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He K, Chen M, Liu J, Du S, Ren C, Zhang J. Nanomedicine for cancer targeted therapy with autophagy regulation. Front Immunol 2024; 14:1238827. [PMID: 38239356 PMCID: PMC10794438 DOI: 10.3389/fimmu.2023.1238827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 12/13/2023] [Indexed: 01/22/2024] Open
Abstract
Nanoparticles have unique physical and chemical properties and are currently widely used in disease diagnosis, drug delivery, and new drug development in biomedicine. In recent years, the role of nanomedical technology in cancer treatment has become increasingly obvious. Autophagy is a multi-step degradation process in cells and an important pathway for material and energy recovery. It is closely related to the occurrence and development of cancer. Because nanomaterials are highly targeted and biosafe, they can be used as carriers to deliver autophagy regulators; in addition to their favorable physicochemical properties, nanomaterials can be employed to carry autophagy inhibitors, reducing the breakdown of chemotherapy drugs by cancer cells and thereby enhancing the drug's efficacy. Furthermore, certain nanomaterials can induce autophagy, triggering oxidative stress-mediated autophagy enhancement and cell apoptosis, thus constraining the progression of cancer cells.There are various types of nanoparticles, including liposomes, micelles, polymers, metal-based materials, and carbon-based materials. The majority of clinically applicable drugs are liposomes, though other materials are currently undergoing continuous optimization. This review begins with the roles of autophagy in tumor treatment, and then focuses on the application of nanomaterials with autophagy-regulating functions in tumor treatment.
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Affiliation(s)
- Ketai He
- Department of Neurology, Joint Research Institution of Altitude Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- West China School of Stomatology, Sichuan University, Sichuan, China
| | - Mingkun Chen
- West China School of Stomatology, Sichuan University, Sichuan, China
| | - Jiao Liu
- Department of Pharmacy, Chengdu Fifth People’s Hospital, Sichuan, China
| | - Shufang Du
- West China School of Stomatology, Sichuan University, Sichuan, China
| | - Changyu Ren
- Department of Pharmacy, Chengdu Fifth People’s Hospital, Sichuan, China
| | - Jifa Zhang
- Department of Neurology, Joint Research Institution of Altitude Health, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Bai Y, Su B, Cheng X, Liu Q, Zeng L, Fu P. Gossypol Affects Viral Replication by Inhibiting Pseudorabies Virus Adsorption. Transbound Emerg Dis 2023; 2023:9073566. [PMID: 40303819 PMCID: PMC12017124 DOI: 10.1155/2023/9073566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/15/2023] [Accepted: 09/20/2023] [Indexed: 05/02/2025]
Abstract
Pseudorabies virus (PRV) has spread widely in swine herds since it was introduced into China, and PRV variants have appeared in many regions in China since 2011. Owing to the ongoing emergence of viral mutations, the protective efficacy of PRV vaccines faces great challenges. Gossypol is a polyphenolic natural compound purified from cotton roots, stems, or seeds. This study found that gossypol has a notable inhibitory effect on PRV. Based on the biological effects of gossypol, the anti-PRV effect of gossypol was studied from the aspects of mitochondrial damage, reactive oxygen species, energy metabolism, and autophagy. The results showed that gossypol had no direct inactivation effect on PRV in solution within concentrations of ≤3 µM; gossypol did not stimulate interferon-β to exert an anti-PRV effect by triggering mitochondrial DNA leakage; the anti-PRV effect of gossypol was reactive oxygen species and ATP-independent in cells; and the PRV-inhibitory effect of gossypol was independent of its induced autophagy. By adding gossypol to PRV-infected cells at different stages of infection and performing virus titer detection, atomic force microscopy, qPCR, fluorescence microscopy, and firefly luciferase activity assays, we found that gossypol exerted an anti-PRV effect by inhibiting the adsorption of PRV on the cell surface.
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Affiliation(s)
- Yilin Bai
- Laboratory of Indigenous Cattle Germplasm Innovation, School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450046, Henan, China
- Zhengzhou Research Base, State Key Laboratory of Cotton Biology, School of Agricultural Sciences, Zhengzhou University, Zhengzhou 450046, Henan, China
| | - Bingqian Su
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China
| | - Xuan Cheng
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China
| | - Qianwen Liu
- College of Life Science and Engineering, Henan University of Urban Construction, Pingdingshan 467044, Henan, China
| | - Lei Zeng
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan, China
| | - Pengfei Fu
- College of Life Science and Engineering, Henan University of Urban Construction, Pingdingshan 467044, Henan, China
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Chen Y, Zhang X, Yang H, Liang T, Bai X. The "Self-eating" of cancer-associated fibroblast: A potential target for cancer. Biomed Pharmacother 2023; 163:114762. [PMID: 37100015 DOI: 10.1016/j.biopha.2023.114762] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 04/13/2023] [Accepted: 04/20/2023] [Indexed: 04/28/2023] Open
Abstract
Autophagy helps maintain energy homeostasis and protect cells from stress effects by selectively removing misfolded/polyubiquitylated proteins, lipids, and damaged mitochondria. Cancer-associated fibroblasts (CAFs) are cellular components of tumor microenvironment (TME). Autophagy in CAFs inhibits tumor development in the early stages; however, it has a tumor-promoting effect in advanced stages. In this review, we aimed to summarize the modulators responsible for the induction of autophagy in CAFs, such as hypoxia, nutrient deprivation, mitochondrial stress, and endoplasmic reticulum stress. In addition, we aimed to present autophagy-related signaling pathways in CAFs, and role of autophagy in CAF activation, tumor progression, tumor immune microenvironment. Autophagy in CAFs may be an emerging target for tumor therapy. In summary, autophagy in CAFs is regulated by a variety of modulators and can reshape tumor immune microenvironment, affecting tumor progression and treatment.
