western blotting were used to determine the mRNA and protein expression levels of TRPV1 and other related molecules. Tumour xenografts in BALB/C and C57BL/6J mice were used to determine the effects of TRPV1 on NSCLC development in vivo. Neurotransmitter content was examined by LC-MS/MS, ELISA and Immunohistochemistry. Immune cell infiltration was assessed by flow cytometry. RESULTS In this study, we found that TRPV1 expression was significantly upregulated in NSCLC and that patients with high TRPV1 expression had a poor prognosis. TRPV1 knockdown can significantly inhibit NSCLC proliferation and induce cell apoptosis through Ca2+-IGF1R signaling. In addition, TRPV1 knockdown resulted in increased infiltration of CD4+ T cells, CD8+ T cells, GZMB+CD8+ T cells and DCs and decreased infiltration of immunosuppressive MDSCs in NSCLC. In addition, TRPV1 knockout effectively decreased the expression of M2 macrophage markers CD163 and increased the expression of M1-associated, costimulatory markers CD86. Knockdown or knockout of TRPV1 significantly inhibit tumour growth and promoted an antitumour immune response through supressing γ-aminobutyric acid (GABA) secretion in NSCLC. CONCLUSION Our study suggests that TRPV1 acts as a tumour promoter in NSCLC, mediating pro-proliferative and anti-apoptotic effects on NSCLC through IGF1R signaling and regulating GABA release to affect the tumour immune response.
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Affiliation(s)
- Yang Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Yu Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Jing Ouyang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Hanying Yi
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Shiyu Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Dongbo Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Yingying Dai
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
| | - Kun Song
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China
| | - Wenwu Pei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China
| | - Ziyang Hong
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China
| | - Ling Chen
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, 3 Hunan, Changsha, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaoqian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Howard L Mcleod
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China
- Center for Precision Medicine, Utah Tech University, St George, UT, USA
| | - Yijing He
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Xiang Ya Road 110, Changsha, 410000, Hunan, China.
- Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, P. R. China.
- Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Central South University, Changsha, P. R. China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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9
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Zhao Y, Chen KL, Shen XY, Li MK, Wan YJ, Yang C, Yu RJ, Long YT, Yan F, Ying YL. HFM-Tracker: a cell tracking algorithm based on hybrid feature matching. Analyst 2024; 149:2629-2636. [PMID: 38563459 DOI: 10.1039/d4an00199k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Cell migration is known to be a fundamental biological process, playing an essential role in development, homeostasis, and diseases. This paper introduces a cell tracking algorithm named HFM-Tracker (Hybrid Feature Matching Tracker) that automatically identifies cell migration behaviours in consecutive images. It combines Contour Attention (CA) and Adaptive Confusion Matrix (ACM) modules to accurately capture cell contours in each image and track the dynamic behaviors of migrating cells in the field of view. Cells are firstly located and identified via the CA module-based cell detection network, and then associated and tracked via a cell tracking algorithm employing a hybrid feature-matching strategy. This proposed HFM-Tracker exhibits superiorities in cell detection and tracking, achieving 75% in MOTA (Multiple Object Tracking Accuracy) and 65% in IDF1 (ID F1 score). It provides quantitative analysis of the cell morphology and migration features, which could further help in understanding the complicated and diverse cell migration processes.
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Affiliation(s)
- Yan Zhao
- School of Information Science and Engineering, East China University of Science and Technology, 130 Meilong Road, 200237 Shanghai, P. R. China.
| | - Ke-Le Chen
- School of Chemistry and Chemical Engineering, Molecular Sensing and Imaging Center (MSIC), Nanjing University, Nanjing 210023, P. R. China.
| | - Xin-Yu Shen
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
| | - Ming-Kang Li
- School of Chemistry and Chemical Engineering, Molecular Sensing and Imaging Center (MSIC), Nanjing University, Nanjing 210023, P. R. China.
| | - Yong-Jing Wan
- School of Information Science and Engineering, East China University of Science and Technology, 130 Meilong Road, 200237 Shanghai, P. R. China.
| | - Cheng Yang
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
| | - Ru-Jia Yu
- School of Chemistry and Chemical Engineering, Molecular Sensing and Imaging Center (MSIC), Nanjing University, Nanjing 210023, P. R. China.
| | - Yi-Tao Long
- School of Chemistry and Chemical Engineering, Molecular Sensing and Imaging Center (MSIC), Nanjing University, Nanjing 210023, P. R. China.
| | - Feng Yan
- School of Electronic Sciences and Engineering, Nanjing University, Nanjing, 210023, China
| | - Yi-Lun Ying
- School of Information Science and Engineering, East China University of Science and Technology, 130 Meilong Road, 200237 Shanghai, P. R. China.
- Chemistry and Biomedicine Innovation Center, Nanjing University, Nanjing 210023, P. R. China
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10
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Tripathy S, Singh S, Banerjee M, Modi DR, Prakash A. Coagulation proteases and neurotransmitters in pathogenicity of glioblastoma multiforme. Int J Neurosci 2024; 134:398-408. [PMID: 35896309 DOI: 10.1080/00207454.2022.2107514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 07/10/2022] [Accepted: 07/15/2022] [Indexed: 10/16/2022]
Abstract
Glioblastoma is an aggressive type of cancer that begins in cells called astrocytes that support nerve cells that can occur in the brain or spinal cord. It can form in the brain or spinal cord. Despite the variety of modern therapies against GBM, it is still a deadly disease. Patients usually have a median survival of approximately 14 to 15 months from the diagnosis. Glioblastoma is also known as glioblastoma multiforme. The pathogenesis contributing to the proliferation and metastasis of cancer involves aberrations of multiple signalling pathways through multiple genetic mutations and altered gene expression. The coagulant factors like thrombin and tissue factor play a noteworthy role in cancer invasion. They are produced in the microenvironment of glioma through activation of protease-activated receptors (PARs) which are activated by coagulation proteases. PARs are members of family G-protein-coupled receptors (GPCRs) that are activated by coagulation proteases. These components play a key role in tumour cell angiogenesis, migration, invasion, and interactions with host vascular cells. Further, the release of neurotransmitters is also found to regulate malignancy in gliomas. Exploration of the interplay between malignant neural circuitry with the normal conditions is also decisive in finding effective therapies for these apparently invasive tumours. The present review discusses the molecular classification of gliomas, activation of PARs by coagulation protease, and its role in metastasis of gliomas. Further, the differential involvement of neurotransmitters in the pathogenesis of gliomas has also been discussed. Targeting these molecules may present a potential therapeutic approach for the treatment of gliomas.
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Affiliation(s)
- Sukanya Tripathy
- Molecular & Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, India
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, India
| | - Sanjay Singh
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, India
| | - Monisha Banerjee
- Molecular & Human Genetics Laboratory, Department of Zoology, University of Lucknow, Lucknow, India
| | - Dinesh Raj Modi
- Department of Biotechnology, Babasaheb Bhimrao Ambedkar University, Lucknow, India
| | - Anand Prakash
- Department of Biotechnology, Mahatma Gandhi Central University, Motihari, India
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11
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Wang Y, Wang T, Liu W, Luo G, Lu G, Zhang Y, Wang H. Anticancer effects of solasonine: Evidence and possible mechanisms. Biomed Pharmacother 2024; 171:116146. [PMID: 38198952 DOI: 10.1016/j.biopha.2024.116146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 01/04/2024] [Accepted: 01/05/2024] [Indexed: 01/12/2024] Open
Abstract
The effectiveness and safety of traditional Chinese medicine's active ingredients in anti-tumor effects have attracted widespread attention worldwide. Solasonine is the main anti-tumor component of the traditional Chinese medicine Solanum nigrum L, which can inhibit tumor cell proliferation, induce apoptosis, induce ferroptosis in tumor cells, and inhibit of tumor cell metastasis, thereby inhibiting tumor progression. Therefore, we summarized anti-tumor mechanisms and targets of solasonine to provide new ideas and theoretical basis for its further development and application.
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Affiliation(s)
- YingZheng Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - Tong Wang
- School of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China
| | - WeiDong Liu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - GuangZhi Luo
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - GuangYing Lu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - YaNan Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China.
| | - HuaXin Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China.
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12
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Kamdem MHK, Zingue S, Grein T, Maxeiner S, Rutz J, Mmutlane EM, Njamen D, Blaheta RA, Ndinteh DT. Aridanin and oleanane-3- O-β-D-glucoside-2'-acetamide obtained from Tetrapleura tetraptera (Schumach. & Thonn) Taub. (Fabaceae) induces potent apoptotic activity in human prostate cancer cells. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117298. [PMID: 37866463 DOI: 10.1016/j.jep.2023.117298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Revised: 10/04/2023] [Accepted: 10/07/2023] [Indexed: 10/24/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Tetrapleura tetraptera (Schumach. and Thonn.) Taub. (Fabaceae) is a tropical plant that is used in Cameroon pharmacopeia for the treatment of many cancers including prostate cancer (PCa), which is a major cause of men's death worldwide. The objective of this study was to evaluate the anticancer properties as well as underlying mechanisms of isolates from T. tetraptera on DU145, PC3 and LNCaP cancer cell lines. MATERIALS AND METHODS Eight (8) compounds were purified from T. tetraptera stem bark extract through silica gel column chromatography (CC) and characterized using spectroscopic techniques (1D and 2D NMR), HRESIMS. Cell growth was assessed by a well-characterized MTT assay, while BrdU and clonogenicity assays provided information on the cell proliferation index. Further, the impact of the compounds on cell cycle progression and cell death were performed through Flow cytometry. Cell adhesion, cell migration and chemotaxis along with some proteins of epithelial-mesenchymal transition (EMT) were assayed. RESULTS Out of the eight (1-8) isolates from T. tetraptera only oleanane-3-O-β-D-glucoside-2'-acetamide and aridanin showed potent cell growth arrest with an estimated CC50 of 15, 23, 16 and 17, 26, 16 μg/mL on DU145, PC3 and LNCaP cells, respectively. A 15% (DU145) and 25% (LNCaP) increase in apoptotic cells induced by oleanane-3-O-β-D-glucoside-2'-acetamide and aridanin at 10 μg/mL were noticed. Oleanane-3-O-β-D-glucoside-2'-acetamide and aridanin at 2.5 and 10 μg/mL reduced the number of cells in S-phase and raised cells in G2/M phase. At the same concentrations, they decreased the number of invading DU145 cells and increased the adherence of DU145 cells to fibronectin and collagen matrix at tested concentrations, accompanied by an increase in integrin β-1 (10 μg/mL) and integrin β-4 (2.5 μg/mL) expression. Furthermore, a down-regulation of pcdk1, cdk2, Bcl-2, N-Cad, vimentin and cytokeratine 8-18 was noticed while, p19, p27, p53 pAKT, Bax, caspase-3 and E-Cad were up-regulated. CONCLUSIONS This study outlines for the first time, the anticancer ability of compounds oleanane-3-O-β-D-glucoside-2'-acetamide (4) and aridanin (6) from Tetrapleura tetraptera and proposes their putative mechanisms of action.
