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Jongjang P, Likitnukul S, Reabroi S, Mangmool S, Nutho B, Pinthong D. Anticancer Effect of Pinostrobin on Human Breast Cancer Cells Through Regulation of Epithelial Mesenchymal Transition. Integr Cancer Ther 2025; 24:15347354251341438. [PMID: 40383961 PMCID: PMC12089712 DOI: 10.1177/15347354251341438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 04/26/2025] [Indexed: 05/20/2025] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, with a high incidence of metastasis and chemoresistance. Epithelial-mesenchymal transition (EMT) is one of the molecular mechanisms that has been linked to the promotion of metastasis, and it can be promoted by several activators including the NF-κB signaling pathway. As a result, targeting EMT may be a potential strategy for treating TNBC. Pinostrobin is one of the important flavonoids found in the rhizome and rootlet of Boesenbergia rotunda (L.) Mansf. (fingerroot) that exhibits anticancer activities. However, the precise mechanism underlying the anticancer effect of pinostrobin on breast cancer remains unclear, and additional evidence is needed. In this study, the MCF-7 and MDA-MB-231 breast cancer cells were treated with various concentrations of pinostrobin. To determine the effect of pinostrobin on cell viability, an MTT assay was performed. Wound healing and Transwell chamber assays were conducted to examine the effect of pinostrobin on migration ability. RT-PCR was used to detect the expression of mRNA involved in NF-κB and EMT signaling pathways. The results revealed that low concentrations of pinostrobin did not affect cell viability, while higher concentrations produced an inhibitory effect on the viability of both cell lines. Pinostrobin also impeded migration and suppressed the expression of N-cadherin, a mesenchymal marker. Molecular docking analysis also suggested that the pinostrobin may target N-cadherin with higher binding affinity than IKK complex and NF-κB p65. These findings indicate that pinostrobin may serve as a potential treatment for TNBC.
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Park MY, Lee S, Kim HH, Jeong SH, Abusaliya A, Bhosale PB, Seong JK, Park KI, Heo JD, Ahn M, Kim HW, Kim GS. Correlation with Apoptosis Process through RNA-Seq Data Analysis of Hep3B Hepatocellular Carcinoma Cells Treated with Glehnia littoralis Extract (GLE). Int J Mol Sci 2024; 25:9462. [PMID: 39273406 PMCID: PMC11394729 DOI: 10.3390/ijms25179462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024] Open
Abstract
Glehnia littoralis is a perennial herb found in coastal sand dunes throughout East Asia. This herb has been reported to have hepatoprotective, immunomodulatory, antioxidant, antibacterial, antifungal, anti-inflammatory, and anticancer activities. It may be effective against hepatocellular carcinoma (HCC). However, whether this has been proven through gene-level RNA-seq analysis is still being determined. Therefore, we are attempting to identify target genes for the cell death process by analyzing the transcriptome of Hep3B cells among HCC treated with GLE (Glehnia littoralis extract) using RNA-seq. Hep3B was used for the GLE treatment, and the MTT test was performed. Hep3B was then treated with GLE at a set concentration of 300 μg/mL and stored for 24 h, followed by RNA isolation and sequencing. We then used the data to create a plot. As a result of the MTT analysis, cell death was observed when Hep3B cells were treated with GLE, and the IC50 was about 300 μg/mL. As a result of making plots using the RNA-seq data of Hep3B treated with 300 μg/mL GLE, a tendency for the apoptotic process was found. Flow cytometry and annexin V/propidium iodide (PI) staining verified the apoptosis of HEP3B cells treated with GLE. Therefore, an increase or decrease in the DEGs involved in the apoptosis process was confirmed. The top five genes increased were GADD45B, DDIT3, GADD45G, CHAC1, and PPP1R15A. The bottom five genes decreased were SGK1, CX3CL1, ZC3H12A, IER3, and HNF1A. In summary, we investigated the RNA-seq dataset of GLE to identify potential targets that may be involved in the apoptotic process in HCC. These goals may aid in the identification and management of HCC.
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Affiliation(s)
- Min-Yeong Park
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Republic of Korea
| | - Sujin Lee
- Research Institute of Molecular Alchemy, Gyeongsang National University, 501, Jinju-daero, Jinju 52828, Republic of Korea
| | - Hun-Hwan Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Republic of Korea
| | - Se-Hyo Jeong
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Republic of Korea
| | - Abuyaseer Abusaliya
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Republic of Korea
| | - Pritam Bhangwan Bhosale
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Republic of Korea
| | - Je-Kyung Seong
- Laboratory of Developmental Biology and Genomics, BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea
| | - Kwang-Il Park
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Republic of Korea
| | - Jeong-Doo Heo
- Biological Resources Research Group, Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institute of Toxicology, 17 Jegok-gil, Jinju 52834, Republic of Korea
| | - Meejung Ahn
- Department of Animal Science, College of Life Science, Sangji University, Wonju 26339, Republic of Korea
| | - Hyun-Wook Kim
- Division of Animal Bioscience and Integrated Biotechnology, Jinju 52725, Republic of Korea
| | - Gon-Sup Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Republic of Korea
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Gunasekaran V, Dhakshinamurthy SS. Computational Insights into the Interaction of Pinostrobin with Bcl-2 Family Proteins: A Molecular Docking Analysis. Asian Pac J Cancer Prev 2024; 25:507-512. [PMID: 38415536 PMCID: PMC11077126 DOI: 10.31557/apjcp.2024.25.2.507] [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: 08/12/2023] [Accepted: 02/18/2024] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Cancer research has emphasized the Bcl-2 family of proteins because of their interaction in apoptosis process, a critical mechanism that regulates cellular survival and death. Recently small molecules from diverse sources have gained much attention in anticancer research due to their promising inhibitory action against Bcl-2 and Bcl-XL that are pointedly known as the members of anti-apoptotic Bcl-2 family of proteins. Pinostrobin (PN) is a natural flavonoid with diverse pharmacological potential emerged as a molecule of interest as anticancer agent. The present study aims to screen the interaction of PN with anti-apoptotic protagonists Bcl-2 and Bcl- XL at the molecular level through docking studies. METHOD The molecular docking was performed using the Schrodinger software. The docking score of PN with the Bcl-2 (4IEH) and Bcl-XL (3ZK6) and their molecular interactions was examined and analysed. RESULTS The result of the molecular docking analysis showed that PN and the anti-apoptotic proteins 4IEH and 3ZK6 had significant interactions and docking energy scores (ΔG) were found to be -5.112 kcal/mol and -7.822 kcal/mol respectively. The small molecule PN illustrated effective interaction with the active site amino acids of the Bcl-2 and Bcl-XL proteins and has been associated through traditional hydrogen bond with 4IEH. Further, it was observed that PN and anti-apoptotic Bcl-2 proteins interaction was stabilized by other non-covalent interactions, such as π-alkyl or π-π interactions and van der Waals forces. CONCLUSIONS This was the first study to reveal the inhibitory action of PN against anti-apoptotic Bcl-2 and Bcl-XL proteins at the molecular level. The findings of this study concludes that PN ability to inhibit anti-apoptotic proteins, Bcl-2 and Bcl-XL could be useful to induce intracellular apoptosis in tumorous cells.