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Affiliation(s)
- Yan Chen
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaozhen Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hanshen Yang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, China.
| | - Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, China.
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Bata N, Cosford NDP. Cell Survival and Cell Death at the Intersection of Autophagy and Apoptosis: Implications for Current and Future Cancer Therapeutics. ACS Pharmacol Transl Sci 2021; 4:1728-1746. [PMID: 34927007 DOI: 10.1021/acsptsci.1c00130] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Indexed: 12/25/2022]
Abstract
Autophagy and apoptosis are functionally distinct mechanisms for cytoplasmic and cellular turnover. While these two pathways are distinct, they can also regulate each other, and central components of the apoptosis or autophagy pathway regulate both processes directly. Furthermore, several upstream stress-inducing signaling pathways can influence both autophagy and apoptosis. The crosstalk between autophagy and apoptosis has an integral role in pathological processes, including those related to cancer, homeostasis, and aging. Apoptosis is a form of programmed cell death, tightly regulated by various cellular and biochemical mechanisms, some of which have been the focus of drug discovery efforts targeting cancer therapeutics. Autophagy is a cellular degradation pathway whereby cells recycle macromolecules and organelles to generate energy when subjected to stress. Autophagy can act as either a prodeath or a prosurvival process and is both tissue and microenvironment specific. In this review we describe five groups of proteins that are integral to the apoptosis pathway and discuss their role in regulating autophagy. We highlight several apoptosis-inducing small molecules and biologics that have been developed and advanced into the clinic and discuss their effects on autophagy. For the most part, these apoptosis-inducing compounds appear to elevate autophagy activity. Under certain circumstances autophagy demonstrates cytoprotective functions and is overactivated in response to chemo- or radiotherapy which can lead to drug resistance, representing a clinical obstacle for successful cancer treatment. Thus, targeting the autophagy pathway in combination with apoptosis-inducing compounds may be a promising strategy for cancer therapy.
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Affiliation(s)
- Nicole Bata
- Cell and Molecular Biology of Cancer Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Nicholas D P Cosford
- Cell and Molecular Biology of Cancer Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, United States
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Wu Y, Jiao Z, Wan Z, Qu S. Role of autophagy and oxidative stress to astrocytes in fenpropathrin-induced Parkinson-like damage. Neurochem Int 2021; 145:105000. [PMID: 33617931 DOI: 10.1016/j.neuint.2021.105000] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 01/31/2021] [Accepted: 02/15/2021] [Indexed: 11/17/2022]
Abstract
Fenpropathrin is an insecticide that is widely used in agriculture. It remains unknown whether fenpropathrin exposure increases the risk of Parkinson's disease. We found that fenpropathrin increased oxidative stress both in vitro and in vivo. Additionally, fenpropathrin increased production of ROS, NOS2, and HO-1, and decreased SOD and GSH in astrocytes. We further found that fenpropathrin-mediated oxidative stress might inhibit autophagic flow, including decreased expression of LC3A/B and enhanced expression of SQSTM1 via down-regulation of CDK-5, an upstream marker of autophagy. In mice, autophagy was slightly different from that found in astrocytes, as reflected in the increased expressions of LC3A/B and SQSTM1. Our findings elucidate the toxicological phenomena and pathogenic mechanisms of fenpropathrin and may provide guidance for improved pesticide control and environmental protection.
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Affiliation(s)
- Yixuan Wu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong, 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong, 510515, China; School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Zhigang Jiao
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong, 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong, 510515, China; School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Zhiting Wan
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong, 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong, 510515, China
| | - Shaogang Qu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China; Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, Guangdong, 510515, China; Key Laboratory of Mental Health of the Ministry of Education, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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6
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Cournoyer S, Addioui A, Belounis A, Beaunoyer M, Nyalendo C, Le Gall R, Teira P, Haddad E, Vassal G, Sartelet H. GX15-070 (Obatoclax), a Bcl-2 family proteins inhibitor engenders apoptosis and pro-survival autophagy and increases Chemosensitivity in neuroblastoma. BMC Cancer 2019; 19:1018. [PMID: 31664947 PMCID: PMC6819521 DOI: 10.1186/s12885-019-6195-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 09/24/2019] [Indexed: 12/19/2022] Open
Abstract
Background Neuroblastoma (NB) is a frequent pediatric tumor associated with poor prognosis. The disregulation of Bcl-2, an anti-apoptotic protein, is crucial for the tumoral development and chemoresistance. Autophagy is also implicated in tumor cell survival and chemoresistance. The aim of our study was to demonstrate therapeutic efficiency of GX 15–070, a pan-Bcl-2 family inhibitor, used alone and in combination with conventional drugs or with hydroxychloroquine (HCQ), an autophagy inhibitor. Methods Five neuroblastoma cell lines were tested for the cytotoxic activity of GX 15–070 alone or in combination with cisplatin, doxorubicin, HCQ or Z-VAD-FMK a broad-spectrum caspase inhibitor. Apoptosis and autophagy levels were studied by western-blot and FACS. Orthotopic injections were performed on NOD/LtSz-scid/IL-2Rgamma null mice that were treated with either GX 15–070 alone or in combination with HCQ. Results Synergistic cytotoxicity was observed for the drug combination in all of the 5 neuroblastoma cell lines tested, including MYCN amplified lines and in cancer stem cells. GX 15–070 significantly increased apoptosis and autophagy in neuroblastoma cells as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by HCQ, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agent plays a cytoprotective role. In vivo, GX 15–070 combined with HCQ significantly decreased the growth of the tumor and the number of distant metastases. Conclusions Based on the synergistic effect of HCQ and GX 15–070 observed in this study, the combination of these two drugs may be utilized as a new therapeutic approach for neuroblastoma.