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Affiliation(s)
- Michael Hermann Kengne Kamdem
- Centre for Natural Product Research, Department of Chemical Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg, 2028, South Africa; Research Center for Synthesis and Catalysis, Department of Chemical Sciences, University of Johannesburg-Kingsway Campus, Auckland Park, 2008, South Africa.
| | - Stéphane Zingue
- Centre for Natural Product Research, Department of Chemical Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg, 2028, South Africa; Department of Urology, University Hospital Frankfurt, Johann Wolfgang Goethe-University, D-60596, Frankfurt am Main, Germany; Department of Pharmacotoxicology and Pharmacokinetics, University of Yaounde 1, P.O. Box 1364, Yaounde, Cameroon.
| | - Timothy Grein
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Johannes Gutenberg-Universität Mainz, D-55131, Mainz, Germany.
| | - Sebastian Maxeiner
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Johannes Gutenberg-Universität Mainz, D-55131, Mainz, Germany.
| | - Jochen Rutz
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Johannes Gutenberg-Universität Mainz, D-55131, Mainz, Germany.
| | - Edwin Mpho Mmutlane
- Centre for Natural Product Research, Department of Chemical Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg, 2028, South Africa; Research Center for Synthesis and Catalysis, Department of Chemical Sciences, University of Johannesburg-Kingsway Campus, Auckland Park, 2008, South Africa.
| | - Dieudonné Njamen
- Department of Animal Biology and Physiology, University of Yaoundé 1, P.O. Box 812, Yaounde, Cameroon.
| | - Roman A Blaheta
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Johannes Gutenberg-Universität Mainz, D-55131, Mainz, Germany.
| | - Derek Tantoh Ndinteh
- Centre for Natural Product Research, Department of Chemical Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg, 2028, South Africa; Research Center for Synthesis and Catalysis, Department of Chemical Sciences, University of Johannesburg-Kingsway Campus, Auckland Park, 2008, South Africa.
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13
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Pasha A, Tondo A, Favre C, Calvani M. Inside the Biology of the β3-Adrenoceptor. Biomolecules 2024; 14:159. [PMID: 38397396 PMCID: PMC10887351 DOI: 10.3390/biom14020159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/24/2024] [Accepted: 01/27/2024] [Indexed: 02/25/2024] Open
Abstract
Since the first discovery in 1989, the β3-adrenoceptor (β3-AR) has gained great attention because it showed the ability to regulate many physiologic and metabolic activities, such as thermogenesis and lipolysis in brown and white adipose tissue, respectively (BAT, WAT), negative inotropic effects in cardiomyocytes, and relaxation of the blood vessels and the urinary bladder. The β3-AR has been suggested as a potential target for cancer treatment, both in adult and pediatric tumors, since under hypoxia its upregulation in the tumor microenvironment (TME) regulates stromal cell differentiation, tumor growth and metastases, signifying that its agonism/antagonism could be useful for clinical benefits. Promising results in cancer research have proposed the β3-AR being targeted for the treatment of many conditions, with some drugs, at present, undergoing phase II and III clinical trials. In this review, we report the scientific journey followed by the research from the β3-Ars' discovery, with focus on the β3-Ars' role in cancer initiation and progression that elects it an intriguing target for novel antineoplastic approaches. The overview highlights the great potential of the β3-AR, both in physiologic and pathologic conditions, with the intention to display the possible benefits of β3-AR modulation in cancer reality.
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Affiliation(s)
- Amada Pasha
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (A.P.); (A.T.); (C.F.)
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy
| | - Annalisa Tondo
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (A.P.); (A.T.); (C.F.)
| | - Claudio Favre
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (A.P.); (A.T.); (C.F.)
| | - Maura Calvani
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (A.P.); (A.T.); (C.F.)
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14
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Wang L, Ni B, Wang J, Zhou J, Wang J, Jiang J, Sui Y, Tian Y, Gao F, Lyu Y. Research Progress of Scutellaria baicalensis in the Treatment of Gastrointestinal Cancer. Integr Cancer Ther 2024; 23:15347354241302049. [PMID: 39610320 PMCID: PMC11605761 DOI: 10.1177/15347354241302049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 10/31/2024] [Accepted: 11/07/2024] [Indexed: 11/30/2024] Open
Abstract
Gastrointestinal (GI) cancer stands as one of the most prevalent forms of cancer globally, presenting a substantial medical and economic burden on cancer treatment. Despite advancements in therapies, it continues to exhibit the second highest mortality rate, primarily attributed to drug resistance and post-treatment side effects. There is an urgent need for novel therapeutic approaches to tackle this persistent challenge. Scutellaria baicalensis, widely used in Traditional Chinese Medicine (TCM), holds a profound pharmaceutical legacy. Modern pharmacological studies have unveiled its anticancer, antioxidant, and immune-enhancing properties. S. baicalensis contains hundreds of active ingredients, with flavonoids, polysaccharides, phenylethanoid glycosides, terpenoids, and sterols being the principal components. These constituents contribute to the treatment of GI cancer by inducing apoptosis in tumor cells, arresting the cell cycle, inhibiting tumor proliferation and metastasis, regulating the tumor microenvironment, modulating epigenetics, and reversing drug resistance. Furthermore, the utilization of modern drug delivery technologies can enhance the bioavailability and therapeutic efficacy of TCM. The treatment of GI cancer with S. baicalensis is characterized by its multi-component, multi-target, and multi-pathway advantages, and S. baicalensis has a broad prospect of becoming a clinical adjuvant or even the main therapy for GI cancer.
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Affiliation(s)
- Lankang Wang
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Baoyi Ni
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jia Wang
- Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, China
| | - Jilai Zhou
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Junyi Wang
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jiakang Jiang
- The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Yutong Sui
- Shenzhen Hospital of Southern Medical University, Shenzhen, China
| | - Yaoyao Tian
- Heilongjiang University of Chinese Medicine, Harbin, China
| | - Feng Gao
- Mudanjiang Hospital of Chinese Medicine, Mudanjiang, China
| | - Yufeng Lyu
- Hongqi Hospital of Mudanjiang Medical University, Mudanjiang, China
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15
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Vishwas S, Paul SD, Singh D. An Insight on Skin Cancer About Different Targets With Update on Clinical Trials and Investigational Drugs. Curr Drug Deliv 2024; 21:852-869. [PMID: 37496132 DOI: 10.2174/1567201820666230726150642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 12/12/2022] [Accepted: 01/10/2023] [Indexed: 07/28/2023]
Abstract
Cancer is a diverse disease caused by transcriptional changes involving genetic and epigenetic features that influence a huge variety of genes and proteins. Skin cancer is a potentially fatal disease that affects equally men and women globally and is characterized by many molecular changes. Despite the availability of various improved approaches for detecting and treating skin cancer, it continues to be the leading cause of death throughout society. This review highlights a general overview of skin cancer, with an emphasis on epidemiology, types, risk factors, pathological and targeted facets, biomarkers and molecular markers, immunotherapy, and clinical updates of investigational drugs associated with skin cancer. The skin cancer challenges are acknowledged throughout this study, and the potential application of novel biomarkers of skin cancer formation, progression, metastasis, and prognosis is explored. Although the mechanism of skin carcinogenesis is currently poorly understood, multiple articles have shown that genetic and molecular changes are involved. Furthermore, several skin cancer risk factors are now recognized, allowing for efficient skin cancer prevention. There have been considerable improvements in the field of targeted treatment, and future research into additional targets will expand patients' therapeutic choices. In comparison to earlier articles on the same issue, this review focused on molecular and genetic factors and examined various skin cancer-related factors in depth.
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Affiliation(s)
- Suraj Vishwas
- Shankaracharya Technical Campus, Faculty of Pharmaceutical Sciences, Bhilai (C.G.) India
- Sanskar City College of Pharmacy, Rajnandgaon, Bhilai (C.G.) India
| | - Swarnali Das Paul
- Shri Shankaracharya College of Pharmaceutical Sciences, Bhilai (C.G.) India
| | - Deepika Singh
- Shri Shankaracharya Technical Campus, Faculty of Pharmaceutical Sciences, Bhilai (C.G.) India
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16
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Blasko F, Horvathova L. The relationship between the tumor and its innervation: historical, methodical, morphological, and functional assessments - A minireview. Endocr Regul 2024; 58:68-82. [PMID: 38563296 DOI: 10.2478/enr-2024-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2024] Open
Abstract
The acceptance of the tumor as a non-isolated structure within the organism has opened a space for the study of a wide spectrum of potential direct and indirect interactions, not only between the tumor tissue and its vicinity, but also between the tumor and its macroenvironment, including the nervous system. Although several lines of evidence have implicated the nervous system in tumor growth and progression, for many years, researchers believed that tumors lacked innervation and the notion of indirect neuro-neoplastic interactions via other systems (e.g., immune, or endocrine) predominated. The original idea that tumors are supplied not only by blood and lymphatic vessels, but also autonomic and sensory nerves that may influence cancer progression, is not a recent phenomenon. Although in the past, mainly due to the insufficiently sensitive methodological approaches, opinions regarding the presence of nerves in tumors were inconsistent. However, data from the last decade have shown that tumors are able to stimulate the formation of their own innervation by processes called neo-neurogenesis and neo-axonogenesis. It has also been shown that tumor infiltrating nerves are not a passive, but active components of the tumor microenvironment and their presence in the tumor tissue is associated with an aggressive tumor phenotype and correlates with poor prognosis. The aim of the present review was to 1) summarize the available knowledge regarding the course of tumor innervation, 2) present the potential mechanisms and pathways for the possible induction of new nerve fibers into the tumor microenvironment, and 3) highlight the functional significance/consequences of the nerves infiltrating the tumors.
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Affiliation(s)
- Filip Blasko
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
- Institute of Physiology, Faculty of Medicine, Comenius University Bratislava, Bratislava, Slovakia
| | - Lubica Horvathova
- Institute of Experimental Endocrinology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia
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17
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Smyth P, Ferguson L, Burrows JF, Burden RE, Tracey SR, Herron ÚM, Kovaleva M, Williams R, Porter AJ, Longley DB, Barelle CJ, Scott CJ. Evaluation of variable new antigen receptors (vNARs) as a novel cathepsin S (CTSS) targeting strategy. Front Pharmacol 2023; 14:1296567. [PMID: 38116078 PMCID: PMC10728302 DOI: 10.3389/fphar.2023.1296567] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/16/2023] [Indexed: 12/21/2023] Open
Abstract
Aberrant activity of the cysteine protease Cathepsin S (CTSS) has been implicated across a wide range of pathologies. Notably in cancer, CTSS has been shown to promote tumour progression, primarily through facilitating invasion and migration of tumour cells and augmenting angiogenesis. Whilst an attractive therapeutic target, more efficacious CTSS inhibitors are required. Here, we investigated the potential application of Variable New Antigen Receptors (vNARs) as a novel inhibitory strategy. A panel of potential vNAR binders were identified following a phage display panning process against human recombinant proCTSS. These were subsequently expressed, purified and binding affinity confirmed by ELISA and SPR based approaches. Selected lead clones were taken forward and were shown to inhibit CTSS activity in recombinant enzyme activity assays. Further assessment demonstrated that our lead clones functioned by a novel inhibitory mechanism, by preventing the activation of proCTSS to the mature enzyme. Moreover, using an intrabody approach, we exhibited the ability to express these clones intracellularly and inhibit CTSS activity whilst lead clones were also noted to impede cell invasion in a tumour cell invasion assay. Collectively, these findings illustrate a novel mechanistic approach for inhibiting CTSS activity, with anti-CTSS vNAR clones possessing therapeutic potential in combating deleterious CTSS activity. Furthermore, this study exemplifies the potential of vNARs in targeting intracellular proteins, opening a range of previously "undruggable" targets for biologic-based therapy.