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Wang W, Chen P, Yuan S. Programmed cell death-index (PCDi) as a prognostic biomarker and predictor of drug sensitivity in cervical cancer: a machine learning-based analysis of mRNA signatures. J Cancer 2024; 15:1378-1396. [PMID: 38356704 PMCID: PMC10861809 DOI: 10.7150/jca.91798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 12/30/2023] [Indexed: 02/16/2024] Open
Abstract
Purpose: Cervical cancer is a significant public health concern, particularly in developing countries. Despite available treatment strategies, the prognosis for patients with locally advanced cervical cancer and beyond remains poor. Therefore, an accurate prediction model that can reliably forecast prognosis is essential in clinical setting. Programmed cell death (PCD) mechanisms are diverse and play a critical role in tumor growth, survival, and metastasis, making PCD a potential reliable prognostic marker for cervical cancer. Methods: In this study, we created a novel prognostic indicator, programmed cell death-index (PCDi), based on a 10-fold cross-validation framework for comprehensive analysis of PCD-associated genes. Results: Our PCDi-based prognostic model outperformed previously published signature models, stratifying cervical cancer patients into two distinct groups with significant differences in overall survival prognosis, tumor immune features, and drug sensitivity. Higher PCDi scores were associated with poorer prognosis. The nomogram survival model integrated PCDi and clinical characteristics, demonstrating higher prognostic prediction performance. Furthermore, our study investigated the immune features of cervical cancer patients and found that those with high PCDi scores had lower infiltrating immune cells, lower potential of T cell dysfunction, and higher potential of T cell exclusion. Patients with high PCDi scores were resistant to classic chemotherapy regimens, including cisplatin, docetaxel, and paclitaxel, but showed sensitivity to the inhibitor SB505124 and Trametinib. Conclusion: Our findings suggest that PCD-related gene signature could serve as a useful biomarker to reliably predict prognosis and guide treatment decisions in cervical cancer.
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Affiliation(s)
- Wei Wang
- Department of Obstetrics and Gynecology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong, China
| | - Pengchen Chen
- Dongguan Maternal and Child Health Care Hospital, Postdoctoral Innovation Practice Base of Southern Medical University, Gongguan, 523125, Guangdong, China
| | - Songhua Yuan
- Department of Obstetrics and Gynecology, The First People's Hospital of Foshan, Foshan, 528000, Guangdong, China
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Ali Abed Wahab B, Ain Salehen N, Abdulla MA, A.j. Jabbar A, Abdel Aziz Ibrahim I, Almaimani G, AbdulMonam Zainel M, Bamagous GA, Almaimani RA, Almasmoum HA, Ghaith MM, Farrash WF, Almutawif YA. Pinostrobin attenuates azoxymethane-induced colorectal cytotoxicity in rats through augmentation of apoptotic Bax/Bcl-2 proteins and antioxidants. SAGE Open Med 2023; 11:20503121231216585. [PMID: 38078205 PMCID: PMC10710114 DOI: 10.1177/20503121231216585] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 11/05/2023] [Indexed: 02/23/2024] Open
Abstract
OBJECTIVES Pinostrobin (5-hydroxy-7-methoxyflavanone; PN) is a natural active ingredient with numerous biological activities extensively utilized in tumour chemotherapy. The present study investigates the chemo-preventive potentials of PN on azoxymethane-mediated colonic aberrant crypt foci in rats. METHODS Sprague Dawley rats clustered into five groups, normal control (A) and cancer controls were subcutaneously injected with normal saline and 15 mg/kg azoxymethane, respectively, and nourished on 10% tween 20 and fed on 10% tween 20; reference control (C), injected with 15 mg/kg azoxymethane and injected (intraperitoneal) with 35 mg/kg 5-fluorouracil (5-FU); D and E rat groups received a subcutaneous injection of 15 mg/kg azoxymethane and nourished on 30 and 60 mg/kg of PN, respectively. RESULTS The acute toxicity trial showed a lack of any abnormal signs or mortality in rats ingested with 250 and 500 mg/kg of PN. The gross morphology of colon tissues revealed significantly lower total colonic aberrant crypt foci incidence in PN-treated rats than that of cancer controls. Histological examination of colon tissues showed increased aberrant crypt foci availability with bizarrely elongated nuclei, stratified cells and higher depletion of the submucosal glands in cancer controls. PN treatment caused positive modulation of apoptotic (Bax and Bcl-2) proteins and inflammatory cytokines (TNF-α, IL-6 and IL-10). Moreover, rats fed on PN had significantly higher antioxidants (superoxide dismutase) and lower malondialdehyde concentrations in their colon tissue homogenates. CONCLUSION The chemoprotective efficiency of PN against azoxymethane-induced aberrant crypt foci is shown by lower aberrant crypt foci values and higher aberrant crypt foci inhibition percentage, possibly through augmentation of genes responsible for apoptotic cascade and inflammations originating from azoxymethane oxidative stress insults.
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Affiliation(s)
- Bassam Ali Abed Wahab
- Faculty of Vet Medicine, Department of Physiology, Biochemistry and Pharmacology, University of Kufa, Kufa, Iraq
| | - Nur Ain Salehen
- Faculty of Medicine, Department of Biomedical Sciences, University of Malaya, Kuala Lumpur, Malaysia
| | - Mahmood Ameen Abdulla
- Department of Medical Microbiology, College of Science, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Ahmed A.j. Jabbar
- Department of Medical Laboratory Technology, Erbil Technical Health and Medical College, Erbil Polytechnic University, Erbil 44001, Iraq
| | - Ibrahim Abdel Aziz Ibrahim
- Faculty of Medicine, Department of Pharmacology and Toxicology, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Ghassan Almaimani
- Faculty of Medicine, Department of Surgery, Umm Al-Qura University, Al Abdeyah, Makkah, Saudi Arabia
| | | | - Ghazi A Bamagous
- Faculty of Medicine, Department of Pharmacology and Toxicology, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Riyad A Almaimani
- Faculty of Medicine, Department of Biochemistry, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Hussain A Almasmoum
- Faculty of Applied Medical Sciences, Department of Clinical Laboratory Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Mazen M Ghaith
- Faculty of Applied Medical Sciences, Department of Clinical Laboratory Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Wesam F Farrash
- Faculty of Applied Medical Sciences, Department of Clinical Laboratory Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Yahya A Almutawif
- Department of Medical Laboratories Technology, College of Applied Medical Sciences, Taibah University, Madinah, Saudi Arabia
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Zhao LL, Jayeoye TJ, Ashaolu TJ, Olatunji OJ. Pinostrobin, a dietary bioflavonoid exerts antioxidant, anti-inflammatory, and anti-apoptotic protective effects against methotrexate-induced ovarian toxicity in rats. Tissue Cell 2023; 85:102254. [PMID: 37866152 DOI: 10.1016/j.tice.2023.102254] [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: 07/30/2023] [Revised: 10/02/2023] [Accepted: 10/19/2023] [Indexed: 10/24/2023]
Abstract
This study investigated the protective activities of pinostrobin (PIN) against methotrexate (MTX)-induced ovarian toxicity. Female rats were administered with PIN (50 mg/kg) for 4 weeks, while MTX was administered from weeks 2-4 of PIN treatment. Serum hormonal profiles, ovarian oxidative stress, inflammatory and apoptotic biomarkers as well as ovarian histomorphometry were evaluated. MTX administration elicited profound deficit in serum progesterone and estrogen (E2) levels, while luteinizing hormone (LH) and follicle stimulating hormone (FSH) were significantly increased. Additionally, MTX administration was associated with significant increases in ovarian malondialdehyde, nitric oxide, NF-кB, TNF-α, IL-6, IL-1β, iNOS and caspase-3 activity, as well as notable reduction in the activities of glutathione peroxidase, catalase and superoxide dismutase as well as the level of glutathione. Whereas, treatment with PIN significantly decreased serum levels of FSH and LH, as well as ovarian levels of NO, MDA, caspase 3, NF-κB, IL-1β, IL-6, TNF-α and iNOS. PIN also significantly upregulated GSH, GPx, CAT and SOD in the ovarian tissues as well as increased serum E2 and progesterone levels compared to the MTX group. Furthermore, PIN significantly restored altered ovarian histoarchitecture in the treated group. These findings suggests that PIN exerts protective effects against MTX-triggered ovarian damages.