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Affiliation(s)
- Sonia Cournoyer
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada
| | - Anissa Addioui
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada.,Department of Pathology and Cellular Biology, Université de Montréal, Montreal, QC, Canada
| | - Assila Belounis
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada.,Department of Pathology and Cellular Biology, Université de Montréal, Montreal, QC, Canada
| | - Mona Beaunoyer
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada.,Department of Pediatric Surgery, Sainte-Justine University Hospital Center, Montreal, QC, Canada
| | - Carine Nyalendo
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada
| | - Roxane Le Gall
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada
| | - Pierre Teira
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada.,Department of Pediatric Hemato-Oncology, Sainte-Justine University Hospital Center, Montreal, QC, Canada
| | - Elie Haddad
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada
| | - Gilles Vassal
- Department of Pediatric Oncology, Institut Gustave Roussy, Villejuif, France
| | - Hervé Sartelet
- Research Center, Sainte Justine University Hospital Center, Montreal, QC, Canada. .,Department of Pathology and Cellular Biology, Université de Montréal, Montreal, QC, Canada. .,Département d'anatomie et cytologie pathologiques, Institut de Biologie et Pathologie, CHU A Michallon, 38043, Grenoble cedex 09, France.
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7
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Pharmacokinetics, biodistribution, and bioavailability of gossypol-loaded Pluronic ® F127 nanoparticles. J Drug Deliv Sci Technol 2018. [DOI: 10.1016/j.jddst.2018.04.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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8
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Obatoclax impairs lysosomal function to block autophagy in cisplatin-sensitive and -resistant esophageal cancer cells. Oncotarget 2018; 7:14693-707. [PMID: 26910910 PMCID: PMC4924745 DOI: 10.18632/oncotarget.7492] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Accepted: 12/29/2015] [Indexed: 12/13/2022] Open
Abstract
Obatoclax, a pan-inhibitor of anti-apoptotic Bcl-2 proteins, exhibits cytotoxic effect on cancer cells through both apoptosis-dependent and -independent pathways. Here we show that obatoclax caused cytotoxicity in both cisplatin-sensitive and -resistant esophageal cancer cells. Although obatoclax showed differential apoptogenic effects in these cells, it consistently blocked autophagic flux, which was evidenced by concomitant accumulation of LC3-II and p62. Obatoclax was trapped in lysosomes and induced lysosome clustering. Obatoclax also substantially reduced the expression of lysosomal cathepsins B, D and L. Moreover, cathepsin knockdown was sufficient to induce cytotoxicity, connecting lysosomal function to cell viability. Consistent with the known function of autophagy, obatoclax caused the accumulation of polyubiquitinated proteins and showed synergy with proteasome inhibition. Taken together, our studies unveiled impaired lysosomal function as a novel mechanism whereby obatoclax mediates its cytotoxic effect in esophageal cancer cells.
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9
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ABT-263 induces G 1/G 0-phase arrest, apoptosis and autophagy in human esophageal cancer cells in vitro. Acta Pharmacol Sin 2017; 38:1632-1641. [PMID: 28713162 DOI: 10.1038/aps.2017.78] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Accepted: 02/21/2017] [Indexed: 12/11/2022]
Abstract
Both the anti- and pro-apoptotic members of the Bcl-2 family are regulated by a conserved Bcl-2 homology (BH3) domain. ABT-263 (Navitoclax), a novel BH3 mimetic and orally bioavailable Bcl-2 family inhibitor with high affinity for Bcl-xL, Bcl-2 and Bcl-w has entered clinical trials for cancer treatment. But the anticancer mechanisms of ABT-263 have not been fully elucidated. In this study we investigated the effects of ABT-263 on human esophageal cancer cells in vitro and to explore its anticancer mechanisms. Treatment with ABT-263 dose-dependently suppressed the viability of 3 human esophageal cancer cells with IC50 values of 10.7±1.4, 7.1±1.5 and 8.2±1.6 μmol/L, in EC109, HKESC-2 and CaES-17 cells, respectively. ABT-263 (5-20 μmol/L) dose-dependently induced G1/G0-phase arrest in the 3 cancer cell lines and induced apoptosis evidenced by increased the Annexin V-positive cell population and elevated levels of cleaved caspase 3, cleaved caspase 9 and PARP. We further demonstrated that ABT-263 treatment markedly increased the expression of p21Waf1/Cip1 and decreased the expression of cyclin D1 and phospho-Rb (retinoblastoma tumor suppressor protein) (Ser780) proteins that contributed to the G1/G0-phase arrest. Knockdown of p21Waf1/Cip1 attenuated ABT-263-induced G1/G0-phase arrest. Moreover, ABT-263 treatment enhanced pro-survival autophagy, shown as the increased LC3-II levels and decreased p62 levels, which counteracted its anticancer activity. Our results suggest that ABT-263 exerts cytostatic and cytotoxic effects on human esophageal cancer cells in vitro and enhances pro-survival autophagy, which counteracts its anticancer activity.
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10
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Chen LM, Song TJ, Xiao JH, Huang ZH, Li Y, Lin TY. Tripchlorolide induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR pathway and improves cisplatin sensitivity in A549/DDP cells. Oncotarget 2017; 8:63911-63922. [PMID: 28969040 PMCID: PMC5609972 DOI: 10.18632/oncotarget.19201] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 06/20/2017] [Indexed: 12/13/2022] Open
Abstract
Tripchlorolide (T4) has been shown to induce A549 lung cancer cell death predominantly by activating an autophagy pathway. However, the underlying mechanism remains unclear. Herein, we demonstrated that compared with T4 treatment alone, pretreatment with wortmannin (an inhibitor of phosphatidylinositol 3-kinase), perifosine (an inhibitor of AKT) or rapamycin (an inhibitor of mTOR) combined with a subsequent T4 treatment significantly impaired the cell viability of A549 and A549/DDP lung cancer cells. We found that either treatment scheme markedly reduced the activity of P13K and AKT. Expression of LC3II increased in parallel to the increase of the T4 concentration in both A549 and A549/DDP cells and was repressed by overexpression of AKT. The expression levels of PI3-K, PI3-P, AKT, TSC2, mTOR, p70S6K and 4E-BP1 were minimally affected by the wortmannin, perifosine, or rapamycin plus T4 treatments, but their phosphorylated products were greatly affected in A549 lung cancer cells and slightly affected in A549/DDP lung cancer cells. These results indicate that T4 induces autophagy in lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway. We further found that T4 decreased expression of MDR1 and improved cisplatin sensitivity of A549/DDP cells. Altogether, these results have meaningful implications for tumor therapy in the future.