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Affiliation(s)
- P. Smyth
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
| | | | - J. F. Burrows
- School of Pharmacy, Queen’s University Belfast, Belfast, United Kingdom
| | - R. E. Burden
- School of Pharmacy, Queen’s University Belfast, Belfast, United Kingdom
| | - S. R. Tracey
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
| | - Ú. M. Herron
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
| | | | - R. Williams
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
| | - A. J. Porter
- Elasmogen Ltd., Aberdeen, United Kingdom
- Scottish Biologics Facility, Institute of Medical Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, United Kingdom
| | - D. B. Longley
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
| | | | - C. J. Scott
- Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
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Zheng XM, Chen YS, Ban YJ, Wang YJ, Dong YX, Lei L, Guo B, Wang JT, Tang L, Li HL, Zhang JQ. Design, synthesis and bioevaluation of PI3Kα-selective inhibitors as potential colorectal cancer drugs. Eur J Med Chem 2023; 260:115754. [PMID: 37651880 DOI: 10.1016/j.ejmech.2023.115754] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/02/2023]
Abstract
The dysregulation of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin signaling pathway has been implicated in various human cancers, and isoform-selective inhibitors targeting PI3Kα have received significant interest in recent years. In this study, we have designed and synthesized three series of substituted benzoxazole derivatives based on the clinical candidate TAK-117 (8a). A detailed structure-activity relationship (SAR) study has identified the optimal compound 18a bearing a quinoxaline scaffold. Compared to the control 8a, 18a exhibited 4.4-fold more potent inhibitory activity against PI3Kα (IC50: 2.5 vs 11 nM) and better isoform-selective profiles over other PI3Ks. In addition, 18a showed a 1.5-fold more potent antiproliferative effect against HCT-116 cell lines (IC50: 3.79 vs 5.80 μM) and a better selectivity over the normal tissue cells. The potential antitumor mechanism and in vitro metabolic stability of 18a were also investigated. Notably, pharmacokinetic assays indicated that 18a had a higher plasma exposure, a higher maximum concentration and shorter elimination time compared to 8a.
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Affiliation(s)
- Xue-Mei Zheng
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang, 550025, China
| | - Yuan-Si Chen
- School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, China
| | - Yu-Juan Ban
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang, 550025, China
| | - Yu-Jie Wang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang, 550025, China
| | - Yong-Xi Dong
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang, 550025, China
| | - Li Lei
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Bing Guo
- Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, College of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Jian-Ta Wang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang, 550025, China
| | - Lei Tang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang, 550025, China.
| | - Hong-Liang Li
- School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, China.
| | - Ji-Quan Zhang
- Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, College of Pharmacy, Guizhou Medical University, Guiyang, 550025, China.
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Zhang P, Liu W, Wang Y. The mechanisms of tanshinone in the treatment of tumors. Front Pharmacol 2023; 14:1282203. [PMID: 37964867 PMCID: PMC10642231 DOI: 10.3389/fphar.2023.1282203] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 10/18/2023] [Indexed: 11/16/2023] Open
Abstract
Tanshinone is a lipophilic compound that is present in traditional Chinese medicine and is derived from the roots of Salvia miltiorrhiza (Danshen). It has been proven to be highly effective in combating tumors in various parts of the body, including liver carcinoma, gastric cancer, ovarian cancer, cervix carcinoma, breast cancer, colon cancer, and prostate cancer. Tanshinone can efficiently prevent the reproduction of cancerous cells, induce cell death, and inhibit the spread of cancerous cells, which are mainly involved in the PI3K/Akt signaling pathway, NF-κB pathway, Bcl-2 family, Caspase cascades, MicroRNA, MAPK signaling pathway, p21, STAT3 pathway, miR30b-P53-PTPN11/SHP2 axis, β-catenin, and Skp2. However, the properties and mechanisms of tanshinone's anti-tumor effects remain unclear currently. Thus, this study aims to review the research progress on tumor prevention and mechanisms of tanshinone to gain new perspectives for further development and clinical application of tanshinone.
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Affiliation(s)
- Pengyu Zhang
- The Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wendi Liu
- School of Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yuan Wang
- Department of Histology and Embryology, Shandong University of Traditional Chinese Medicine, Jinan, China
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Choi HK, Choi JH, Yoon J. An Updated Review on Electrochemical Nanobiosensors for Neurotransmitter Detection. BIOSENSORS 2023; 13:892. [PMID: 37754127 PMCID: PMC10526534 DOI: 10.3390/bios13090892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 09/28/2023]
Abstract
Neurotransmitters are chemical compounds released by nerve cells, including neurons, astrocytes, and oligodendrocytes, that play an essential role in the transmission of signals in living organisms, particularly in the central nervous system, and they also perform roles in realizing the function and maintaining the state of each organ in the body. The dysregulation of neurotransmitters can cause neurological disorders. This highlights the significance of precise neurotransmitter monitoring to allow early diagnosis and treatment. This review provides a complete multidisciplinary examination of electrochemical biosensors integrating nanomaterials and nanotechnologies in order to achieve the accurate detection and monitoring of neurotransmitters. We introduce extensively researched neurotransmitters and their respective functions in biological beings. Subsequently, electrochemical biosensors are classified based on methodologies employed for direct detection, encompassing the recently documented cell-based electrochemical monitoring systems. These methods involve the detection of neurotransmitters in neuronal cells in vitro, the identification of neurotransmitters emitted by stem cells, and the in vivo monitoring of neurotransmitters. The incorporation of nanomaterials and nanotechnologies into electrochemical biosensors has the potential to assist in the timely detection and management of neurological disorders. This study provides significant insights for researchers and clinicians regarding precise neurotransmitter monitoring and its implications regarding numerous biological applications.
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Affiliation(s)
- Hye Kyu Choi
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA;
| | - Jin-Ha Choi
- School of Chemical Engineering, Clean Energy Research Center, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Jinho Yoon
- Department of Biomedical-Chemical Engineering, The Catholic University of Korea, Bucheon 14662, Republic of Korea
- Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Republic of Korea
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21
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Wang Y, Wang T, Wang H, Liu W, Li X, Wang X, Zhang Y. A mechanistic updated overview on Cepharanthine as potential anticancer agent. Biomed Pharmacother 2023; 165:115107. [PMID: 37423171 DOI: 10.1016/j.biopha.2023.115107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/25/2023] [Accepted: 06/28/2023] [Indexed: 07/11/2023] Open
Abstract
The antitumor effects of traditional drugs have received increasing attention and active antitumor components extracted from traditional drugs have shown good efficacy with minimal adverse events. Cepharanthine(CEP for short) is an active component derived from the Stephania plants of Menispermaceae, which can regulate multiple signaling pathways alone or in combination with other therapeutic drugs to inhibit tumor cell proliferation, induce apoptosis, regulate autophagy, and inhibit angiogenesis, thereby inhibiting tumor progression. Therefore, we retrieved studies concerning CEP's antitumor effects in recent years and summarized the antitumor mechanism and targets, in order to gain new insights and establish a theoretical basis for further development and application of CEP.
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Affiliation(s)
- YingZheng Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - Tong Wang
- School of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China
| | - HuaXin Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - WeiDong Liu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - Xiao Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - XiaoYan Wang
- College of Acupuncture and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - YaNan Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China.
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22
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Abdullahi A, Wong TWL, Ng SSM. Putative role of non-invasive vagus nerve stimulation in cancer pathology and immunotherapy: Can this be a hidden treasure, especially for the elderly? Cancer Med 2023; 12:19081-19090. [PMID: 37587897 PMCID: PMC10557911 DOI: 10.1002/cam4.6466] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 07/09/2023] [Accepted: 07/16/2023] [Indexed: 08/18/2023] Open
Abstract
Cancer is globally a disease of significant public health concern owing to its prevalence, and association with morbidity and mortality. Thus, cost-effective treatments for cancer are important to help reduce its significant morbidity and mortality. However, the current therapeutic options for cancer such as chemotherapy, radiotherapy, and surgery may produce serious adverse events such as nausea, vomiting, fatigue, and peripheral neuropathy, especially in the long term. In addition, these therapeutic options may not be well tolerated by the elderly especially those who are frail. The current article is aimed at discussing an alternative therapeutic option, non-invasive vagus nerve stimulation (VNS), and the roles it plays in cancer pathology and immunotherapy. The VNS does this by reducing oxidative stress via silent information regulator 1 (SIRT1); inhibiting inflammation via both hypothalamic-pituitary-axis (HPA) and the release of corticosteroid from the adrenal gland, and cholinergic anti-inflammatory pathway (CAP), and increasing vagal activity which helps in the regulation of cell proliferation, differentiation, apoptosis, and metabolism, and increase chance of survival. Furthermore, it helps with reducing complications due to cancer or its treatments such as postoperative ileus and severity of peripheral neuropathy induced by chemotherapy, and improves cancer-related fatigue, lymphopenia, and quality of life. These suggest that the importance of non-invasive VNS in cancer pathology and immunotherapy cannot be overemphasized. Therefore, considering the safety of non-invasive VNS and its cost-effectiveness, it is a therapeutic option worth trying for these patients, especially in combination with other therapies.
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Affiliation(s)
- Auwal Abdullahi
- Department of Rehabilitation SciencesThe Hong Kong Polytechnic UniversityKowloonHong Kong Special Administrative RegionChina
| | - Thomson W. L. Wong
- Department of Rehabilitation SciencesThe Hong Kong Polytechnic UniversityKowloonHong Kong Special Administrative RegionChina
| | - Shamay S. M. Ng
- Department of Rehabilitation SciencesThe Hong Kong Polytechnic UniversityKowloonHong Kong Special Administrative RegionChina
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23
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Bakam BY, Pambe JCN, Grey T, Maxeiner S, Rutz J, Njamen D, Blaheta RA, Zingue S. Cucumis sativus (Cucurbitaceae) seed oil prevents benzo(a)pyrene-induced prostate cancer in vitro and in vivo. ENVIRONMENTAL TOXICOLOGY 2023; 38:2069-2083. [PMID: 37310102 DOI: 10.1002/tox.23830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 04/26/2023] [Accepted: 05/01/2023] [Indexed: 06/14/2023]
Abstract
Despite enormous progress in modern medicine, prostate cancer (PCa) remains a major public health problem due to its high incidence and mortality. Although studies have shown in vitro antitumor effects of cucurbitacins from Cucumis sativus, the in vivo anticancer effect of the seed oil as a whole, has yet to be demonstrated. The present study evaluated the in vitro anticancer mechanisms of C. sativus (CS) seed oil and its possible chemopreventive potential on benzo(a)pyrene (BaP)-induced PCa in Wistar rat. In vitro cell growth, clone formation, cell death mechanism, cell adhesion and migration as well as expression of integrins β-1 and β-4 were assessed. In vivo PCa was induced in 56 male rats versus 8 normal control rats, randomized in normal (NOR) and negative (BaP) control groups which, received distilled water; the positive control group (Caso) was treated with casodex (13.5 mg/kg BW). One group received the total seed extract at the dose of 500 mg/kg BW; while the remaining three groups were treated with CS seed oil at 42.5, 85, and 170 mg/kg BW. The endpoints were: morphologically (prostate tumor weight and volume), biochemically (total protein, prostate specific antigen (PSA), oxidative stress markers such as MDA, GSH, catalase, and SOD) and histologically. As results, CS seed oil significantly and concentration-dependently reduced the DU145 prostate cancer cell growth and clone formation (optimum = 100 μg/mL). It slightly increased the number of apoptotic cells and inhibited the migration and invasion of DU145 cells, while it decreased their adhesion to immobilized collagen and fibrinogen. The expression of integrin β-1 and β-4 was increased in presence of 100 μg/mL CS oil. In vivo, the BaP significantly elevated the incidence of PC tumors (75%), the total protein and PSA levels, pro-inflammatory cytokines (TNF-α, IL-1, and IL-6) and MDA levels compared to NOR. CS seeds oil significantly counteracted the effect of BaP by decreasing significantly the PC incidence (12.5%), and increasing the level of antioxidant (SOD, GSH, and catalase) and anti-inflammatory cytokine IL-10 in serum. While in BaP group PCa adenocarninoma was the most representative neoplasm, rats treated with 85 and 170 mg/kg prevented it in the light of the casodex. It is conclude that CS may provide tumor suppressive effects in vitro and in vivo which makes it an interesting candidate to support the current treatment protocol.