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Affiliation(s)
- Ling-Ling Zhao
- Department of Chemistry and Chemical Engineering, Yancheng Institute of Technology, Yancheng, China
| | - Titilope John Jayeoye
- Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand
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Chen PY, Lin CY, Wu CL, Keak PY, Liou JW, Gao WY, Lin LI, Yen JH. Pinostrobin modulates FOXO3 expression, nuclear localization, and exerts antileukemic effects in AML cells and zebrafish xenografts. Chem Biol Interact 2023; 385:110729. [PMID: 37777166 DOI: 10.1016/j.cbi.2023.110729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/30/2023] [Accepted: 09/21/2023] [Indexed: 10/02/2023]
Abstract
Acute myeloid leukemia (AML) is a disease characterized by abnormal cell proliferation in the bone marrow and is the most common quickly progressive leukemia in adults. Pinostrobin, a flavonoid phytochemical, has been reported to exhibit antioxidant, anti-inflammatory, and anticancer properties. In this study, we aimed to investigate the antileukemic effects of pinostrobin and its molecular mechanisms in human AML cells. Our study found that pinostrobin (0-80 μM) significantly reduced the viability of human AML cells, with the pronounced cytotoxic effects observed in MV4-11 > MOLM-13 > HL-60 > U-937 > THP-1 cells. Pinostrobin was found to suppress leukemia cell proliferation, modulate cell cycle progression, promote cell apoptosis, and induce monocytic differentiation in MV4-11 cells. In animal studies, pinostrobin significantly suppressed the growth of leukemia cells in a zebrafish xenograft model. Microarray-based transcriptome analysis showed that the differentially expressed genes (DEGs) in pinostrobin-treated cells were strongly associated with enriched Gene Ontology (GO) terms related to apoptotic process, cell death, cell differentiation, cell cycle progression, and cell division. Combining DisGeNET and STRING database analysis revealed that pinostrobin upregulates forkhead box 3 (FOXO3), a tumor suppressor in cancer development, and plays an essential role in controlling AML cell viability. Our study demonstrated that pinostrobin increases FOXO3 gene expression and promotes its nuclear translocation, leading to the inhibition of cell growth. Finally, the study found that pinostrobin, when combined with cytarabine, synergistically reduces the viability of AML cells. Our current findings shed light on pinostrobin's mechanisms in inhibiting leukemia cell growth, highlighting its potential as a chemotherapeutic agent or nutraceutical supplement for AML prevention or treatment.
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Affiliation(s)
- Pei-Yi Chen
- Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970374, Taiwan; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, 970374, Taiwan
| | - Ching-Yen Lin
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, 970374, Taiwan
| | - Chia-Ling Wu
- Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, 970374, Taiwan
| | - Pei Ying Keak
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, 970374, Taiwan
| | - Je-Wen Liou
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien, 970374, Taiwan
| | - Wan-Yun Gao
- Institute of Medical Sciences, Tzu Chi University, Hualien, 970374, Taiwan
| | - Liang-In Lin
- Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, 10048, Taiwan
| | - Jui-Hung Yen
- Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, 970374, Taiwan; Institute of Medical Sciences, Tzu Chi University, Hualien, 970374, Taiwan.
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Norkaew C, Subkorn P, Chatupheeraphat C, Roytrakul S, Tanyong D. Pinostrobin, a fingerroot compound, regulates miR-181b-5p and induces acute leukemic cell apoptosis. Sci Rep 2023; 13:8084. [PMID: 37208425 DOI: 10.1038/s41598-023-35193-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 05/14/2023] [Indexed: 05/21/2023] Open
Abstract
Pinostrobin (PN) is the most abundant flavonoid found in fingerroot. Although the anti-leukemic properties of PN have been reported, its mechanisms are still unclear. MicroRNAs (miRNAs) are small RNA molecules that function in posttranscriptional silencing and are increasingly being used in cancer therapy. The aims of this study were to investigate the effects of PN on proliferation inhibition and induction of apoptosis, as well as the involvement of miRNAs in PN-mediated apoptosis in acute leukemia. The results showed that PN reduced cell viability and induced apoptosis in acute leukemia cells via both intrinsic and extrinsic pathways. A bioinformatics approach and Protein-Protein Interaction (PPI) network analysis revealed that ataxia-telangiectasia mutated kinase (ATM), one of the p53 activators that responds to DNA damage-induced apoptosis, is a crucial target of PN. Four prediction tools were used to predict ATM-regulated miRNAs; miR-181b-5p was the most likely candidate. The reduction in miR-181b-5 after PN treatment was found to trigger ATM, resulting in cellular apoptosis. Therefore, PN could be developed as a drug for acute leukemia; in addition, miR-181b-5p and ATM may be promising therapeutic targets.
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Affiliation(s)
- Chosita Norkaew
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Paweena Subkorn
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Chawalit Chatupheeraphat
- Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, 73170, Thailand
| | - Sittiruk Roytrakul
- Functional Proteomics Technology Laboratory, Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology for Development Agency, Pathum Thani, 12120, Thailand
| | - Dalina Tanyong
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom, 73170, Thailand.
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Norkaew C, Roytrakul S, Charoenlappanit S, Thaisakun S, Tanyong D. Pinostrobin induces acute leukemia cell apoptosis via the regulation of miR-410-5p and SFRP5. Life Sci 2023; 325:121739. [PMID: 37164308 DOI: 10.1016/j.lfs.2023.121739] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/16/2023] [Accepted: 04/24/2023] [Indexed: 05/12/2023]
Abstract
AIMS This study attempted to explore the mechanisms involved in pinostrobin (PN)-mediated acute leukemia cell apoptosis regulated by miR-410-5p. MATERIAL AND METHODS NB4 and MOLT-4 cells were cultured and treated with PN at the IC50 concentration. Apoptosis was examined by Annexin V-FITC/PI staining. RT-qPCR was used to measure the expression of caspase-3, BAK, BCL-W, and MCL-1. The target protein of PN was identified using LC-MS/MS followed by bioinformatic analysis. TargetScan, DIANA, and miRDB were used for the prediction of miRNAs involved in the PN-induced apoptosis mechanism. miRNA mimic transfection, RT-qPCR, and western blot analysis were performed to evaluate the regulatory effect of miRNA on its target and the involvement of miRNA in apoptosis induction by PN. In addition, the synergistic effect of PN and daunorubicin (DNR) were investigated by using the MTT assay. KEY FINDINGS The results showed that PN reduced cell viability and induced apoptosis in both leukemia cell lines. From the LC-MS/MS and bioinformatics analysis, SFRP5 and miR-410-5p were selected as a potential PN target protein and miRNA, respectively. After miRNA mimic transfection, miR-410-5p, which is an onco-miRNA, was decreased and led to increased apoptosis in both cell lines, indicating that this miRNA is involved in PN-mediated apoptosis mechanisms. Moreover, PN demonstrated a synergistic effect with DNR, suggesting that PN may be used in combination with conventional chemotherapy drugs. SIGNIFICANCE PN regulates the expression of miR-410-5p and SFRP5 to promote apoptosis in acute leukemia cells. It could be developed as an alternative treatment for leukemia in the future.