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Affiliation(s)
- Li-Min Chen
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China.,Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China.,Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Tian-Jiao Song
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China.,Department of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China.,Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Jian-Hong Xiao
- Department of Respiratory Medicine, Mindong Hospital of Ningde City, Fu'an, Fujian 355000, People's Republic of China
| | - Zheng-Hui Huang
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Yong Li
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
| | - Ting-Yan Lin
- Department of Respiratory Medicine, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, People's Republic of China
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Yu J, Zhao X, Zhang N, You C, Yao G, Zhu J, Xu L, Sun B. Identification of novel 3-nitroacridines as autophagy inducers in gastric cancer cells. NEW J CHEM 2017. [DOI: 10.1039/c7nj00119c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Nine novel 3-nitroacridines were synthesized, of which 3 compounds inhibited gastric cancer cell proliferation via an autophagy-associated cell death pathway.
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Affiliation(s)
- Jia Yu
- School of Chemistry and Chemical Engineering
- Southeast University
- Nanjing 210089
- China
| | - Xiaoqing Zhao
- Department of Chemical and Pharmaceutical Engineering
- Southeast University Chenxian College
- Nanjing 210000
- China
| | - Nanmengzi Zhang
- Department of Chemical and Pharmaceutical Engineering
- Southeast University Chenxian College
- Nanjing 210000
- China
| | - Chaoqun You
- School of Chemistry and Chemical Engineering
- Southeast University
- Nanjing 210089
- China
| | - Gang Yao
- Department of Chemical and Pharmaceutical Engineering
- Southeast University Chenxian College
- Nanjing 210000
- China
| | - Jin Zhu
- Key Laboratory of Antibody Technique of Ministry of Health
- School of Pathology
- Nanjing Medical University
- Nanjing 210093
- China
| | - Liang Xu
- Department of Molecular Biosciences
- University of Kansas
- Kansas 66045
- USA
| | - Baiwang Sun
- School of Chemistry and Chemical Engineering
- Southeast University
- Nanjing 210089
- China
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12
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Li S, Li J, Hu T, Zhang C, Lv X, He S, Yan H, Tan Y, Wen M, Lei M, Zuo J. Bcl-2 overexpression contributes to laryngeal carcinoma cell survival by forming a complex with Hsp90β. Oncol Rep 2016; 37:849-856. [PMID: 27959448 DOI: 10.3892/or.2016.5295] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 07/19/2016] [Indexed: 11/06/2022] Open
Abstract
Laryngeal carcinoma (LC) is one of the most common malignant tumors of all head and neck squamous cell carcinomas (HNSCCs). However, the molecular mechanism and genetic basis of the development of LC have not been fully elucidated. To explore the possible mechanism, targeted proteomic analysis was performed on Bcl-2-associated proteins from LC cells. According to our results, 35 proteins associated with Bcl-2 were identified and Hsp90β was confirmed by co-immunoprecipitation and western blot analysis. Protein‑protein interaction (PPI) analysis indicated that Bcl-2‑Hsp90β interactions may be involved in the anti-apoptotic progression of LC. Further results revealed that disruption of the Bcl-2-Hsp90β interaction inhibited the anti-apoptotic ability of Bcl-2 and decreased the caspase activation in LC, which has broad implications for the better understanding of tumor formation, tumor cell survival and development of metastasis due to Bcl-2. Collectively, we report the mechanism by which Bcl-2 functions in LC as an anti-apoptotic factor in relation to its association with proteins and potentially identify a Bcl-2/Hsp90β axis as a novel target for LC therapy.
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Affiliation(s)
- Sai Li
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jincheng Li
- Medical School, Shaoyang University, Shaoyang, Hunan 422000, P.R. China
| | - Tian Hu
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Chuhong Zhang
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiu Lv
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Sha He
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Hanxing Yan
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yixi Tan
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Meiling Wen
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Mingsheng Lei
- Department of Respiratory and Critical Care Medicine, The People's Hospital of Zhangjiajie City, Zhangjiajie, Hunan 427000, P.R. China
| | - Jianhong Zuo
- Oncology Department, The Affiliated Nanhua Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
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Li X, Su J, Xia M, Li H, Xu Y, Ma C, Ma L, Kang J, Yu H, Zhang Z, Sun L. Caspase-mediated cleavage of Beclin1 inhibits autophagy and promotes apoptosis induced by S1 in human ovarian cancer SKOV3 cells. Apoptosis 2016; 21:225-38. [PMID: 26573276 DOI: 10.1007/s10495-015-1197-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
S1, a novel BH3 mimetic, can induce apoptosis dependent on Bax/Bak through inhibition of Bcl-2 in various tumors. S1 also induces autophagy through interrupting the interaction of Bcl-2 and Beclin1. Our results showed that S1 induces apoptosis in human ovarian cancer SKOV3 cells in a time- and dose-dependent manner. Autophagy precedes apoptosis, in SKOV3 cells treated with S1 (6 μmol/L), autophagy reached the maximum peak at 12 h after treatment and decreased to 24 h. In SKOV3 cells treated with different concentrations of S1 for 24 h, the highest level of autophagy was observed with 5 μmol/L and decreased to 10 μmol/L. Autophagy inhibitors 3-MA and CQ enhanced apoptosis induced by S1 in SKOV3 cells. However, overactivation of caspases in apoptosis induced by S1 may inhibit the autophagy-inducing function of Beclin1. Because the pan-caspase inhibitor Z-VAD recovered the autophagy-inducing function of Beclin1 through reduction of activated caspase-mediated cleavage of Beclin1. Furthermore, the Beclin1 cleavage products could further increase apoptosis induced by S1 in SKOV3 cells. This indicates that apoptosis induced by high doses and long exposure of S1 causes the overactivation of caspases and subsequent cleavage of Beclin1, and inhibits the protection of autophagy. Moreover, the cleaved product of Beclin1 further promotes apoptosis induced by S1 in SKOV3 cells. Our results suggest this may be a molecular mechanism for enhancing the sensitivity of cancer cells to apoptosis induced by small molecular compound targeting Bcl-2.