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Affiliation(s)
- Berlise Yengwa Bakam
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, Yaounde, Cameroon
| | - Judith Christiane Ngo Pambe
- Department of Morphological Sciences and Pathological Anatomy, Faculty of Medicine and Biomedical Sciences, University of Garoua, Garoua, Cameroon
| | - Timothy Grey
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Johannes Gutenberg-Universität Mainz, Mainz, Germany
| | - Sebastian Maxeiner
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Johannes Gutenberg-Universität Mainz, Mainz, Germany
| | - Jochen Rutz
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Johannes Gutenberg-Universität Mainz, Mainz, Germany
| | - Dieudonne Njamen
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, Yaounde, Cameroon
| | - Roman A Blaheta
- Department of Urology and Pediatric Urology, University Medical Center Mainz, Johannes Gutenberg-Universität Mainz, Mainz, Germany
| | - Stéphane Zingue
- Department of Urology, University Hospital Frankfurt, Johann Wolfgang Goethe Universität, Frankfurt am Main, Germany
- Department of Pharmacotoxicology and Pharmacokinetics, Faculty of Medicine and Biomedical Sciences, University of Yaounde 1, Yaounde, Cameroon
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24
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Wang Y, Wang Q, Wang X, Yao P, Dai Q, Qi X, Yang M, Zhang X, Huang R, Yang J, Wang Q, Xia P, Zhang D, Sun F. Docetaxel-loaded pH/ROS dual-responsive nanoparticles with self-supplied ROS for inhibiting metastasis and enhancing immunotherapy of breast cancer. J Nanobiotechnology 2023; 21:286. [PMID: 37608285 PMCID: PMC10464340 DOI: 10.1186/s12951-023-02013-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 07/18/2023] [Indexed: 08/24/2023] Open
Abstract
BACKGROUND Although stimuli-responsive nanoplatforms were developed to deliver immunogenic cell death (ICD) inducers to enhance cancer immunotherapy, the complete release of ICD inducers into the tumor microenvironment (TME) was limited by the inadequate supplementation of endogenous stimulus (e.g., reactive oxygen species (ROS)). To address this issue, we synthesized a self-responsive nanomaterial with self-supplied ROS, which mainly consists of a ROS responsive moiety HPAP and cinnamaldehyde (CA) as the ROS-generating agent. The endogenous ROS can accelerate the degradation of HPAP in materials to release docetaxel (DTX, an ICD inducer). In intracellular acidic environment, the pH-sensitive acetal was cleaved to release CA. The released CA in turn induces the generation of more ROS through mitochondrial damage, resulting in amplified DTX release. Using this self-cycling and self-responsive nanomaterial as a carrier, DTX-loaded pH/ROS dual-responsive nanoparticles (DTX/FA-CA-Oxi-αCD NPs) were fabricated and evaluated in vitro and in vivo. RESULTS In vitro experiments validated that the NPs could be effectively internalized by FA-overexpressed cells and completely release DTX in acidic and ROS microenvironments to induce ICD effect. These NPs significantly blocked 4T1 cell migration and decreased cell invasion. In vivo experiments demonstrated that the tumor-targeted NPs significantly inhibited tumor growth and blocked tumor metastasis. More importantly, these NPs significantly improved immunotherapy through triggering effector T-cell activation and relieving the immunosuppressive state of the TME. CONCLUSIONS Our results demonstrated that DTX/FA-CA-Oxi-αCD NPs displayed great potential in preventing tumor metastasis, inhibiting tumor growth, and improving the efficacy of anti-PD-1antibody.
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Affiliation(s)
- Yu Wang
- Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Qianmei Wang
- Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
- Department of Chemistry, College of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xiaowen Wang
- Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Pu Yao
- Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Qing Dai
- Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xiaowei Qi
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Ming Yang
- Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Nanchong, 637000, China
| | - Xiao Zhang
- Department of Stem Cell and Regenerative Medicine, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Rong Huang
- Department of Chemistry, College of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Jing Yang
- Department of Chemistry, College of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Qian Wang
- Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Peiyuan Xia
- Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
| | - Dinglin Zhang
- Department of Chemistry, College of Basic Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
- Department of Urology, Southwest Hospital, Third Military Medical University (Amy Medical University), Chongqing, 400038, China.
| | - Fengjun Sun
- Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
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Gui H, Chen X, Li L, Zhu L, Jing Q, Nie Y, Zhang X. Psychological distress influences lung cancer: Advances and perspectives on the immune system and immunotherapy. Int Immunopharmacol 2023; 121:110251. [PMID: 37348230 DOI: 10.1016/j.intimp.2023.110251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 04/18/2023] [Accepted: 04/25/2023] [Indexed: 06/24/2023]
Abstract
Lung cancer has the highest incidence rate and mortality worldwide. Moreover, multiple factors may cause heterogeneity in the efficacy of immunotherapy for lung cancer, and preclinical studies have gradually uncovered the promotive effects of psychological distress (PD) on tumor hallmarks. Therefore, treatment targeted at PD may be a vital factor in adjusting and improving immunotherapy for lung cancer. Here, by focusing on the central nervous system, as well as stress-related crucial neurotransmitters and hormones, we highlight the effects of PD on the lung immune system, the lung tumor microenvironment (TME) and immunotherapy, which brings a practicable means and psychosocial perspective to lung cancer treatment.
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Affiliation(s)
- Huan Gui
- Department of Hyperbaric Oxygen, People`s Hospital of Qianxinan Buyi and Miao Minority Autonomous Prefecture, Xingyi 562400, China; School of Medicine, Guizhou University, Guiyang 550025, China
| | - Xulong Chen
- School of Medicine, Guizhou University, Guiyang 550025, China; Department of Urology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
| | - Linzhao Li
- School of Medicine, Guizhou University, Guiyang 550025, China
| | - Lan Zhu
- School of Medicine, Guizhou University, Guiyang 550025, China
| | - Qianyu Jing
- NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - Yingjie Nie
- School of Medicine, Guizhou University, Guiyang 550025, China; NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China.
| | - Xiangyan Zhang
- School of Medicine, Guizhou University, Guiyang 550025, China; NHC Key Laboratory of Pulmonary Immunological Diseases, Guizhou Provincial People's Hospital, Guiyang 550002, China.
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Fotsing SI, Ngo Pambe JC, Silihe KK, Yembeau NL, Choupo A, Njamen D, Pieme CA, Zingue S. Breast cancer cell growth arrest and chemopreventive effects of Passiflora edulis Sims (Passifloraceae) ethanolic leaves extract on a rat model of mammary carcinoma. JOURNAL OF ETHNOPHARMACOLOGY 2023; 311:116408. [PMID: 36966851 DOI: 10.1016/j.jep.2023.116408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 03/10/2023] [Accepted: 03/19/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Despite various prevention and treatment measures, the incidence and mortality due to breast cancer has been increasing globally. Passiflora edulis Sims is a plant used for the treatment of various diseases in traditional medicine, including cancers. AIM OF THE STUDY To assess the anti-breast cancer activity of the ethanolic extract of P. edulis leaves in vitro and in vivo. MATERIAL AND METHODS In vitro, the cell growth and proliferation were determined based on the MTT and BrdU assays. The flow cytometry was used to analyze the cell death mechanism while, cell migration, cell adhesion and chemotaxis were assayed for anti-metastatic potential. In vivo, 56 female Wistar rats aged 45-50 days (∼75 g) were exposed to 7,12-dimethylbenz(a)anthracene-DMBA except the normal group. Negative control group (DMBA) received solvent dilution throughout the study; standards groups (tamoxifen - 3.3 mg/kg BW and letrozole - 1 mg/kg BW) as well as P. edulis leaves ethanolic extract groups (50, 100 and 200 mg/kg) treated for 20 weeks. Tumor incidence, tumor burden and volume, CA 15-3 serum' level, antioxidant, inflammatory status and histopathology were assessed. RESULTS P. edulis extract showed a significant and concentration-dependent inhibition of MCF-7 and MDA-MB 231 cells growth at 100 μg/mL. It inhibited cell proliferation and clones' formation and induced apoptosis in MDA-MB 231 cells. The migration of cell into the zone freed of cells and the number of invading cells after the 48 and 72 h were significantly diminished while, it increased their adherence to collagen and fibronectin extracellular matrix as does Doxorubicin. In vivo, all rats in the DMBA group exhibited a significant (p < 0.001) increase in tumor volume, tumor burden and grade (adenocarcinoma of SBR III) and pro-inflammatory cytokine levels (TNF-α, INF-γ, IL-6 and IL-12). P. edulis extract at all tested doses significantly inhibited the DMBA-induced increase in tumor incidence, tumor burden and grade (SBR I) as well as pro-inflammatory cytokines. Moreover, it increased enzymatic and non-enzymatic antioxidants (SOD, catalase, and GSH) and decreased MDA levels although a greater effect was observed with Tamoxifen and Letrozole. P. edulis has medium content on polyphenols, flavonoids and tannins. CONCLUSION P. edulis has chemo-preventive effects against DMBA-induced breast cancer in rats probably through its antioxidative, anti-inflammatory and apoptosis-inducing potentials.
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Affiliation(s)
- Sorelle Ines Fotsing
- Department of Biochemistry, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon.
| | - Judith Christiane Ngo Pambe
- Department of Morphological Sciences and Pathological Anatomy, Faculty of Medicine and Biomedical Sciences, University of Garoua, P.O. Box 317, Garoua, Cameroon.
| | - Kevine Kamga Silihe
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon; Department of Pharmacotoxicology and Pharmacokinetics, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, P.O. Box 1364, Yaoundé, Cameroon.
| | - Natacha Lena Yembeau
- Department of Biochemistry and Physiological Sciences, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, P.O. Box 1364, Yaoundé, Cameroon.
| | - Armand Choupo
- Department of Biochemistry, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon.
| | - Dieudonné Njamen
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaoundé 1, P.O. Box 812, Yaoundé, Cameroon.
| | - Constant Anatole Pieme
- Department of Biochemistry and Physiological Sciences, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, P.O. Box 1364, Yaoundé, Cameroon.
| | - Stéphane Zingue
- Department of Pharmacotoxicology and Pharmacokinetics, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, P.O. Box 1364, Yaoundé, Cameroon.
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Xiao L, Li X, Fang C, Yu J, Chen T. Neurotransmitters: promising immune modulators in the tumor microenvironment. Front Immunol 2023; 14:1118637. [PMID: 37215113 PMCID: PMC10196476 DOI: 10.3389/fimmu.2023.1118637] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 04/12/2023] [Indexed: 05/24/2023] Open
Abstract
The tumor microenvironment (TME) is modified by its cellular or acellular components throughout the whole period of tumor development. The dynamic modulation can reprogram tumor initiation, growth, invasion, metastasis, and response to therapies. Hence, the focus of cancer research and intervention has gradually shifted to TME components and their interactions. Accumulated evidence indicates neural and immune factors play a distinct role in modulating TME synergistically. Among the complicated interactions, neurotransmitters, the traditional neural regulators, mediate some crucial regulatory functions. Nevertheless, knowledge of the exact mechanisms is still scarce. Meanwhile, therapies targeting the TME remain unsatisfactory. It holds a great prospect to reveal the molecular mechanism by which the interplay between the nervous and immune systems regulate cancer progression for laying a vivid landscape of tumor development and improving clinical treatment.