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Affiliation(s)
- Chosita Norkaew
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Sittiruk Roytrakul
- Functional Proteomics Technology Laboratory, Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology for Development Agency, Pathum Thani 12120, Thailand
| | - Sawanya Charoenlappanit
- Functional Proteomics Technology Laboratory, Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology for Development Agency, Pathum Thani 12120, Thailand
| | - Siriwan Thaisakun
- Functional Proteomics Technology Laboratory, Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology for Development Agency, Pathum Thani 12120, Thailand
| | - Dalina Tanyong
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand.
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Athapaththu AMGK, Sanjaya SS, Lee KT, Karunarathne WAHM, Choi YH, Hur SP, Kim GY. Pinostrobin Suppresses the α-Melanocyte-Stimulating Hormone-Induced Melanogenic Signaling Pathway. Int J Mol Sci 2023; 24:ijms24010821. [PMID: 36614262 PMCID: PMC9821324 DOI: 10.3390/ijms24010821] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/27/2022] [Accepted: 12/27/2022] [Indexed: 01/05/2023] Open
Abstract
Pinostrobin is a dietary flavonoid found in several plants that possesses pharmacological properties, such as anti-cancer, anti-virus, antioxidant, anti-ulcer, and anti-aromatase effects. However, it is unclear if pinostrobin exerts anti-melanogenic properties and, if so, what the underlying molecular mechanisms comprise. Therefore, we, in this study, investigated whether pinostrobin inhibits melanin biosynthesis in vitro and in vivo, as well as the potential associated mechanism. Pinostrobin reduced mushroom tyrosinase activity in vitro in a concentration-dependent manner, with an IC50 of 700 μM. Molecular docking simulations further revealed that pinostrobin forms a hydrogen bond, as well as other non-covalent interactions, between the C-type lectin-like fold and polyphenol oxidase chain, rather than the previously known copper-containing catalytic center. Additionally, pinostrobin significantly decreased α-melanocyte-stimulating hormone (α-MSH)-induced extracellular and intracellular melanin production, as well as tyrosinase activity, in B16F10 melanoma cells. More specifically, pinostrobin inhibited the α-MSH-induced melanin biosynthesis signaling pathway by suppressing the cAMP-CREB-MITF axis. In fact, pinostrobin also attenuated pigmentation in α-MSH-stimulated zebrafish larvae without causing cardiotoxicity. The findings suggest that pinostrobin effectively inhibits melanogenesis in vitro and in vivo via regulation of the cAMP-CREB-MITF axis.
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Affiliation(s)
| | | | - Kyoung Tae Lee
- Forest Bioresources Department, Forest Microbiology Division, National Institute of Forest Science, Suwon 16631, Republic of Korea
| | | | - Yung Hyun Choi
- Department of Biochemistry, College of Korean Medicine, Dong-Eui University, Busan 47227, Republic of Korea
| | - Sung-Pyo Hur
- Department of Marine Life Science, Jeju National University, Jeju 63243, Republic of Korea
| | - Gi-Young Kim
- Department of Marine Life Science, Jeju National University, Jeju 63243, Republic of Korea
- Correspondence:
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Hamad Shareef S, Al-Medhtiy MH, Al Rashdi AS, Aziz PY, Abdulla MA. Hepatoprotective Effect of Pinostrobin against Thioacetamide-Induced Liver Cirrhosis in Rats. Saudi J Biol Sci 2022; 30:103506. [DOI: 10.1016/j.sjbs.2022.103506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 10/23/2022] [Accepted: 11/11/2022] [Indexed: 11/18/2022] Open
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12
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Sharma J, Prabha P, Sharma R, Gupta S, Dixit A. Anti-leukemic principle(s) from Momordica charantia seeds induce differentiation of HL-60 cells through ERK/MAPK signalling pathway. Cytotechnology 2022; 74:591-611. [PMID: 36238266 PMCID: PMC9525536 DOI: 10.1007/s10616-022-00547-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 08/10/2022] [Indexed: 11/24/2022] Open
Abstract
Myeloid leukemia is one of the major causes of deaths among elderly with very poor prognosis. Due to the adverse effects of existing chemotherapeutic agents, plant-derived components are being screened for their anti-leukemic potential. Momordica charantia (bitter gourd) possesses a variety of therapeutic activities. We have earlier demonstrated anti-leukemic activity of acetone extract of M. charantia seeds. The present study reports purification of differentiation inducing principle(s) from further fractionated seed extract (hexane fraction of the acetone extract, Mc2-Ac-hex) using HL-60 cells. Out of the 5 peak fractions (P1-P5) obtained from normal phase HPLC of the Mc2-Ac-hex, only peak fraction 3 (P3) induced differentiation of HL-60 cells as evident from an increase in NBT-positive cells and increased expression of cell surface marker CD11b. The P3 differentiated the HL-60 cells to granulocytic lineage, established by increased CD15 (granulocytic cell surface marker) expression in the treated cells. Further, possible molecular mechanism and the signalling pathway involved in the differentiation of HL-60 cells were also investigated. Use of specific signalling pathway inhibitors in the differentiation study, and proteome array analysis of the treated cells collectively revealed the involvement the of ERK/MAPK mediated pathway. Partial characterization of the P3 by GC-MS analysis revealed the presence of dibutyl phthalate, and derivatives of 2,5-dihydrofuran to be the highest among the 5 identified compounds. This study thus demonstrated that purified differentiation-inducing principle(s) from M. charantia seed extract induce HL-60 cells to granulocytic lineage through ERK/MAPK signalling pathway. Supplementary Information The online version contains supplementary material available at 10.1007/s10616-022-00547-x.
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Affiliation(s)
- Jeetesh Sharma
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067 India
| | - Punit Prabha
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067 India
| | - Rohit Sharma
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067 India
| | - Shalini Gupta
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067 India
| | - Aparna Dixit
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067 India
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13
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Jabir NR, Khan MS, Alafaleq NO, Naz H, Ahmed BA. Anticancer potential of yohimbine in drug-resistant oral cancer KB-ChR-8-5 cells. Mol Biol Rep 2022; 49:9565-9573. [PMID: 35970968 DOI: 10.1007/s11033-022-07847-7] [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] [Received: 06/07/2022] [Accepted: 08/05/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND The demand for environmentally friendly and cost-effective plant-based products for the development of cancer therapeutics has been increasing. Yohimbine (α2-adrenergic receptor antagonist) is a stimulant and aphrodisiac used to improve erectile dysfunction. In this study, we aimed to evaluate the anticancer potential of yohimbine in drug-resistant oral cancer KB-ChR-8-5 cells using different biomolecular techniques. METHODS We estimated the anticancer efficacy of yohimbine using different assays, such as MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell cytotoxicity, cell morphology, cell apoptosis, reactive oxygen species (ROS) formation, and modulation in the mitochondrial membrane potential (MMP). RESULTS Yohimbine showed a dose-dependent increase in cytotoxicity with a 50% inhibitory concentration (IC50) of 44 µM against KB-ChR-8-5 cancer cell lines. Yohimbine treatment at 40 µM and 50 µM resulted in a considerable change in cell morphology, including shrinkage, detachment, membrane blebbing, and deformed shape. Moreover, at the dose of IC50 and above, a significant induction was observed in the generation of ROS and depolarization of MMP. The possible mechanisms of action of yohimbine underlying the dose-dependent increase in cytotoxicity may be due to the induction of apoptosis, ROS generation, and modulation of MMP. CONCLUSION Overall, yohimbine showed a significant anticancer potential against drug-resistant oral cancer KB-ChR-8-5 cells. Our study suggests that besides being an aphrodisiac, yohimbine can be used as a drug repurposing agent. However, more research is required in different in vitro and in vivo models to confirm the feasibility of yohimbine in clinics.