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Affiliation(s)
- Xiaoning Li
- Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, 130021, China
| | - Jing Su
- Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, 130021, China
| | - Meihui Xia
- Department of Obstetrics and Gynecology, Jilin University First Hospital, Changchun, 130021, China
| | - Hongyan Li
- Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, 130021, China
| | - Ye Xu
- Medical Research Laboratory, Jilin Medical College, Jilin, 132013, China
| | - Chunhui Ma
- Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, 130021, China
| | - Liwei Ma
- Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, 130021, China
| | - Jingsong Kang
- Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, 130021, China
| | - Huimei Yu
- Department of Pathogenic Microorganisms, Basic Medical College, Jilin University, Changchun, 130021, China
| | - Zhichao Zhang
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, 116012, Liaoning, China
| | - Liankun Sun
- Department of Pathophysiology, Basic Medical College, Jilin University, Changchun, 130021, China.
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14
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Targeting cell death signalling in cancer: minimising 'Collateral damage'. Br J Cancer 2016; 115:5-11. [PMID: 27140313 PMCID: PMC4931361 DOI: 10.1038/bjc.2016.111] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 03/11/2016] [Accepted: 03/16/2016] [Indexed: 01/12/2023] Open
Abstract
Targeting apoptosis for the treatment of cancer has become an increasingly attractive strategy, with agents in development to trigger extrinsic apoptosis via TRAIL signalling, or to prevent the anti-apoptotic activity of BCL-2 proteins or inhibitor of apoptosis (IAP) proteins. Although the evasion of apoptosis is one of the hallmarks of cancer, many cancers have intact apoptotic signalling pathways, which if unblocked could efficiently kill cancerous cells. However, it is becoming increasing clear that without a detailed understanding of both apoptotic and non-apoptotic signalling, and the key proteins that regulate these pathways, there can be dose-limiting toxicity and adverse effects associated with their modulation. Here we review the main apoptotic pathways directly targeted for anti-cancer therapy and the unforeseen consequences of their modulation. Furthermore, we highlight the importance of an in-depth mechanistic understanding of both the apoptotic and non-apoptotic functions of those proteins under investigation as anti-cancer drug targets and outline some novel approaches to sensitise cancer cells to apoptosis, thereby improving the efficacy of existing therapies when used in combination with novel targeted agents.
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ZHENG RUINIAN, YOU ZHIJIAN, JIA JUN, LIN SHUNHUAN, HAN SHUAI, LIU AIXUE, LONG HUIDONG, WANG SENMING. Curcumin enhances the antitumor effect of ABT-737 via activation of the ROS-ASK1-JNK pathway in hepatocellular carcinoma cells. Mol Med Rep 2016; 13:1570-1576. [PMID: 26707143 PMCID: PMC4732838 DOI: 10.3892/mmr.2015.4715] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 10/14/2015] [Indexed: 01/07/2023] Open
Abstract
At present, the therapeutic treatment strategies for patients with hepatocellular carcinoma (HCC) remain unsatisfactory, and novel methods are urgently required to treat this disease. Members of the B cell lymphoma (Bcl)-2 family are anti‑apoptotic proteins, which are commonly expressed at high levels in certain HCC tissues and positively correlate with the treatment resistance of patients with HCC. ABT-737, an inhibitor of Bcl-2 anti-apoptotic proteins, has been demonstrated to exhibit potent antitumor effects in several types of tumor, including HCC. However, treatment with ABT-737 alone also activates certain pro-survival signaling pathways, which attenuate the antitumor validity of ABT-737. Curcumin, which is obtained from Curcuma longa, is also an antitumor potentiator in multiple types of cancer. In the present study, the synergistic effect of curcumin and ABT-737 on HCC cells was investigated for the first time, to the best of our knowledge. It was found that curcumin markedly enhanced the antitumor effects of ABT-737 on HepG2 cells, which was partially dependent on the induction of apoptosis, according to western blot analysis and flow cytometric apoptosis analysis. In addition, the sustained activation of the ROS-ASK1-c-Jun N-terminal kinase pathway may be an important mediator of the synergistic effect of curcumin and ABT-737. Collectively, these results indicated that the combination of curcumin and ABT-737 can efficaciously induce the death of HCC cells, and may offer a potential treatment strategy for patients with HCC.