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Affiliation(s)
- Luxi Xiao
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Xunjun Li
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Chuanfa Fang
- Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi, China
| | - Jiang Yu
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Tao Chen
- Department of General Surgery and Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
- Department of Gastrointestinal and Hernia Surgery, Ganzhou Hospital-Nanfang Hospital, Southern Medical University, Ganzhou, Jiangxi, China
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Soltani D, Azizi B, Sima S, Tavakoli K, Hosseini Mohammadi NS, Vahabie AH, Akbarzadeh-Sherbaf K, Vasheghani-Farahani A. A systematic review of the effects of transcutaneous auricular vagus nerve stimulation on baroreflex sensitivity and heart rate variability in healthy subjects. Clin Auton Res 2023; 33:165-189. [PMID: 37119426 DOI: 10.1007/s10286-023-00938-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 03/27/2023] [Indexed: 05/01/2023]
Abstract
PURPOSE This systematic review aimed to evaluate the effect of transcutaneous auricular vagus nerve stimulation on heart rate variability and baroreflex sensitivity in healthy populations. METHOD PubMed, Scopus, the Cochrane Library, Embase, and Web of Science were systematically searched for controlled trials that examined the effects of transcutaneous auricular vagus nerve stimulation on heart rate variability parameters and baroreflex sensitivity in apparently healthy individuals. Two independent researchers screened the search results, extracted the data, and evaluated the quality of the included studies. RESULTS From 2458 screened studies, 21 were included. Compared with baseline measures or the comparison group, significant changes in the standard deviation of NN intervals, the root mean square of successive RR intervals, the proportion of consecutive RR intervals that differ by more than 50 ms, high-frequency power, low-frequency to high-frequency ratio, and low-frequency power were found in 86%, 75%, 69%, 47%, 36%, and 25% of the studies evaluating the effects of transcutaneous auricular vagus nerve stimulation on these indices, respectively. Baroreflex sensitivity was evaluated in six studies, of which a significant change was detected in only one. Some studies have shown that the worse the basic autonomic function, the better the response to transcutaneous auricular vagus nerve stimulation. CONCLUSION The results were mixed, which may be mainly attributable to the heterogeneity of the study designs and stimulation delivery dosages. Thus, future studies with comparable designs are required to determine the optimal stimulation parameters and clarify the significance of autonomic indices as a reliable marker of neuromodulation responsiveness.
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Affiliation(s)
- Danesh Soltani
- Cardiac Primary Prevention Research Center (CPPRC), Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Bayan Azizi
- Cardiac Primary Prevention Research Center (CPPRC), Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sepehr Sima
- Department of Psychology, University of Tehran, Tehran, Iran
| | - Kiarash Tavakoli
- Cardiac Primary Prevention Research Center (CPPRC), Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Negin Sadat Hosseini Mohammadi
- Cardiac Primary Prevention Research Center (CPPRC), Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
- Students' Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Abdol-Hossein Vahabie
- Control and Intelligent Processing Center of Excellence (CIPCE), Cognitive Systems Laboratory, School of Electrical and Computer Engineering, College of Engineering, University of Tehran, Tehran, Iran
- Department of Psychology, Faculty of Psychology and Education, University of Tehran, Tehran, Iran
| | - Kaveh Akbarzadeh-Sherbaf
- Department of Computer Engineering and Information Technology, Imam Reza International University, Mashhad, Iran
| | - Ali Vasheghani-Farahani
- Cardiac Primary Prevention Research Center (CPPRC), Cardiovascular Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
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Yu L, Lee H, Rho SB, Park MK, Lee CH. Ethacrynic Acid: A Promising Candidate for Drug Repurposing as an Anticancer Agent. Int J Mol Sci 2023; 24:ijms24076712. [PMID: 37047688 PMCID: PMC10094867 DOI: 10.3390/ijms24076712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/28/2023] [Accepted: 03/30/2023] [Indexed: 04/07/2023] Open
Abstract
Ethacrynic acid (ECA) is a diuretic that inhibits Na-K-2Cl cotransporter (NKCC2) present in the thick ascending loop of Henle and muculo dens and is clinically used for the treatment of edema caused by excessive body fluid. However, its clinical use is limited due to its low bioavailability and side effects, such as liver damage and hearing loss at high doses. Despite this, ECA has recently emerged as a potential anticancer agent through the approach of drug repositioning, with a novel mechanism of action. ECA has been shown to regulate cancer hallmark processes such as proliferation, apoptosis, migration and invasion, angiogenesis, inflammation, energy metabolism, and the increase of inhibitory growth factors through various mechanisms. Additionally, ECA has been used as a scaffold for synthesizing a new material, and various derivatives have been synthesized. This review explores the potential of ECA and its derivatives as anticancer agents, both alone and in combination with adjuvants, by examining their effects on ten hallmarks of cancer and neuronal contribution to cancer. Furthermore, we investigated the trend of synthesis research of a series of ECA derivatives to improve the bioavailability of ECA. This review highlights the importance of ECA research and its potential to provide a cost-effective alternative to new drug discovery and development for cancer treatment.
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Affiliation(s)
- Lu Yu
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
| | - Ho Lee
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cancer Center, Goyang 10408, Republic of Korea
| | - Seung Bae Rho
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cancer Center, Goyang 10408, Republic of Korea
| | - Mi Kyung Park
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy National Cancer Center, Goyang 10408, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea
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Khater M, Brazier JA, Greco F, Osborn HMI. Anticancer evaluation of new organometallic ruthenium(ii) flavone complexes. RSC Med Chem 2023; 14:253-267. [PMID: 36846373 PMCID: PMC9945865 DOI: 10.1039/d2md00304j] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/22/2022] [Indexed: 12/23/2022] Open
Abstract
Targeting multiple malignancy features such as angiogenesis, proliferation and metastasis with one molecule is an effective strategy in developing potent anticancer agents. Ruthenium metal complexation to bioactive scaffolds is reported to enhance their biological activities. Herein, we evaluate the impact of Ru chelation on the pharmacological activities of two bioactive flavones (1 and 2) as anticancer candidates. The novel Ru complexes (1Ru and 2Ru) caused a loss of their parent molecules' antiangiogenic activities in an endothelial cell tube formation assay. 1Ru enhanced the antiproliferative and antimigratory activities of its 4-oxoflavone 1 on MCF-7 breast cancer cells (IC50 = 66.15 ± 5 μM and 50% migration inhibition, p < 0.01 at 1 μM). 2Ru diminished 4-thioflavone's (2) cytotoxic activity on MCF-7 and MDA-MB-231 yet significantly enhanced 2's migration inhibition (p < 0.05) particularly on the MDA-MB-231 cell line. The test derivatives also showed non-intercalative interaction with VEGF and c-myc i-motif DNA sequences.
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Affiliation(s)
- Mai Khater
- School of Pharmacy, University of Reading Whiteknights Reading RG6 6AD UK .,Therapeutic Chemistry Department, Pharmaceutical & Drug Industries Research Division, National Research Centre Cairo Egypt
| | - John A. Brazier
- School of Pharmacy, University of ReadingWhiteknightsReadingRG6 6ADUK
| | - Francesca Greco
- School of Pharmacy, University of Reading Whiteknights Reading RG6 6AD UK
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Chen Z, Fang Y, Jiang W. Important Cells and Factors from Tumor Microenvironment Participated in Perineural Invasion. Cancers (Basel) 2023; 15:1360. [PMID: 36900158 PMCID: PMC10000249 DOI: 10.3390/cancers15051360] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/09/2023] [Accepted: 02/17/2023] [Indexed: 02/24/2023] Open
Abstract
Perineural invasion (PNI) as the fourth way for solid tumors metastasis and invasion has attracted a lot of attention, recent research reported a new point that PNI starts to include axon growth and possible nerve "invasion" to tumors as the component. More and more tumor-nerve crosstalk has been explored to explain the internal mechanism for tumor microenvironment (TME) of some types of tumors tends to observe nerve infiltration. As is well known, the interaction of tumor cells, peripheral blood vessels, extracellular matrix, other non-malignant cells, and signal molecules in TME plays a key role in the occurrence, development, and metastasis of cancer, as to the occurrence and development of PNI. We aim to summarize the current theories on the molecular mediators and pathogenesis of PNI, add the latest scientific research progress, and explore the use of single-cell spatial transcriptomics in this invasion way. A better understanding of PNI may help to understand tumor metastasis and recurrence and will be beneficial for improving staging strategies, new treatment methods, and even paradigm shifts in our treatment of patients.
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Affiliation(s)
- Zirong Chen
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
| | - Yan Fang
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
| | - Weihong Jiang
- Department of Otolaryngology-Head and Neck Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
- Otolaryngology Major Disease Research Key Laboratory of Hunan Province, Changsha 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, China
- Anatomy Laboratory of Division of Nose and Cranial Base, Clinical Anatomy Center of Xiangya Hospital, Central South University, Changsha 410008, China
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Vagal Nerve Activity Predicts Prognosis in Diffused Large B-Cell Lymphoma and Multiple Myeloma. J Clin Med 2023; 12:jcm12030908. [PMID: 36769556 PMCID: PMC9917757 DOI: 10.3390/jcm12030908] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/17/2023] [Accepted: 01/19/2023] [Indexed: 01/26/2023] Open
Abstract
This study examined the prognostic role of vagal nerve activity in patients with relapsed/refractory diffused large B-cell lymphoma (R/R-DLBCL) treated with chimeric antigen receptor cell therapy (CAR-T) and in patients with multiple myeloma (MM) undergoing an autologous hematopoietic cell transplantation (AutoHCT). Participants included 29 patients with R/R-DLBCL and 37 patients with MM. Inclusion criteria were: (1) age over 18; (2) diagnosed with DLBCL or MM; (3) being treated with CAR-T or AutoHCT; and (4) having an ECG prior to cell transfusion. The predictor was vagal nerve activity indexed by heart rate variability (HRV) and obtained retroactively from 10 s ECGs. The main endpoint for R/R-DLBCL was overall survival (OS), and for MM the endpoint was progression-free survival (PFS). Data of 122 patients were obtained, 66 of whom were included in the study. In DLBCL, HRV significantly predicted OS independently of confounders (e.g., performance status, disease status at cell therapy), hazard ratio (HR), and 95% confidence interval (HR = 0.20; 95%CI: 0.06-0.69). The prognostic role of disease severity was moderated by HRV: among severely disease patients, 100% died with low HRV, while only 37.5% died with high HRV. In MM, HRV significantly predicted PFS (HR = 0.19; 95%CI: 0.04-0.90) independently of confounders. Vagal nerve activity independently predicts prognosis in patients with R/R-DLBCL and with MM undergoing cell therapy. High vagal activity overrides the prognostic role of disease severity. Testing the effects of vagal nerve activation on prognosis in blood cancers is recommended.
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Dhara V, Shetty SS, de Arruda JAA, Silva TA, Russo RC, Shetty NJ, Pidaparthi M, Wollenberg B, Rao VUS, Gopinath TPS. Decoding the influence of the immune system and immunotherapy targets on carcinomas: A hidden prism in oral cancer therapy. Dis Mon 2023; 69:101353. [PMID: 35311656 DOI: 10.1016/j.disamonth.2022.101353] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
In recent decades, understanding tumorigenesis and the complex interaction between the host and the immune system has been the pillar for significant advances in anticancer therapy. Conventional anticancer therapy (e.g., cut, burn, and cytotoxic drugs) involves multiple targeting of tumor cells. However, the tumor tissue microenvironment can present a dysregulated, stimulating, or subverted immune response which, in turn, reveals pro-tumor activities favoring tumor expansion and progression. Recently, new potential targets have been identified based on immunomodulatory therapies, which are crafted to re-establish the host anti-tumoral immune response. Clinicians should fully understand the intricate interactions between carcinogens, the tumor milieu, the immune system, and traditional anticancer therapies in order to progress and to overcome the refractory/recurrent challenges and morbidity of the disease. Thus, in this article, we highlight the complex milieu of the oral cancer immune response, pointing out potential therapeutic immunotargets for oral squamous cell carcinomas. The impact of traditional anticancer therapy on the immune system is also outlined.