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Affiliation(s)
- Nasimudeen R Jabir
- Department of Biochemistry, Centre for Research and Development, PRIST University, Vallam, Thanjavur, Tamil Nadu, 613403, India
| | - Mohd Shahnawaz Khan
- Department of Biochemistry, College of Sciences, King Saud University, Riyadh, 11451, Saudi Arabia.
| | - Nouf Omar Alafaleq
- Department of Biochemistry, College of Sciences, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Huma Naz
- Department of Medicine, University of Missouri, Columbia, MO, 65201, USA
| | - Bakrudeen Ali Ahmed
- Department of Biochemistry, Centre for Research and Development, PRIST University, Vallam, Thanjavur, Tamil Nadu, 613403, India.
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14
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Kim HH, Jeong SH, Ha SE, Park MY, Bhosale PB, Abusaliya A, Won CK, Heo JD, Kim HW, Kim GS. Cellular Regulation of Kynurenic Acid-Induced Cell Apoptosis Pathways in AGS Cells. Int J Mol Sci 2022; 23:ijms23168894. [PMID: 36012164 PMCID: PMC9408556 DOI: 10.3390/ijms23168894] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/02/2022] [Accepted: 08/08/2022] [Indexed: 11/30/2022] Open
Abstract
Kynurenic acid was included in the three compounds (caffeic acid, chlorogenic acid, and kynurenic acid) that showed high antioxidant and anti-inflammatory potential among the phenolic compounds contained in Gynura procumbens. In this study, the mechanism of cancer cell death induced by kynurenic acid (KYNA), which has the highest molecular binding affinity, in the gastric cancer cell line AGS was confirmed in molecular docking analysis. KYNA showed the most cancer cell death effect on AGS cells among several gastric cancer cell lines (MKN, AGS, and SNU). AGS cells were used for later experiments, and KYNA concentrations of 0, 150, 200, and 250 µM were used. KYNA inhibited cell migration and proliferation in AGS cells in a concentration-dependent manner. G2/M phase cell cycle arrest and reduction of related proteins (Cdc25C, CDK1 and CyclinB1) were confirmed in KYNA-treated AGS cells. Apoptosis of KYNA-treated AGS cells was confirmed by Annexin V/propidium iodide (PI) staining flow cytometry analysis. As a result of morphological chromatin condensation through DAPI (4′,6-diamidino-2-phenylindole), intense blue fluorescence was confirmed. The mechanism of apoptosis induction of KYNA-treated AGS cells was confirmed by western blotting. In the extrinsic pathway, apoptosis induction markers FasL, Fas, and Caspase-3 and -8 were increased in a concentration-dependent manner upon KYNA treatment. In the intrinsic pathway, the expression of anti-apoptotic factors PI3K, AKT, and Bcl-xL was down-regulated, and the expression of apoptosis-inducing factors BAD, Bak, Bax, Cytochrom C, and Caspase-9 was up-regulated. Therefore, in the present study, we strongly imply that KYNA induces apoptosis in AGS gastric cancer cells. This suggests that KYNA, a natural compound, could be the basis for drug for the treatment of gastric cancer.
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Affiliation(s)
- Hun Hwan Kim
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
| | - Se Hyo Jeong
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
| | - Sang Eun Ha
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
- Biological Resources Research Group, Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institute of Toxicology, 17 Jegok-gil, Jinju 52834, Korea
| | - Min Yeong Park
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
| | - Pritam Bhagwan Bhosale
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
| | - Abuyaseer Abusaliya
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
| | - Chung Kil Won
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
| | - Jeong Doo Heo
- Biological Resources Research Group, Gyeongnam Department of Environment Toxicology and Chemistry, Korea Institute of Toxicology, 17 Jegok-gil, Jinju 52834, Korea
| | - Hyun Wook Kim
- Division of Animal Bioscience & Integrated Biotechnology, Jinju 52725, Korea
| | - Gon Sup Kim
- Research Institute of Life Science, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Korea
- Correspondence: ; Tel.: +82-55-772-2346
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15
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Siswodihardjo S, Pratama MRF, Praditapuspa EN, Kesuma D, Poerwono H, Widiandani T. Boesenbergia Pandurata as an Anti-Breast Cancer Agent: Molecular Docking
and ADMET Study. LETT DRUG DES DISCOV 2022. [DOI: 10.2174/1570180819666211220111245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
Boesenbergia pandurata or fingerroot is known to have various pharmacological
activities, including anticancer properties. Extracts from these plants are known to inhibit the growth of
cancer cells, including breast cancer. Anti-breast cancer activity is significantly influenced by the inhibition
of two receptors: ER-α and HER2. However, it is unknown which metabolites of B. pandurata play
the most crucial role in exerting anticancer activity.
Objective:
This study aimed to determine the metabolites of B. pandurata with the best potential as ER-α
and HER2 inhibitors.
Method:
The method used was molecular docking of several B. pandurata metabolites to ER-α and
HER2 receptors, followed by an ADMET study of several metabolites with the best docking results.
Results:
The docking results showed eight metabolites with the best docking results for the two receptors
based on the docking score and ligand-receptor interactions. Of these eight compounds, compounds 11
((2S)-7,8-dihydro-5-hydroxy-2-methyl-2-(4''-methyl-3''-pentenyl)-8-phenyl-2H,6H-benzo(1,2-b-5,4-
b')dipyran-6-one) and 34 (geranyl-2,4-dihydroxy-6-phenethylbenzoate) showed the potential to inhibit
both receptors. Both ADMET profiles also showed mixed results; however, there is a possibility of further
development.
Conclusion:
In conclusion, the metabolites of B. pandurata, especially compounds 11 and 34, can be
developed as anti-breast cancer agents by inhibiting ER-α and HER2.
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Affiliation(s)
- Siswandono Siswodihardjo
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Airlangga, Surabaya
60115, Indonesia
| | - Mohammad Rizki Fadhil Pratama
- Doctoral Program of Pharmaceutical Science, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia
- Department of Pharmacy, Faculty of Health Science, Universitas Muhammadiyah Palangkaraya, Palangka Raya
73111, Indonesia
| | - Ersanda Nurma Praditapuspa
- Master Program of Pharmaceutical Science, Faculty of Pharmacy, Universitas Airlangga, Surabaya
60115, Indonesia
| | - Dini Kesuma
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Surabaya, Surabaya
60293, Indonesia
| | - Hadi Poerwono
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Airlangga, Surabaya
60115, Indonesia
| | - Tri Widiandani
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Airlangga, Surabaya
60115, Indonesia
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16
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Zhu Y, Yang L, Chen Y. Anhuienoside C inhibits human ovarian cancer cell growth by inducing apoptosis, suppression of cell migration and invasion, and targeting PI3K/AKT/mTOR signaling pathway. Mol Cell Biochem 2022; 477:1887-1892. [PMID: 35348981 DOI: 10.1007/s11010-022-04406-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 03/02/2022] [Indexed: 11/26/2022]
Abstract
The present study was initiated to examine the anticancer effects of Anhuienoside C (AC) against ovarian cancer and postulates the possible molecular mechanism of its action. 3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay was implemented for determination of the effects of AC on cell viability of the ovarian cancer OVACAR-3 cell line. To study cellular morphology, phase contrast microscopy was performed. Apoptosis was examined via acridine orange/ethidium bromide used staining assays. Flow cytometry was used to check the different phases of the cell cycle. Cell migration and invasion assays were performed via transwell chamber assay. The effects of AC on expression of phosphoinositide 3-kinases (PI3K), protein kinase B (AKT), and mammalian target of rapamycin (mTOR) protein in ovarian cell were assessed using western blotting assay. The results indicated that the cell proliferation rate lowered in AC-treated OVACAR-3 cells as compared to the untreated controls in a dose-dependent manner. Cell morphology changed substantially by the exposure to AC and remained dose dependent. These morphological changes were indicative of apoptotic cell death. Apoptosis analysis showed dose-dependent increase of apoptosis. The cell migration and invasion of OVACAR-3 cells was reduced to a minimum by AC in a dose-dependent manner. Finally, western blotting assay showed blocking of PI3K/AKT/mTOR signaling pathway with increasing AC doses. Taking all together, AC is a potential ovarian cancer inhibitor. It induces its anti-ovarian cancer effects via induction of apoptosis, delaying cell migration and invasion, and blocking PI3K/AKT/mTOR signaling pathway.