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Affiliation(s)
- RUINIAN ZHENG
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
- Department of Oncology, Dongguan People's Hospital, Dongguan, Guangdong 523000, P.R. China
| | - ZHIJIAN YOU
- Department of Oncology, Dongguan People's Hospital, Dongguan, Guangdong 523000, P.R. China
| | - JUN JIA
- Department of Oncology, Dongguan People's Hospital, Dongguan, Guangdong 523000, P.R. China
| | - SHUNHUAN LIN
- Department of Oncology, Dongguan People's Hospital, Dongguan, Guangdong 523000, P.R. China
| | - SHUAI HAN
- Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
| | - AIXUE LIU
- Department of Oncology, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518035, P.R. China
| | - HUIDONG LONG
- Department of Internal Medicine, Affiliated Cancer Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China
| | - SENMING WANG
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, P.R. China
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Zhong D, Gu C, Shi L, Xun T, Li X, Liu S, Yu L. Obatoclax induces G1/G0-phase arrest via p38/p21(waf1/Cip1) signaling pathway in human esophageal cancer cells. J Cell Biochem 2015; 115:1624-35. [PMID: 24788582 DOI: 10.1002/jcb.24829] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 04/29/2014] [Indexed: 12/15/2022]
Abstract
Pan-Bcl-2 family inhibitor obatoclax has been demonstrated to be effective against various cancers, of which the mechanism of action is not fully understood. In this study, we demonstrate that obatoclax suppressed esophageal cancer cell viability with concomitant G1/G0-phase cell cycle arrest. At the tested concentrations (1/2 IC50 and IC50), obatoclax neither induced PARP cleavage nor increased the Annexin V-positive population, suggesting G1/G0-phase arrest rather than apoptosis accounts for most of the reduction of cell viability produced by obatoclax. Double knockdown of Bak and Bax by small interference RNA failed to block obatoclax-induced G1/G0-phase arrest, implying its role in cell cycle progression is Bak/Bax-independent. The cell cycle arresting effect of obatoclax was associated with up-regulation of p21(waf1/Cip1). Knockdown of p21(waf1/Cip1) significantly attenuated obatoclax-induced G1/G0-phase arrest. Although obatoclax stimulated phosphorylation of Erk, p38, and JNK, pharmacological inhibition of p38 but not Erk or JNK blocked obatoclax-induced G1/G0-phase arrest. Moreover, knockdown of p38 abolished the cell cycle arresting effect of obatoclax. In consistent with this finding, inhibition of p38 blocked obatoclax-induced p21(waf1/Cip1) expression while inhibition of Erk or JNK failed to exert similar effect. To conclude, these findings suggest that obatoclax induced cell cycle arrest via p38/p21(waf1/Cip1) signaling pathway. This study may shed a new light on the anti-cancer activity of obatoclax in relation to cell cycle arrest.
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Affiliation(s)
- Desheng Zhong
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
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17
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Mani J, Vallo S, Rakel S, Antonietti P, Gessler F, Blaheta R, Bartsch G, Michaelis M, Cinatl J, Haferkamp A, Kögel D. Chemoresistance is associated with increased cytoprotective autophagy and diminished apoptosis in bladder cancer cells treated with the BH3 mimetic (-)-Gossypol (AT-101). BMC Cancer 2015; 15:224. [PMID: 25885284 PMCID: PMC4409725 DOI: 10.1186/s12885-015-1239-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 03/20/2015] [Indexed: 12/19/2022] Open
Abstract
Background Acquired resistance to standard chemotherapy causes treatment failure in patients with metastatic bladder cancer. Overexpression of pro-survival Bcl-2 family proteins has been associated with a poor chemotherapeutic response, suggesting that Bcl-2-targeted therapy may be a feasible strategy in patients with these tumors. The small-molecule pan-Bcl-2 inhibitor (−)-gossypol (AT-101) is known to induce apoptotic cell death, but can also induce autophagy through release of the pro-autophagic BH3 only protein Beclin-1 from Bcl-2. The potential therapeutic effects of (−)-gossypol in chemoresistant bladder cancer and the role of autophagy in this context are hitherto unknown. Methods Cisplatin (5637rCDDP1000, RT4rCDDP1000) and gemcitabine (5637rGEMCI20, RT4rGEMCI20) chemoresistant sub-lines of the chemo-sensitive bladder cancer cell lines 5637 and RT4 were established for the investigation of acquired resistance mechanisms. Cell lines carrying a stable lentiviral knockdown of the core autophagy regulator ATG5 were created from chemosensitive 5637 and chemoresistant 5637rGEMCI20 and 5637rCDDP1000 cell lines. Cell death and autophagy were quantified by FACS analysis of propidium iodide, Annexin and Lysotracker staining, as well as LC3 translocation. Results Here we demonstrate that (−)-gossypol induces an apoptotic type of cell death in 5637 and RT4 cells which is partially inhibited by the pan-caspase inhibitor z-VAD. Cisplatin- and gemcitabine-resistant bladder cancer cells exhibit enhanced basal and drug-induced autophagosome formation and lysosomal activity which is accompanied by an attenuated apoptotic cell death after treatment with both (−)-gossypol and ABT-737, a Bcl-2 inhibitor which spares Mcl-1, in comparison to parental cells. Knockdown of ATG5 and inhibition of autophagy by 3-MA had no discernible effect on apoptotic cell death induced by (−)-gossypol and ABT-737 in parental 5637 cells, but evoked a significant increase in early apoptosis and overall cell death in BH3 mimetic-treated 5637rGEMCI20 and 5637rCDDP1000 cells. Conclusions Our findings show for the first time that (−)-gossypol concomitantly triggers apoptosis and a cytoprotective type of autophagy in bladder cancer and support the notion that enhanced autophagy may underlie the chemoresistant phenotype of these tumors. Simultaneous targeting of Bcl-2 proteins and the autophagy pathway may be an efficient new strategy to overcome their “autophagy addiction” and acquired resistance to current therapy.
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Affiliation(s)
- Jens Mani
- Department of Urology, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Stefan Vallo
- Department of Urology, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Stefanie Rakel
- Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Patrick Antonietti
- Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Florian Gessler
- Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Roman Blaheta
- Department of Urology, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Georg Bartsch
- Department of Urology, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Martin Michaelis
- Institute for Medical Virology, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany. .,School of Biosciences, The University of Kent, Canterbury, Kent, CT2 7NZ, UK.
| | - Jindrich Cinatl
- Institute for Medical Virology, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Axel Haferkamp
- Department of Urology, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
| | - Donat Kögel
- Experimental Neurosurgery, Neuroscience Center, Goethe University Hospital, Theodor-Stern-Kai 7, D-60590, Frankfurt am Main, Germany.