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Affiliation(s)
- Vasantha Dhara
- Consultant Maxillofacial Surgeon, Hyderabad, Telangana, India
| | - Sameep S Shetty
- Department of Oral and Maxillofacial Surgery, Manipal College of Dental Sciences, Mangalore, Manipal Academy of Higher Education, A constituent of MAHE, Manipal, Karnataka, India.
| | - José Alcides Almeida de Arruda
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
| | - Tarcília Aparecida Silva
- Department of Oral Surgery, Pathology and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Remo Castro Russo
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Neetha J Shetty
- Department of Periodontology, Manipal College of Dental Sciences, Mangalore, Manipal Academy of Higher Education, A constituent of MAHE, Mangalore, Karnataka, India
| | | | - Barbara Wollenberg
- Klinik für Hals-, Nasen- und Ohrenheilkunde, Klinikum rechts der Isar der TU München, Ismaningerstraße 22, 81675 München, Germany
| | - Vishal U S Rao
- Department of Head and Neck Surgical Oncology, HealthCare Global Enterprises Ltd., Bangalore, Karnataka, India
| | - Thilak P S Gopinath
- Nitte (Deemed to be University) , AB Shetty Memorial Institute of Dental Sciences (ABSMIDS) , Department of Oral and Maxillofacial Surgery, Mangalore, India
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Du J, Rui F, Hao Z, Hang Y, Shu J. Transcription Factor E2F1 Regulates the Expression of ADRB2. Int J Anal Chem 2023; 2023:8210685. [PMID: 37128280 PMCID: PMC10148742 DOI: 10.1155/2023/8210685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 02/09/2023] [Accepted: 02/24/2023] [Indexed: 05/03/2023] Open
Abstract
Adrenergic beta-2-receptor (ADRB2) is highly expressed in various tissue cells, affecting the susceptibility, development, and drug efficacy of diseases such as bronchial asthma and malignant tumor. However, the transcriptional regulatory mechanism of the human ADRB2 gene remains unclear. This study aimed to clarify whether E2F transcription factor 1 (E2F1) was involved in the transcriptional regulation of the human ADRB2 gene. First, the 5' flanking region of the human ADRB2 gene was cloned, and its activity was detected using A549 and BEAS-2B cells. Second, it was found that the overexpression of E2F1 could increase promoter activity by a dual-luciferase reporter gene assay. In contrast, treatment of knockdown of E2F1 significantly resulted in a decrease in its promoter activity. Moreover, mutation of the binding site of E2F1 greatly reduced the potential of human ADRB2 promoter transcriptional activity to be regulated by E2F1 overexpression and knockdown. Additionally, by real-time quantitative PCR and Western blot analysis, we demonstrated that overexpression of E2F1 elevated the ADRB2 mRNA expression and protein levels while si-E2F1 reduced its expression. Finally, the consequence of the chromatin immunoprecipitation assay showed that E2F1 was able to bind to the promoter region of ADRB2 in vivo. These results confirmed that E2F1 upregulated the expression of the human ADRB2 gene.
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Affiliation(s)
- Juan Du
- Department of Pediatrics, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Feifei Rui
- Department of Neonatology, Changzhou Maternal and Child Health Hospital, Changzhou, Jiangsu, China
| | - Zhongfen Hao
- Department of Pediatrics, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yun Hang
- Department of Pediatrics, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jin Shu
- Department of Pediatrics, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China
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Li F, He C, Yao H, Zhao Y, Ye X, Zhou S, Zou J, Li Y, Li J, Chen S, Han F, Huang K, Lian G, Chen S. Glutamate from nerve cells promotes perineural invasion in pancreatic cancer by regulating tumor glycolysis through HK2 mRNA-m6A modification. Pharmacol Res 2023; 187:106555. [PMID: 36403721 DOI: 10.1016/j.phrs.2022.106555] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/08/2022] [Accepted: 11/11/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Perineural invasion (PNI) has a high incidence and poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Our study aimed to identify the underlying molecular mechanism of PNI and propose effective intervention strategies. METHODS To observe PNI in vitro and in vivo, a Matrigel/ dorsal root ganglia (DRG) model and a murine sciatic nerve invasion model were respectively used. Magnetic resonance (MR) imaging and positron emission tomography/computed tomography (PET-CT) imaging were also used to evaluate tumor growth. Publicly available datasets and PDAC tissues were used to verify how the nerve cells regulate PDAC cells' PNI. RESULTS Our results showed that glutamate from nerve cells could cause calcium influx in PDAC cells via the N-methyl-d-aspartate receptor (NMDAR), subsequently activating the downstream Ca2+ dependent protein kinase CaMKII/ERK-MAPK pathway and promoting the mRNA transcription of gene METTL3. Next, METTL3 upregulates the expression of hexokinase 2 (HK2) through N6-methyladenosine (m6A) modification in mRNA, enhances the PDAC cells' glycolysis, and promotes PNI. Furthermore, the IONPs-PEG-scFvCD44v6-scAbNMDAR2B nanoparticles dual targeting CD44 variant isoform 6 (CD44v6) and t NMDAR subunit 2B (NMDAR2B) on PDAC cells were synthesized and verified showing a satisfactory blocking effect on PNI. CONCLUSIONS Here, we firstly provided evidence that glutamate from the nerve cells could upregulate the expression of HK2 through mRNA m6A modification via NMDAR2B and downstream Ca2+ dependent CaMKII/ERK-MAPK pathway, enhance the glycolysis in PDAC cells, and ultimately promote PNI. In addition, the dual targeting nanoparticles we synthesized were verified to block PNI effectively in PDAC.
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Affiliation(s)
- Fengjiao Li
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Gastroenterology, Shandong Provincial Hospital Afliated to Shandong First Medical University, Jinan 250021, Shandong, China
| | - Chong He
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Hanming Yao
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yue Zhao
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Xijiu Ye
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Shurui Zhou
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jinmao Zou
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Yaqing Li
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Jiajia Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Shaojie Chen
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China
| | - Fanghai Han
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of Gastrointestinal Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
| | - Kaihong Huang
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
| | - Guoda Lian
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
| | - Shangxiang Chen
- Department of Gastroenterology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China.
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Liu Y, Gu R, Gao M, Wei Y, Shi Y, Wang X, Gu Y, Gu X, Zhang H. Emerging role of substance and energy metabolism associated with neuroendocrine regulation in tumor cells. Front Endocrinol (Lausanne) 2023; 14:1126271. [PMID: 37051193 PMCID: PMC10084767 DOI: 10.3389/fendo.2023.1126271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 02/07/2023] [Indexed: 03/29/2023] Open
Abstract
Cancer is the second most common cause of mortality in the world. One of the unresolved difficult pathological mechanism issues in malignant tumors is the imbalance of substance and energy metabolism of tumor cells. Cells maintain life through energy metabolism, and normal cells provide energy through mitochondrial oxidative phosphorylation to generate ATP, while tumor cells demonstrate different energy metabolism. Neuroendocrine control is crucial for tumor cells' consumption of nutrients and energy. As a result, better combinatorial therapeutic approaches will be made possible by knowing the neuroendocrine regulating mechanism of how the neuroendocrine system can fuel cellular metabolism. Here, the basics of metabolic remodeling in tumor cells for nutrients and metabolites are presented, showing how the neuroendocrine system regulates substance and energy metabolic pathways to satisfy tumor cell proliferation and survival requirements. In this context, targeting neuroendocrine regulatory pathways in tumor cell metabolism can beneficially enhance or temper tumor cell metabolism and serve as promising alternatives to available treatments.
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Affiliation(s)
- Yingying Liu
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
- School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Renjun Gu
- School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Murong Gao
- Beijing Rehabilitation Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yangwa Wei
- Department of Hepatobiliary Surgery, Hainan Provincial People’s Hospital, Haikou, China
| | - Yu Shi
- Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xu Wang
- School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Yihuang Gu
- School of Acupuncture and Tuina, School of Regimen and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing, China
- The Second Hospital of Nanjing, Nanjing, China
- *Correspondence: Hongru Zhang, ; Xin Gu, ; Yihuang Gu,
| | - Xin Gu
- School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Hongru Zhang, ; Xin Gu, ; Yihuang Gu,
| | - Hongru Zhang
- School of Chinese Medicine and School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- *Correspondence: Hongru Zhang, ; Xin Gu, ; Yihuang Gu,
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Wang XR, Wang S, Mu HX, Xu KY, Wang XT, Shi JT, Cui QH, Zhang LW, Chen SW. Discovery of novel VEGFR-2-PROTAC degraders based on the localization of lysine residues via recruiting VHL for the treatment of gastric cancer. Eur J Med Chem 2022; 244:114821. [DOI: 10.1016/j.ejmech.2022.114821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/26/2022] [Accepted: 10/01/2022] [Indexed: 11/04/2022]
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Smyth P, Sasiwachirangkul J, Williams R, Scott CJ. Cathepsin S (CTSS) activity in health and disease - A treasure trove of untapped clinical potential. Mol Aspects Med 2022; 88:101106. [PMID: 35868042 DOI: 10.1016/j.mam.2022.101106] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 06/24/2022] [Accepted: 07/11/2022] [Indexed: 12/14/2022]
Abstract
Amongst the lysosomal cysteine cathepsin family of proteases, cathepsin S (CTSS) holds particular interest due to distinctive properties including a normal restricted expression profile, inducible upregulation and activity at a broad pH range. Consequently, while CTSS is well-established as a member of the proteolytic cocktail within the lysosome, degrading unwanted and damaged proteins, it has increasingly been shown to mediate a number of distinct, more selective roles including antigen processing and antigen presentation, and cleavage of substrates both intra and extracellularly. Increasingly, aberrant CTSS expression has been demonstrated in a variety of conditions and disease states, marking it out as both a biomarker and potential therapeutic target. This review seeks to contextualise CTSS within the cysteine cathepsin family before providing an overview of the broad range of pathologies in which roles for CTSS have been identified. Additionally, current clinical progress towards specific inhibitors is detailed, updating the position of the field in exploiting this most unique of proteases.
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Affiliation(s)
- Peter Smyth
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Jutharat Sasiwachirangkul
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Rich Williams
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast, BT9 7AE, UK
| | - Christopher J Scott
- The Patrick G Johnston Centre for Cancer Research, Queen's University, 97 Lisburn Road, Belfast, BT9 7AE, UK.
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Ribeiro N, Farinha PF, Pinho JO, Luiz H, Mészáros JP, Galvão AM, Costa Pessoa J, Enyedy ÉA, Reis CP, Correia I, Gaspar MM. Metal Coordination and Biological Screening of a Schiff Base Derived from 8-Hydroxyquinoline and Benzothiazole. Pharmaceutics 2022; 14:pharmaceutics14122583. [PMID: 36559078 PMCID: PMC9785144 DOI: 10.3390/pharmaceutics14122583] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 11/25/2022] Open
Abstract
Designing new metallodrugs for anticancer therapy is a driving force in the scientific community. Aiming to contribute to this field, we hereby report the development of a Schiff base (H2L) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with 2-hydrazinobenzothiazole and its complexation with transition metal ions. All compounds were characterised by analytical and spectroscopic techniques, which disclosed their structure: [Cu(HL)Cl], [Cu(HL)2], [Ni(HL)(acetate)], [Ni(HL)2], [Ru(HL)Cl(DMSO)], [VO(HL)2] and [Fe(HL)2Cl(H2O)]. Different binding modes were proposed, showing the ligand’s coordination versatility. The ligand proton dissociation constants were determined, and the tested compounds showed high lipophilicity and light sensitivity. The stability of all complexes in aqueous media and their ability to bind to albumin were screened. Based on an antiproliferative in vitro screening, [Ni(HL)(acetate)] and [Ru(HL)Cl(DMSO)] were selected for further studies aiming to investigate their mechanisms of action and therapeutic potential towards colon cancer. The complexes displayed IC50 < 21 μM towards murine (CT-26) and human (HCT-116) colon cancer cell lines. Importantly, both complexes exhibited superior antiproliferative properties compared to the clinically approved 5-fluorouracil. [Ni(HL)(acetate)] induced cell cycle arrest in S phase in CT-26 cells. For [Ru(HL)Cl(DMSO)] this effect was observed in both colon cancer cell lines. Additionally, both compounds significantly inhibited cell migration particularly in the human colon cancer cell line, HCT-116. Overall, the therapeutic potential of both metal complexes was demonstrated.