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Affiliation(s)
- Yan Zhu
- Department of Obstetrics and Gynecology, Yancheng No.1 People Hospital, Yancheng, 215000, Jiangsu, China
| | - Lijuan Yang
- Department of Obstetrics and Gynecology, Yancheng No.1 People Hospital, Yancheng, 215000, Jiangsu, China
| | - Youguo Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, 215100, Jiangsu, China.
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17
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Role of Plant-Derived Active Constituents in Cancer Treatment and Their Mechanisms of Action. Cells 2022; 11:cells11081326. [PMID: 35456005 PMCID: PMC9031068 DOI: 10.3390/cells11081326] [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: 03/17/2022] [Revised: 03/31/2022] [Accepted: 04/11/2022] [Indexed: 02/07/2023] Open
Abstract
Despite significant technological advancements in conventional therapies, cancer remains one of the main causes of death worldwide. Although substantial progress has been made in the control and treatment of cancer, several limitations still exist, and there is scope for further advancements. Several adverse effects are associated with modern chemotherapy that hinder cancer treatment and lead to other critical disorders. Since ancient times, plant-based medicines have been employed in clinical practice and have yielded good results with few side effects. The modern research system and advanced screening techniques for plants’ bioactive constituents have enabled phytochemical discovery for the prevention and treatment of challenging diseases such as cancer. Phytochemicals such as vincristine, vinblastine, paclitaxel, curcumin, colchicine, and lycopene have shown promising anticancer effects. Discovery of more plant-derived bioactive compounds should be encouraged via the exploitation of advanced and innovative research techniques, to prevent and treat advanced-stage cancers without causing significant adverse effects. This review highlights numerous plant-derived bioactive molecules that have shown potential as anticancer agents and their probable mechanisms of action and provides an overview of in vitro, in vivo and clinical trial studies on anticancer phytochemicals.
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18
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Kis B, Pavel IZ, Avram S, Moaca EA, Herrero San Juan M, Schwiebs A, Radeke HH, Muntean D, Diaconeasa Z, Minda D, Oprean C, Bojin F, Dehelean CA, Soica C, Danciu C. Antimicrobial activity, in vitro anticancer effect (MCF-7 breast cancer cell line), antiangiogenic and immunomodulatory potentials of Populus nigra L. buds extract. BMC Complement Med Ther 2022; 22:74. [PMID: 35296309 PMCID: PMC8928639 DOI: 10.1186/s12906-022-03526-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 02/02/2022] [Indexed: 11/10/2022] Open
Abstract
PURPOSE The aim of this study was to evaluate the antioxidant potential, antimicrobial activity, the in vitro anticancer effect (tested on MCF-7 breast cancer cell line), as well as the antiangiogenic and immunomodulatory potential of Populus nigra L. bud (Pg) extract collected from the western part of Romania. RESULTS Populus nigra L. bud extract presents an important antioxidant activity, due to the rich phytochemical composition. Regarding the biological activity, results have shown that poplar bud extract presents a significant inhibitory activity against Gram-positive bacteria and a dose-dependent decrease of MCF-7 tumor cell viability with an IC50 of 66.26 μg/mL, while not affecting healthy cells. Phenomena of early apoptotic events at the maximum concentration tested (150 μg/mL) were detected by Annexin V-PI double staining. The extract induced G0/G1 phase cell cycle arrest. In addition, Pg extract showed antiangiogenic potential on the chorioallantoic membrane. Also, at the highest concentration (150 μg/mL), good tolerability and no signs of toxicity upon vascular plexus were observed. Moreover, in low concentrations, the Pg extract had immunomodulatory activity on primary human dendritic cells by upregulating IL-12 and IL-23 subunits. CONCLUSION The study concludes that poplar bud extract elicited antioxidant activity, antitumor properties on the breast cancer cell line, followed by an antiangiogenic effect and an immunomodulatory potential on human primary dendritic cells. The biological activity of Populus nigra L. buds extract may open new directions of research on the topic addressed.
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Affiliation(s)
- Brigitta Kis
- Department of Pharmacognosy, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
| | - Ioana Zinuca Pavel
- Department of Pharmacognosy, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania. .,Research Center for Pharmaco-Toxicological Evaluation, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.
| | - Stefana Avram
- Department of Pharmacognosy, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.,Research Center for Pharmaco-Toxicological Evaluation, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
| | - Elena Alina Moaca
- Research Center for Pharmaco-Toxicological Evaluation, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.,Department of Toxicology, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
| | - Martina Herrero San Juan
- Pharmazentrum frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Hospital of the Goethe University, 60590, Frankfurt/Main, Germany
| | - Anja Schwiebs
- Pharmazentrum frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Hospital of the Goethe University, 60590, Frankfurt/Main, Germany
| | - Heinfried H Radeke
- Pharmazentrum frankfurt/ZAFES, Institute of General Pharmacology and Toxicology, Hospital of the Goethe University, 60590, Frankfurt/Main, Germany
| | - Delia Muntean
- Department of Microbiology, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.
| | - Zorita Diaconeasa
- Department of Food Science and Technology, Faculty of Food Science and Technology, University of Agricultural Science and Veterinary Medicine, Calea Manastur, 3-5, 400372, Cluj-Napoca, Romania
| | - Daliana Minda
- Department of Pharmacognosy, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.,Research Center for Pharmaco-Toxicological Evaluation, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
| | - Camelia Oprean
- Department of Pharmacy I, Drug Analysis, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.,"Pius Brinzeu" Timişoara County Emergency Clinical Hospital, Oncogen Institute, 156 Liviu Rebreanu, 300723, Timişoara, Romania.,Advanced Instrumental Screening Center, Faculty of Pharmacy, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
| | - Florina Bojin
- "Pius Brinzeu" Timişoara County Emergency Clinical Hospital, Oncogen Institute, 156 Liviu Rebreanu, 300723, Timişoara, Romania.,Department of Functional Sciences, Faculty of Medicine, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
| | - Cristina Adriana Dehelean
- Research Center for Pharmaco-Toxicological Evaluation, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.,Department of Toxicology, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
| | - Codruta Soica
- Research Center for Pharmaco-Toxicological Evaluation, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.,Department of Pharmaceutical Chemistry, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
| | - Corina Danciu
- Department of Pharmacognosy, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania.,Research Center for Pharmaco-Toxicological Evaluation, "Victor Babeș" University of Medicine and Pharmacy Timișoara, Romania, Eftimie Murgu Sq. no. 2, 300041, Timișoara, Romania
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19
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Shoaib S, Islam N, Yusuf N. Phytocompounds from the medicinal and dietary plants: Multi-target agents for cancer prevention and therapy. Curr Med Chem 2022; 29:4481-4506. [PMID: 35232338 DOI: 10.2174/0929867329666220301114251] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/15/2021] [Accepted: 12/10/2021] [Indexed: 11/22/2022]
Abstract
Cervical cancer is the fourth leading cause of cancer death among women worldwide. Due to cervical cancer's high incidence and mortality, there is an unmet demand for effective diagnostic, therapeutic, and preventive agents. At present, the preferred treatment strategies for advanced metastatic cervical cancer include surgery, radiotherapy, and chemotherapy. However, cervical cancer is gradually developing resistance to chemotherapy, thereby reducing its efficacy. Over the last several decades, phytochemicals, a general term for compounds produced from plants, have gained attention for their role in preventing cervical cancer. This role in cervical cancer prevention has garnered attention on the medicinal properties of fruits and vegetables. Phytochemicals are currently being evaluated for their ability to block proteins involved in carcinogenesis and chemoresistance against cervical cancer. Chemoresistance to cancer drugs like cisplatin, doxorubicin, and 5-fluorouracil has become a significant limitation of drug-based chemotherapy. However, the combination of cisplatin with other phytochemicals has been identified as a promising alternative to subjugate cisplatin resistance. Phytochemicals are promising chemo-preventive and chemotherapeutic agents as they possess antioxidant, anti-inflammatory, and anti-proliferative potential against many cancers, including cervical cancer. Furthermore, the ability of the phytochemicals to modulate cellular signaling pathways through up and down regulation of various proteins has been claimed for their therapeutic potential. Phytochemicals also display a wide range of biological functions, including cell cycle arrest, apoptosis induction, inhibition of invasion, and migration in cervical cancer cells. Numerous studies have revealed the critical role of different signaling proteins and their signaling pathways in the pathogenesis of cervical cancer. Here, we review the ability of several dietary phytochemicals to alter carcinogenesis by modulating various molecular targets.