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Klukovits A, Krajcsi P. Mechanisms and therapeutic potential of inhibiting drug efflux transporters. Expert Opin Drug Metab Toxicol 2015; 11:907-20. [DOI: 10.1517/17425255.2015.1028917] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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19
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Roles of autophagy induced by natural compounds in prostate cancer. BIOMED RESEARCH INTERNATIONAL 2015; 2015:121826. [PMID: 25821782 PMCID: PMC4364006 DOI: 10.1155/2015/121826] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 12/23/2014] [Indexed: 02/07/2023]
Abstract
Autophagy is a homeostatic mechanism through which intracellular organelles and proteins are degraded and recycled in response to increased metabolic demand or stress. Autophagy dysfunction is often associated with many diseases, including cancer. Because of its role in tumorigenesis, autophagy can represent a new therapeutic target for cancer treatment.
Prostate cancer (PCa) is one of the most common cancers in aged men. The evidence on alterations of autophagy related genes and/or protein levels in PCa cells suggests a potential implication of autophagy in PCa onset and progression. The use of natural compounds, characterized by low toxicity to normal tissue associated with specific anticancer effects at physiological levels in vivo, is receiving increasing attention for prevention and/or treatment of PCa. Understanding the mechanism of action of these compounds could be crucial for the development of new therapeutic or chemopreventive options. In this review we focus on the current evidence showing the capacity of natural compounds to exert their action through autophagy modulation in PCa cells.
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20
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Berghauser Pont LME, Spoor JKH, Venkatesan S, Swagemakers S, Kloezeman JJ, Dirven CMF, van der Spek PJ, Lamfers MLM, Leenstra S. The Bcl-2 inhibitor Obatoclax overcomes resistance to histone deacetylase inhibitors SAHA and LBH589 as radiosensitizers in patient-derived glioblastoma stem-like cells. Genes Cancer 2015; 5:445-59. [PMID: 25568669 PMCID: PMC4279441 DOI: 10.18632/genesandcancer.42] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Accepted: 11/22/2014] [Indexed: 12/15/2022] Open
Abstract
Glioblastoma has shown resistance to histone deacetylase inhibitors (HDACi) as radiosensitizers in cultures with Bcl-XL over-expression. We study the efficacy of SAHA/RTx and LBH589/RTx when manipulating Bcl-2 family proteins using the Bcl-2 inhibitor Obatoclax in patient-derived glioblastoma stem-like cell (GSC) cultures. GSC cultures in general have a deletion in phosphatase and tensin homolog (PTEN). Synergy was determined by the Chou Talalay method. The effects on apoptosis and autophagy were studied by measuring caspase-3/7, Bcl-XL, Mcl-1 and LC3BI/II proteins. The relation between treatment response and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, recurrence and gene expression levels of the tumors were studied. Obatoclax synergized with SAHA and LBH589 and sensitized cells to HDACi/RTx. Over 50% of GSC cultures were responsive to Obatoclax with either single agent. Combined with HDACi/RTx treatment, Obatoclax increased caspase-3/7 and inhibited Bcl-2 family proteins Bcl-XL and Mcl-1 more effectively than other treatments. Genes predictive for treatment response were identified, including the F-box/WD repeat-containing protein-7, which was previously related to Bcl-2 inhibition and HDACi sensitivity. We emphasize the functional relation between Bcl-2 proteins and radiosensitization by HDACi and provide a target for increasing responsiveness in glioblastoma by using the Bcl-2 inhibitor Obatoclax.
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Affiliation(s)
| | - Jochem K H Spoor
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands
| | | | | | - Jenneke J Kloezeman
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands
| | - Clemens M F Dirven
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands
| | | | - Martine L M Lamfers
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands
| | - Sieger Leenstra
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, Rotterdam, The Netherlands ; Department of Neurosurgery, Elisabeth Medical Hospital, Tilburg, The Netherlands
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Radogna F, Dicato M, Diederich M. Cancer-type-specific crosstalk between autophagy, necroptosis and apoptosis as a pharmacological target. Biochem Pharmacol 2015; 94:1-11. [PMID: 25562745 DOI: 10.1016/j.bcp.2014.12.018] [Citation(s) in RCA: 127] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Revised: 12/22/2014] [Accepted: 12/24/2014] [Indexed: 12/15/2022]
Abstract
Cell death plays an essential role in the development of organs, homeostasis, and cancer. Apoptosis and programmed necrosis are two major types of cell death, characterized by different cell morphology and pathways. Accumulating evidence shows autophagy as a new alternative target to treat tumor resistance. Besides its well-known pro-survival role, autophagy can be a physiological cell death process linking apoptosis and programmed necrosis cell death pathways, by various molecular mediators. Here, we summarize the effects of pharmacologically active compounds as modulators of different types of cancer cell death depending on the cellular context. Indeed, current findings show that both natural and synthetic compounds regulate the interplay between apoptosis, autophagy and necroptosis stimulating common molecular mediators and sharing common organelles. In response to specific stimuli, the same death signal can cause cells to switch from one cell death modality to another depending on the cellular setting. The discovery of important interconnections between the different cell death mediators and signaling pathways, regulated by pharmacologically active compounds, presents novel opportunities for the targeted treatment of cancer. The aim of this review is to highlight the potential role of these compounds for context-specific anticancer therapy.