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Affiliation(s)
- Nádia Ribeiro
- Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal
| | - Pedro F. Farinha
- Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - Jacinta O. Pinho
- Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - Hugo Luiz
- Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - János P. Mészáros
- MTA-SZTE Lendület Functional Metal Complexes Research Group, Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary
| | - Adelino M. Galvão
- Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal
| | - João Costa Pessoa
- Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal
| | - Éva A. Enyedy
- MTA-SZTE Lendület Functional Metal Complexes Research Group, Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary
| | - Catarina Pinto Reis
- Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
| | - Isabel Correia
- Centro de Química Estrutural, Institute of Molecular Sciences and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1, 1049-001 Lisboa, Portugal
- Correspondence: (I.C.); (M.M.G.)
| | - Maria Manuela Gaspar
- Research Institute for Medicines, iMed.ULisboa, Faculty of Pharmacy, Universidade de Lisboa, 1649-003 Lisboa, Portugal
- Correspondence: (I.C.); (M.M.G.)
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Ricci A, Salvucci C, Castelli S, Carraturo A, de Vitis C, D’Ascanio M. Adenocarcinomas of the Lung and Neurotrophin System: A Review. Biomedicines 2022; 10:biomedicines10102531. [PMID: 36289793 PMCID: PMC9598928 DOI: 10.3390/biomedicines10102531] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/04/2022] [Accepted: 10/05/2022] [Indexed: 11/24/2022] Open
Abstract
Neurotrophins (NTs) represent a group of growth factors with pleiotropic activities at the central nervous system level. The prototype of these molecules is represented by the nerve growth factor (NGF), but other factors with similar functions have been identified, including the brain derived-growth factor (BDNF), the neurotrophin 3 (NT-3), and NT-4/5. These growth factors act by binding specific low (p75) and high-affinity tyrosine kinase (TrkA, TrkB, and TrkC) receptors. More recently, these growth factors have shown effects outside the nervous system in different organs, particularly in the lungs. These molecules are involved in the natural development of the lungs, and their homeostasis. However, they are also important in different pathological conditions, including lung cancer. The involvement of neurotrophins in lung cancer has been detailed most for non-small cell lung cancer (NSCLC), in particular adenocarcinoma. This review aimed to extensively analyze the current knowledge of NTs and lung cancer and clarify novel molecular mechanisms for diagnostic and therapeutic purposes. Several clinical trials on humans are ongoing using NT receptor antagonists in different cancer cell types for further therapeutic applications. The pharmacological intervention against NT signaling may be essential to directly counteract cancer cell biology, and also indirectly modulate it in an inhibitory way by affecting neurogenesis and/or angiogenesis with potential impacts on tumor growth and progression.
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Affiliation(s)
| | | | | | | | | | - Michela D’Ascanio
- UOC Respiratory Disease, Sant’Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy
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Neuromodulation Applied to Diseases: The Case of HRV Biofeedback. J Clin Med 2022; 11:jcm11195927. [PMID: 36233794 PMCID: PMC9571900 DOI: 10.3390/jcm11195927] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/26/2022] [Accepted: 09/28/2022] [Indexed: 12/02/2022] Open
Abstract
The vagus or “wandering” nerve is the main branch of the parasympathetic nervous system (PNS), innervating most internal organs crucial for health. Activity of the vagus nerve can be non-invasively indexed by heart-rate variability parameters (HRV). Specific HRV parameters predict less all-cause mortality, lower risk of and better prognosis after myocardial infarctions, and better survival in cancer. A non-invasive manner for self-activating the vagus is achieved by performing a slow-paced breathing technique while receiving visual feedback of one’s HRV, called HRV-biofeedback (HRV-B). This article narratively reviews the biological mechanisms underlying the role of vagal activity and vagally mediated HRV in hypertension, diabetes, coronary heart disease (CHD), cancer, pain, and dementia. After searching the literature for HRV-B intervention studies in each condition, we report the effects of HRV-B on clinical outcomes in these health conditions, while evaluating the methodological quality of these studies. Generally, the levels of evidence for the benefits of HRV-B is high in CHD, pain, and hypertension, moderate in cancer, and poor in diabetes and dementia. Limitations and future research directions are discussed.
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Ren L, Bao D, Wang L, Xu Q, Xu Y, Shi Z. Nucleobindin-2/nesfatin-1 enhances the cell proliferation, migration, invasion and epithelial-mesenchymal transition in gastric carcinoma. J Cell Mol Med 2022; 26:4986-4994. [PMID: 36065769 PMCID: PMC9549493 DOI: 10.1111/jcmm.17522] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/27/2022] [Accepted: 08/08/2022] [Indexed: 12/07/2022] Open
Abstract
Nesfatin-1, a newly discovered adipokine derived from nucleobindin-2 (NUCB2), has been described as a new prognostic marker in cancers. This study aimed to explore the functional role of NUCB2/nesfatin-1 in the cell proliferation, migration and invasion in gastric carcinoma (GC). The expressions of NUCB2/nesfatin-1 in GC tissues and normal adjacent tissues (NATs) were compared, and the effect of inhibition of NUCB2/nesfatin-1 on the cell proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in GC cell line SGC-7901 was investigated. Cell transfection was conducted to inhibit NUCB2/nesfatin-1 by short hairpin RNA. Cell proliferation, migration and invasion abilities were determined using cell counting kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU), wound healing and transwell assays, respectively. The expressions of EMT markers E-Cadherin and N-Cadherin were determined using western blotting. The expression of NUCB2/nesfatin-1 protein in GC tissues was significantly increased compared with that in NATs. Consistently, the serum concentrations of NUCB2/nesfatin-1 were significantly higher in patients with GC as compared with those in the control group. Moreover, the results of CCK-8 assay and EdU assay indicated that knockdown of NUCB2/nesfatin-1 could markedly decrease SGC-7901 proliferation. Furthermore, the results of wound healing assay and transwell assay demonstrated that knockdown of NUCB2/nesfatin-1 significantly suppressed SGC-7901 migration and invasion abilities. Additionally, knockdown of NUCB2/nesfatin-1 decreased the expressions of N-Cadherin and increased the expressions of E-Cadherin in SGC-7901 cells. These findings suggest that knockdown of NUCB2/nesfatin-1 suppressed the proliferation, migration, invasion and EMT of SGC-7901 cells, suggesting a potentially promising therapeutic target for GC.
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Affiliation(s)
- Le Ren
- Department of GastroenterologySecond People's Hospital of HefeiHefeiChina
| | - Deming Bao
- Department of GastroenterologySecond People's Hospital of HefeiHefeiChina
| | - Liming Wang
- Department of GastroenterologySecond People's Hospital of HefeiHefeiChina
| | - Qin Xu
- Department of GastroenterologySecond People's Hospital of HefeiHefeiChina
| | - Yayun Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of PharmacyAnhui Institute of Innovative Drugs, Anhui Medical UniversityHefeiChina
| | - Zhenwang Shi
- Department of GastroenterologySecond People's Hospital of HefeiHefeiChina
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Tian L, Chen X, Cao L, Zhang L, Chen J. Effects of plant-based medicinal food on postoperative recurrence and lung metastasis of gastric cancer regulated by Wnt/β-catenin-EMT signaling pathway and VEGF-C/D-VEGFR-3 cascade in a mouse model. BMC Complement Med Ther 2022; 22:233. [PMID: 36056333 PMCID: PMC9438347 DOI: 10.1186/s12906-022-03703-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 08/08/2022] [Indexed: 11/30/2022] Open
Abstract
Background The plant-based medicinal food (PBMF) is a functional compound extracted from 6 medicinal and edible plants: Coix seed, L. edodes, A. officinalis L., H. cordata, Dandelion, and G. frondosa. Our previous studies have confirmed that the PBMF possesses anti-tumor properties in a subcutaneous xenograft model of nude mice. This study aims to further investigate the effects and potential molecular mechanisms of the PBMF on the recurrence and metastasis of gastric cancer (GC). Methods Postoperative recurrence and metastasis model of GC was successfully established in inbred 615 mice inoculated with mouse forestomach carcinoma (MFC) cells. After tumorectomy, 63 GC mice were randomly divided into five groups and respectively subject to different treatments for 15 days as below: model control group, 5-Fu group, and three doses of PBMF (43.22, 86.44, 172.88 g/kg PBMF in diet respectively). The inhibition rate (IR) of recurrence tumor weights and organ coefficients were calculated. Meanwhile, histopathological changes were examined and the metastasis IR in lungs and lymph node tissues was computed. The mRNA expressions related to the canonical Wnt/β-catenin signaling pathway, epithelial-mesenchymal transition (EMT) and lymphangiogenesis were detected by RT-qPCR in recurrence tumors and/or lung tissues. Protein expressions of β-catenin, p-β-catenin (Ser33/37/Thr41), GSK-3β, p-GSK-3β (Ser9), E-cadherin, and Vimentin in recurrence tumors were determined by Western Blot. LYVE-1, VEGF-C/D, and VEGFR-3 levels in recurrence tumors and/or lung tissues were determined by immunohistochemistry staining. Results The mRNA, as well as protein expression of GSK-3β were up-regulated and the mRNA expression of β-catenin was down-regulated after PBMF treatment. Meanwhile, the ratio of p-β-catenin (Ser33/37/Thr41) to β-catenin protein was increased significantly and the p-GSK-3β (Ser9) protein level was decreased. And PMBF could effectively decrease the mRNA and protein levels of Vimentin while increasing those of E-cadherin. Furthermore, PBMF markedly reduced lymphatic vessel density (LVD) (labeled by LYVE-1) in recurrence tumor tissues, and mRNA levels of VEGF-C/D, VEGFR-2/3 of recurrence tumors were all significantly lower in the high-dose group. Conclusions PBMF had a significant inhibitory effect on recurrence and lung metastasis of GC. The potential mechanism may involve reversing EMT by inhabiting the Wnt/β-catenin signaling pathway. Lymphatic metastasis was also inhibited by PBMF via down-regulating the activation of the VEGF-C/D-VEGFR-2/3 signaling cascade. Supplementary Information The online version contains supplementary material available at 10.1186/s12906-022-03703-0.
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The Role of Neural Signaling in the Pancreatic Cancer Microenvironment. Cancers (Basel) 2022; 14:cancers14174269. [PMID: 36077804 PMCID: PMC9454556 DOI: 10.3390/cancers14174269] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 08/25/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
Simple Summary Pancreatic cancer is a highly lethal malignant disease with a dense stroma, called the tumor microenvironment. Accumulating evidence indicates the important role of sympathetic, parasympathetic, and sensory nerves in the tumor microenvironment of various cancers, including pancreatic cancer. Cancer cells and neural cells interact with each other to form a complex network and cooperatively promote cancer growth and invasion. In this review article, we describe the current understanding of the role of nerves in the tumor microenvironment. Abstract Pancreatic cancer is one of the most lethal malignant diseases. Various cells in the tumor microenvironment interact with tumor cells and orchestrate to support tumor progression. Several kinds of nerves are found in the tumor microenvironment, and each plays an essential role in tumor biology. Recent studies have shown that sympathetic, parasympathetic, and sensory neurons are found in the pancreatic cancer microenvironment. Neural signaling not only targets neural cells, but tumor cells and immune cells via neural receptors expressed on these cells, through which tumor growth, inflammation, and anti-tumor immunity are affected. Thus, these broad-range effects of neural signaling in the pancreatic cancer microenvironment may represent novel therapeutic targets. The modulation of neural signaling may be a therapeutic strategy targeting the whole tumor microenvironment. In this review, we describe the current understanding of the role of nerves in the tumor microenvironment of various cancers, with an emphasis on pancreatic cancer. We also discuss the underlying mechanisms and the possibility of therapeutic applications.