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Affiliation(s)
- Shoaib Shoaib
- Department of Biochemistry, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, India
| | - Najmul Islam
- Department of Biochemistry, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, India
| | - Nabiha Yusuf
- Department of Dermatology, University of Alabama at Birmingham, Birmingham AL 35294, United States
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20
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Bose D, Chaudhary A, Padmavati M, Chatterjee J, Banerjee R. In vitro evaluation of anti-proliferative activity of protein from Litchi chinensis honey against human cervical cancer cell line (HeLa). J Herb Med 2022. [DOI: 10.1016/j.hermed.2021.100518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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21
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Singh S, Srivastava PN, Meena A, Luqman S. Dietary flavonoid narirutin as a prospective antagonist of oncogenic pri/pre-microRNAs. Phytother Res 2022; 36:963-983. [PMID: 35040205 DOI: 10.1002/ptr.7367] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 12/02/2021] [Accepted: 12/11/2021] [Indexed: 12/13/2022]
Abstract
MicroRNAs (miRNAs) are involved in cancer progression via translational degradation in a sequence-specific manner of the 3'-untranslated region (3'UTR) of messenger RNA (mRNA). The involvement of miRNA in the biological progression of various cancer types is considered to be a potential target. Primary miRNA (pri-miRNA) and precursor-miRNA (pre-miRNA) synthesize the miRNA by dicer-catalyzed processes thus targeting pri/pre-miRNA by phytochemicals is amongst the appropriate approaches for anticancer therapies. Flavonoids category of phytochemicals is well-known for its chemotherapeutic and chemopreventive potential against multiple cancer types. However, the molecular interactions of flavonoids with miRNAs are not reported so far. Thus, this study aims to identify the promising flavonoids as the antagonist of miRNAs (pre-miR21, pri-miR-208a, pri-miR-378a, pri-miR320b, pri-miR-300, pri-miR-19b, and pre-miR-20b) using molecular docking simulations studies. Among the tested flavonoids, narirutin showed highest binding energy (-11.7 kcal/mol) against pri-miR19b followed by pri-miR-378a (-11.4 kcal/mol) > pri-miR320b (-11.2 kcal/mol) = pri-miR-300 (-11.2 kcal/mol) > pri-miR-208a (-9.0 kcal/mol) > pre-miR-20b (- 8.3 kcal/mol). The molecular dynamic simulation experiment confirmed that narirutin destabilizes the tertiary structure of pri-miRNA in comparison to apo-RNA. The finding indicates that narirutin binding with pre-miRNA causes disruption of pri-RNA structure that creates a loss of DICER-pre-miRNA interactions by hindering the pre-miRNA synthesis, thereby affecting miRNA processing. Further pharmacokinetics and toxicity prediction revealed that it is non-carcinogenic, non-mutagenic, and does not inhibit the CYPs activity. Thus, narirutin could be a possible antagonist of oncogenic miRNAs, therefore could be useful for miRNA-targeted cancer prevention and treatment.
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Affiliation(s)
- Shilpi Singh
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Pratik Narain Srivastava
- Molecular Microbiology and Immunology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, India
| | - Abha Meena
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Suaib Luqman
- Bioprospection and Product Development Division, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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22
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Pawłowska A, Stepczyńska M. Natural Biocidal Compounds of Plant Origin as Biodegradable Materials Modifiers. JOURNAL OF POLYMERS AND THE ENVIRONMENT 2022; 30:1683-1708. [PMID: 34720776 PMCID: PMC8541817 DOI: 10.1007/s10924-021-02315-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/15/2021] [Indexed: 05/07/2023]
Abstract
The article presents a literature review of the plant origin natural compounds with biocidal properties. These compounds could be used as modifiers of biodegradable materials. Modification of polymer material is one of the basic steps in its manufacturing process. Biodegradable materials play a key role in the current development of materials engineering. Natural modifiers are non-toxic, environmentally friendly, and renewable. The substances contained in natural modifiers exhibit biocidal properties against bacteria and/or fungi. The article discusses polyphenols, selected phenols, naphthoquinones, triterpenoids, and phytoncides that are natural antibiotics. Due to the increasing demand for biodegradable materials and the protection of the natural environment against the negative effects of toxic substances, it is crucial to replace synthetic modifiers with plant ones. This work mentions industries where materials containing natural modifying additives could find potential applications. Moreover, the probable examples of the final products are presented. Additionally, the article points out the current world's pandemic state and the use of materials with biocidal properties considering the epidemiological conditions.
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Affiliation(s)
- Alona Pawłowska
- Department of Materials Engineering, Kazimierz Wielki University, J.K. Chodkiewicza 30 street, 85-064 Bydgoszcz, Poland
| | - Magdalena Stepczyńska
- Department of Materials Engineering, Kazimierz Wielki University, J.K. Chodkiewicza 30 street, 85-064 Bydgoszcz, Poland
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23
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Manogaran P, Somasundaram B, Viswanadha VP. Reversal of cisplatin resistance by neferine/isoliensinine and their combinatorial regimens with cisplatin-induced apoptosis in cisplatin-resistant colon cancer stem cells (CSCs). J Biochem Mol Toxicol 2021; 36:e22967. [PMID: 34921482 DOI: 10.1002/jbt.22967] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 08/24/2021] [Accepted: 10/18/2021] [Indexed: 12/28/2022]
Abstract
Cisplatin chemotherapy to the colorectal cancer cells (CRCs) is accompanied by dose-limiting adverse effects along with the acquisition of drug resistance implicating low therapeutic outcomes. The present study is aimed to evaluate the chemosensitizing efficacy of neferine/isoliensinine or combinatorial regimen of neferine/isoliensinine with cisplatin against CSCs (cisplatin resistant colon stem cells). CSCs were developed using pulse exposure of cisplatin to parental HCT-15 cells. Neferine/isoliensinine or combinatorial regimens of Neferine/isoliensinine and cisplatin exhibited a stronger cytotoxic activity against CSCs compared to control. IC50 doses were found to be 6.5 μM for neferine, 12.5 μM for isoliensinine, and 120 μM for cisplatin respectively. Furthermore, the combinatorial regimen of a low dose of cisplatin (40 μM) with 4 μM neferine/8 μM isoliensinine induced cell death in a synergistic manner as described by isobologram. Neferine/isoliensinine could confer extensive intracellular reactive oxygen species generation in CSCs. Neferine/isoliensinine or combinatorial regimens dissipated mitochondrial membrane potential and enhanced intracellular [Ca2+ ]i, which were measured by spectroflurimetry. Furthermore, these combinatorial regimens induced a significant increase in the sub G0 phase of cell cycle arrest and PI uptake and alleviated the expression of ERCC1 in CSCs. Combinatorial regimens or neferine/isoliensinine treatments downregulated the cell survival protein expression (PI3K/pAkt/mTOR) and activated mitochondria-mediated apoptosis by upregulating Bax, cytochrome c, caspase-3, and PARP cleavage expression while downregulating the BCl-2 expression in CSCs. Our study confirms the chemosensitizing efficacy of neferine/isoliensinine or combinatorial regimens of neferine/isoliensinine with a low dose of cisplatin against CSCs.