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Affiliation(s)
- Flavia Radogna
- Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg
| | - Mario Dicato
- Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg
| | - Marc Diederich
- College of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
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22
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Xie C, Edwards H, Caldwell JT, Wang G, Taub JW, Ge Y. Obatoclax potentiates the cytotoxic effect of cytarabine on acute myeloid leukemia cells by enhancing DNA damage. Mol Oncol 2014; 9:409-21. [PMID: 25308513 DOI: 10.1016/j.molonc.2014.09.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 09/09/2014] [Accepted: 09/16/2014] [Indexed: 12/13/2022] Open
Abstract
Resistance to cytarabine and anthracycline-based chemotherapy is a major cause of treatment failure for acute myeloid leukemia (AML) patients. Overexpression of Bcl-2, Bcl-xL, and/or Mcl-1 has been associated with chemoresistance in AML cell lines and with poor clinical outcome of AML patients. Thus, inhibitors of anti-apoptotic Bcl-2 family proteins could be novel therapeutic agents. In this study, we investigated how clinically achievable concentrations of obatoclax, a pan-Bcl-2 inhibitor, potentiate the antileukemic activity of cytarabine in AML cells. MTT assays in AML cell lines and diagnostic blasts, as well as flow cytometry analyses in AML cell lines revealed synergistic antileukemic activity between cytarabine and obatoclax. Bax activation was detected in the combined, but not the individual, drug treatments. This was accompanied by significantly increased loss of mitochondrial membrane potential. Most importantly, in AML cells treated with the combination, enhanced early induction of DNA double-strand breaks (DSBs) preceded a decrease of Mcl-1 levels, nuclear translocation of Bcl-2, Bcl-xL, and Mcl-1, and apoptosis. These results indicate that obatoclax enhances cytarabine-induced apoptosis by enhancing DNA DSBs. This novel mechanism provides compelling evidence for the clinical use of BH3 mimetics in combination with DNA-damaging agents in AML and possibly a broader range of malignancies.
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Affiliation(s)
- Chengzhi Xie
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, PR China
| | - Holly Edwards
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - J Timothy Caldwell
- MD/PhD Program, Wayne State University School of Medicine, Detroit, MI, USA; Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI, USA
| | - Guan Wang
- National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, PR China; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Jeffrey W Taub
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI, USA; Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA
| | - Yubin Ge
- Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA; National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, The Ministry of Education, School of Life Sciences, Jilin University, Changchun, PR China.
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Champa D, Russo MA, Liao XH, Refetoff S, Ghossein RA, Di Cristofano A. Obatoclax overcomes resistance to cell death in aggressive thyroid carcinomas by countering Bcl2a1 and Mcl1 overexpression. Endocr Relat Cancer 2014; 21:755-67. [PMID: 25012986 PMCID: PMC4152557 DOI: 10.1530/erc-14-0268] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 (Trp53) in thyroid follicular cells, we have generated a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members, Bcl2a1 (Bcl2a1a) and Mcl1, and can be effectively targeted by Obatoclax, a small-molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model have uncovered a promising druggable feature of aggressive thyroid cancers.
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Affiliation(s)
- Devora Champa
- Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Marika A Russo
- Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Xiao-Hui Liao
- Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Samuel Refetoff
- Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Ronald A Ghossein
- Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA
| | - Antonio Di Cristofano
- Department of Developmental and Molecular BiologyAlbert Einstein College of Medicine, Price Center for Genetic and Translational Medicine, 1301 Morris Park Avenue, Room 302, Bronx, New York 10461, USADepartments of MedicinePediatrics and Committee on GeneticsUniversity of Chicago, Chicago, Illinois, USADepartment of PathologyMemorial Sloan-Kettering Cancer Center, New York, New York, USA
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Sandri M, Robbins J. Proteotoxicity: an underappreciated pathology in cardiac disease. J Mol Cell Cardiol 2014; 71:3-10. [PMID: 24380730 PMCID: PMC4011959 DOI: 10.1016/j.yjmcc.2013.12.015] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 12/03/2013] [Accepted: 12/15/2013] [Indexed: 12/21/2022]
Abstract
In general, in most organ systems, intracellular protein homeostasis is the sum of many factors, including chromosomal state, protein synthesis, post-translational processing and transport, folding, assembly and disassembly into macromolecular complexes, protein stability and clearance. In the heart, there has been a focus on the gene programs that are activated during pathogenic processes, but the removal of damaged proteins and organelles has been underappreciated as playing an important role in the pathogenesis of heart disease. Proteotoxicity refers to the adverse effects of damaged or misfolded proteins and even organelles on the cell. At the cellular level, the ultimate outcome of uncontrolled or severe proteotoxicity is cell death; hence, the pathogenic impact of proteotoxicity is maximally manifested in organs with no or very poor regenerative capability such as the brain and the heart. Evidence for increased cardiac proteotoxicity is rapidly mounting for a large subset of congenital and acquired human heart disease. Studies carried out in animal models and in cell culture have begun to establish both sufficiency and, in some cases, the necessity of proteotoxicity as a major pathogenic factor in the heart. This dictates rigorous testing for the efficacy of proteotoxic attenuation as a new strategy to treat heart disease. This review article highlights some recent advances in our understanding of how misfolded proteins can injure and are handled in the cell, examining the emerging evidence for targeting proteotoxicity as a new therapeutic strategy for heart disease. This article is part of a Special Issue entitled "Protein Quality Control, the Ubiquitin Proteasome System, and Autophagy."
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Affiliation(s)
- Marco Sandri
- Venetian Institute of Molecular Medicine (VIMM), Padova, Italy; Consiglio Nazionale delle Ricerche (CNR) Institute of Neuroscience, Padova, Italy; Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Jeffrey Robbins
- The Heart Institute, Department of Pediatrics, The Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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Abstract
Digestive cancers, such as colorectal cancer, gastric cancer and liver cancer, remain major threats to human health in coming decades and their epidemiology is under dynamic changes. Recent advances in genotyping and sequencing technologies together with other molecular and cellular biology techniques have led to a clearer delineation of the pathogenic mechanisms underlying genetic and environmental factors that contribute to digestive cancers. Such expansion of knowledge continues to fuel the development of novel biomarkers and therapeutics. In this special issue of Seminars in Cancer Biology, hot topics in basic and translational research of digestive cancers will be reviewed.
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