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Dolphin H, Dukelow T, Finucane C, Commins S, McElwaine P, Kennelly SP. “The Wandering Nerve Linking Heart and Mind” – The Complementary Role of Transcutaneous Vagus Nerve Stimulation in Modulating Neuro-Cardiovascular and Cognitive Performance. Front Neurosci 2022; 16:897303. [PMID: 35784842 PMCID: PMC9245542 DOI: 10.3389/fnins.2022.897303] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
The vagus nerve is the longest nerve in the human body, providing afferent information about visceral sensation, integrity and somatic sensations to the CNS via brainstem nuclei to subcortical and cortical structures. Its efferent arm influences GI motility and secretion, cardiac ionotropy, chonotropy and heart rate variability, blood pressure responses, bronchoconstriction and modulates gag and cough responses via palatine and pharyngeal innervation. Vagus nerve stimulation has been utilized as a successful treatment for intractable epilepsy and treatment-resistant depression, and new non-invasive transcutaneous (t-VNS) devices offer equivalent therapeutic potential as invasive devices without the surgical risks. t-VNS offers exciting potential as a therapeutic intervention in cognitive decline and aging populations, classically affected by reduced cerebral perfusion by modulating both limbic and frontal cortical structures, regulating cerebral perfusion and improving parasympathetic modulation of the cardiovascular system. In this narrative review we summarize the research to date investigating the cognitive effects of VNS therapy, and its effects on neurocardiovascular stability.
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Affiliation(s)
- Helena Dolphin
- Department of Age-Related Healthcare, Tallaght University Hospital, Dublin, Ireland
- Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin, Ireland
- *Correspondence: Helena Dolphin,
| | - Tim Dukelow
- Department of Age-Related Healthcare, Tallaght University Hospital, Dublin, Ireland
| | - Ciaran Finucane
- Department of Medical Physics, St James’s Hospital, Dublin, Ireland
| | - Sean Commins
- Department of Psychology, Maynooth University, Maynooth, Ireland
| | - Paul McElwaine
- Department of Age-Related Healthcare, Tallaght University Hospital, Dublin, Ireland
- Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin, Ireland
| | - Sean P. Kennelly
- Department of Age-Related Healthcare, Tallaght University Hospital, Dublin, Ireland
- Department of Medical Gerontology, School of Medicine, Trinity College Dublin, Dublin, Ireland
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Belotti Y, Tolomeo S, Yu R, Lim WT, Lim CT. Prognostic Neurotransmitter Receptors Genes Are Associated with Immune Response, Inflammation and Cancer Hallmarks in Brain Tumors. Cancers (Basel) 2022; 14:2544. [PMID: 35626148 PMCID: PMC9139273 DOI: 10.3390/cancers14102544] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 05/16/2022] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma multiforme (GBM) is one of the most aggressive forms of cancer. Neurotransmitters (NTs) have recently been linked with the uncontrolled proliferation of cancer cells, but the role of NTs in the progression of human gliomas is still largely unexplored. Here, we investigate the genes encoding for neurotransmitter receptors (NTRs) by analyzing public transcriptomic data from GBM and LGG (low-grade glioma) samples. Our results showed that 50 out of the 98 tested NTR genes were dysregulated in brain cancer tissue. Next, we identified and validated NTR-associated prognostic gene signatures for both LGG and GBM. A subset of 10 NTR genes (DRD1, HTR1E, HTR3B, GABRA1, GABRA4, GABRB2, GABRG2, GRIN1, GRM7, and ADRA1B) predicted a positive prognosis in LGG and a negative prognosis in GBM. These genes were progressively downregulated across glioma grades and exhibited a strong negative correlation with genes associated with immune response, inflammasomes, and established cancer hallmarks genes in lower grade gliomas, suggesting a putative role in inhibiting cancer progression. This study might have implications for the development of novel therapeutics and preventive strategies that target regulatory networks associated with the link between the autonomic nervous system, cancer cells, and the tumor microenvironment.
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Affiliation(s)
- Yuri Belotti
- Institute for Health Innovation and Technology, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore;
| | - Serenella Tolomeo
- Institute of High Performance Computing, Agency for Science, Technology and Research (A*STAR), 1 Fusionopolis Way, Singapore 138632, Singapore;
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 16 Medical Drive, Singapore 117600, Singapore
| | - Rongjun Yu
- Department of Management, Hong Kong Baptist University, 34 Renfrew Road, Hong Kong 999077, China;
| | - Wan-Teck Lim
- Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore;
- Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Singapore 138673, Singapore
| | - Chwee Teck Lim
- Institute for Health Innovation and Technology, National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore;
- Department of Biomedical Engineering, National University of Singapore, 4 Engineering Drive 3, Singapore 117583, Singapore
- Mechanobiology Institute, National University of Singapore, 5A Engineering Drive 1, Singapore 117411, Singapore
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Wang XZ, Xia L, Zhang XY, Chen Q, Li X, Mou Y, Wang T, Zhang YN. The multifaceted mechanisms of Paeoniflorin in the treatment of tumors: State-of-the-Art. Biomed Pharmacother 2022; 149:112800. [PMID: 35279012 DOI: 10.1016/j.biopha.2022.112800] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/28/2022] [Accepted: 03/07/2022] [Indexed: 01/30/2023] Open
Abstract
Paeoniflorin is a water-soluble monoterpenoid glycoside that can be derived from multiple herbaceous plants, such as Radix Paeoniae Rubra, Radix Paeoniae Alba, Paeonia suffruticosa and Cimicifugae Foetidae. Multiple studies have suggested that Paeoniflorin possesses an excellent anti-tumor effect in variety of tumors, including liver cancer, gastric cancer, breast cancer, lung cancer, pancreatic cancer, colorectal cancer and bladder cancer. It can induce cell apoptosis, inhibit proliferation, invasion and metastasis via different molecular mechanisms, which are mainly involved in nuclear transcription factor kappα (NF-κB), B-cell lymphoma-2(Bcl-2) family, MicroRNA, neural precursor cell expressed developmentally down-regulated protein 4(NEDD4) signaling pathway, transcription activating factor (STAT3), p21, p53/14-3-3 signaling pathway, transforming growth factor-β1(TGF-β1)/Smads signaling pathway, Mitogen-activated protein kinase (MAPK) signaling pathway and Notch-1. Current studies on anti-tumor effect and mechanism of action of Paeoniflorin remain unclear. Therefore, this study reviews the research progress in the anti-tumor effect and mechanism of Paeoniflorin in an attempt to provide a new thought and theoretical basis for further development and clinical application of Paeoniflorin.
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Affiliation(s)
- Xue Zhen Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China; Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China.
| | - Lei Xia
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China; Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China
| | - Xiao Yu Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China; Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China
| | - Qian Chen
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China; Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China
| | - Xiao Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China
| | - Yue Mou
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China; Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China
| | - Tong Wang
- School of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China.
| | - Ya Nan Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China; Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China.
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Özler S, Pazarci P. Anti-tumoral effect of beta-blockers on prostate and bladder cancer cells via mitogen-activated protein kinase pathways. Anticancer Drugs 2022; 33:384-388. [PMID: 35266887 DOI: 10.1097/cad.0000000000001271] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The incidence of prostate cancer in the world is increasing every year. Death caused by prostate cancer is increased by 13% in men between 1980 and 2005. It is the second leading cause of cancer death in men after lung cancer. Bladder cancer is the second most common of urological malignancies. Most of the bladder cancers are treated with transurethral resection. Even great efforts have been made in the treatment of bladder cancer over the past years, it still remains as a major health problem. New therapeutic approaches are required to prevent the development and metastasis of these diseases. Experimental and clinical studies have shown potential beneficial effects of co-administration of beta-adrenergic receptor antagonists (beta-blockers) during cancer therapy. This study aimed to investigate the anti-tumor activity of beta-blockers on prostate and bladder cancer. Prostate and bladder cancer cell lines were cultured and treated with beta-blocker (propranolol). Then, protein levels and activity of apoptotic pathway mediators and mitogen-activated protein kinase (MAPK) pathway mediators were analyzed by ELISA. Propranolol treatment elevated the activity of caspase-3 and expression of bax, Wee1, GADD153 and apoptosis-inducing factor, but decreased bcl-2 which is an antiapoptotic protein. Propranolol treatment also inhibited ERK and JNK activity. This study showed that propranolol will help to inhibit prostate and bladder cancer by activating apoptotic pathway and by inhibiting MAPK pathway. This is the first study investigating the apoptotic effect of propranolol via MAPK on prostate and bladder cancer.
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Affiliation(s)
- Serkan Özler
- Department of Urology, Faculty of Medicine, Hatay Mustafa Kemal University, Hatay
| | - Percin Pazarci
- Department of Medical Biology, Faculty of Medicine, Cukurova University, Adana, Turkey
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Cheng SS, Qu YQ, Wu J, Yang GJ, Liu H, Wang W, Huang Q, Chen F, Li G, Wong CY, Wong VKW, Ma DL, Leung CH. Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer. Acta Pharm Sin B 2022; 12:1390-1405. [PMID: 35530158 PMCID: PMC9069406 DOI: 10.1016/j.apsb.2021.10.024] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 10/10/2021] [Accepted: 10/25/2021] [Indexed: 12/22/2022] Open
Abstract
Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9-cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.
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Affiliation(s)
- Sha-Sha Cheng
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China
| | - Yuan-Qing Qu
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China
| | - Jia Wu
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China
| | - Guan-Jun Yang
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo 315211, China
- Laboratory of Biochemistry and Molecular Biology, School of Marine Sciences, Ningbo University, Ningbo 315211, China
| | - Hao Liu
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China
| | - Wanhe Wang
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China
- Institute of Medical Research, Northwestern Polytechnical University, Xi'an 710072, China
| | - Qi Huang
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China
| | - Feng Chen
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China
| | - Guodong Li
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China
| | - Chun-Yuen Wong
- Department of Chemistry, City University of Hong Kong, Hong Kong 999077, China
| | - Vincent Kam Wai Wong
- Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China
| | - Dik-Lung Ma
- Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China
| | - Chung-Hang Leung
- Institute of Chinese Medical Sciences and State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao 999078, China
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao 999078, China
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Geng D, Liu X, Wang Y, Wang J. The effect of transcutaneous auricular vagus nerve stimulation on HRV in healthy young people. PLoS One 2022; 17:e0263833. [PMID: 35143576 PMCID: PMC8830655 DOI: 10.1371/journal.pone.0263833] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 01/27/2022] [Indexed: 11/18/2022] Open
Abstract
Transcutaneous auricular vagus nerve stimulation (taVNS) has shown positive effects on a variety of diseases. Considering that decreased heart rate variability (HRV) is closely associated with morbidity and mortality for a variety of diseases, it is important to investigate the effect of taVNS on HRV. In Study 1, we conducted a two-stage cross-over trial to compare the effects of taVNS and sham taVNS (staVNS) on HRV. In Study 2, we systematically tested the effects of different taVNS parameters on high frequency (HF) component of HRV. The results showed that taVNS significantly increased measurements of root mean square of the difference between successive RR intervals (RMSSD), percentage of number of pairs of adjacent RR intervals differing greater than 50ms (pRR50), standard deviation of all RR intervals (SDRR), HF. Significantly, enhancement of HF and pRR50 persisted into recovery period. In addition, higher baseline LF/HF ratio was associated with greater LF/HF ratio decrease. Findings also showed that there was no significant difference in measurements of HF between different taVNS parameters. These studies suggest that taVNS could increase HRV, it may help taVNS in the treatment of low HRV related diseases. However, taVNS may not have parameter-specific effects on HRV.
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Affiliation(s)
- Duyan Geng
- State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin, China
- * E-mail:
| | - Xuanyu Liu
- State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin, China
- Key Laboratory of Electromagnetic Field and Electrical Apparatus Reliability of Hebei Province, Hebei University of Technology, Tianjin, China
| | - Yan Wang
- State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin, China
- Key Laboratory of Electromagnetic Field and Electrical Apparatus Reliability of Hebei Province, Hebei University of Technology, Tianjin, China
| | - Jiaxing Wang
- State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin, China
- Key Laboratory of Electromagnetic Field and Electrical Apparatus Reliability of Hebei Province, Hebei University of Technology, Tianjin, China
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