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Affiliation(s)
- Prasath Manogaran
- Translational Research Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | - Bharath Somasundaram
- Translational Research Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | - Vijaya Padma Viswanadha
- Translational Research Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu, India
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24
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Barathan M, Zulpa AK, Mee Hoong S, Vellasamy KM, Vadivelu J. Synergistic effect of hyperforin and paclitaxel on growth inhibition, apoptotic mediator activation in MCF-7 human breast cancer cells. JOURNAL OF TAIBAH UNIVERSITY FOR SCIENCE 2021. [DOI: 10.1080/16583655.2021.2010910] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Muttiah Barathan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Ahmad Khusairy Zulpa
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - See Mee Hoong
- Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kumutha Malar Vellasamy
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jamuna Vadivelu
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
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25
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Kang H, Sun Y, Hu X, Liu L. Gigantol inhibits proliferation and enhanced oxidative stress-mediated apoptosis through modulating of Wnt/β-catenin signaling pathway in HeLa cells. J Biochem Mol Toxicol 2021; 36:e22944. [PMID: 34729850 DOI: 10.1002/jbt.22944] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 08/10/2021] [Accepted: 10/18/2021] [Indexed: 11/07/2022]
Abstract
Cervical cancer is one of the leading malignant cancers that is the fourth prominent cause of malignancy-related mortality in women globally. There is a predominant validation to a beneficial target in Wnt/β-catenin signaling in cervical carcinogenesis as they are very much deregulated in cancer. Previous studies reported Gigantol (GG) showed suppressive properties on the Wnt/β-catenin pathway in other tumor cells, but no evidence is available regarding GG suppressing Wnt/β-catenin signaling cervical tumor cells. Hence, the current research was planned to examine the suppressive effects of GG on HeLa cells and investigate the mechanism of action. HeLa cells were treated by GG in various doses and then appraising cell viability, oxidant/antioxidant levels, ∆ѰM status, reactive oxygen species (ROS) generation, apoptosis, and cell proliferation via Wnt/β-catenin signaling. We observed that GG noticeably inhibits cell proliferation, increased ROS generation, lipid peroxidation, mitochondrial membrane depolarization (∆ѰM), and increased apoptotic morphological changes of nuclear fragmentation and condensation. Moreover, GG effectively enhances proapoptotic, decreased ∆ѰM and antioxidant amounts, and mitigated Wnt/β-catenin signaling. Concisely, these findings proved that activating apoptosis and suppression of cell proliferation in GG treated HeLa cells was documented by the alleviation of Wnt/β-catenin signaling. Therefore, this study suggested that GG might develop a therapeutic effect against cervical carcinogenesis.
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Affiliation(s)
- Huanan Kang
- Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Yiming Sun
- Department of Andrology, Heilongjiang Provincial Hospital of Traditional Chinese Medicine, Harbin, China
| | - Xijiao Hu
- Second Department of Gynecology, Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
| | - Li Liu
- Department of Hysteroscopy, First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, China
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Magura J, Hassan D, Moodley R, Mackraj I. Hesperidin-loaded nanoemulsions improve cytotoxicity, induce apoptosis, and downregulate miR-21 and miR-155 expression in MCF-7. J Microencapsul 2021; 38:486-495. [PMID: 34510994 DOI: 10.1080/02652048.2021.1979673] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Hesperidin, a ubiquitous plant-based flavanone, was encapsulated into nanoemulsions (HP-NEM) using a spontaneous emulsification method to improve its solubility and enhance bioavailability and efficacy in breast cancer treatment using MCF-7 cell lines. The cytotoxic and apoptotic effects of HP-NEM against MCF-7 and its impact on oncomiRs, microRNA-21, and microRNA-155 expression were also assessed. The optimised HP-NEM displayed a spherical shape with 305 ± 40.8 nm, 0.308 ± 0.04, and -11.6 ± 3.30 mV and 93 ± 0.45% for particle size, polydispersity index (PDI), zeta-potential (ζ), and encapsulation efficiency, respectively. Cytotoxicity studies using MTT assay showed selective toxicity of the HP-NEM against MCF-7 without affecting normal cells (HEK 293). Treatment with the HP-NEM induced cell death through apoptosis, cell cycle arrest in the G2/M phase, and downregulated miR-21 and miR-155 expression in MCF-7. This study supports the use of HP-NEM as a potential therapeutic agent in breast cancer treatment.
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Affiliation(s)
- Judie Magura
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Daniel Hassan
- Discipline of Pharmaceutical Sciences, University of KwaZulu-Natal, Durban, South Africa
| | - Roshila Moodley
- School of Chemistry and Physics, University of KwaZulu-Natal, Durban, South Africa
| | - Irene Mackraj
- Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
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Jones AA, Gehler S. Acacetin and Pinostrobin Inhibit Malignant Breast Epithelial Cell Adhesion and Focal Adhesion Formation to Attenuate Cell Migration. Integr Cancer Ther 2021; 19:1534735420918945. [PMID: 32493139 PMCID: PMC7273556 DOI: 10.1177/1534735420918945] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Naturally occurring flavonoids, such as acacetin and pinostrobin, disrupt a wide
range of processes during tumor progression, such as cell proliferation,
apoptosis, and angiogenesis. Although the antiproliferative and antiapoptotic
effects of acacetin and pinostrobin have been studied using various cell lines,
relatively little is known about the effects of acacetin and pinostrobin on
cancer cell migration and metastasis. For instance, it is unclear whether
acacetin or pinostrobin have any effect on breast cancer cell migration or
adhesion. In this study, we assessed the effects of acacetin and pinostrobin on
malignant MDA-MB-231 and T47D breast epithelial cells and non-tumorigenic MCF10A
breast epithelial cells. Our results demonstrate that both acacetin and
pinostrobin selectively inhibit the migration of both MDA-MB-231 and T47D cells
in a dose-dependent manner while exhibiting blunted effects on MCF10A cells.
Interestingly, neither compound had an effect on cell proliferation in any of
the 3 cell lines. Furthermore, both acacetin and pinostrobin inhibit MDA-MB-231
and T47D cell adhesion, cell spreading, and focal adhesion formation, but have
no significant effect on MCF10A cells. Collectively, these results suggest that
both acacetin and pinostrobin selectively inhibit malignant breast epithelial
cell migration through attenuation of cell adhesion and focal adhesion
formation. These findings indicate that both acacetin and pinostrobin may serve
as potential therapeutic options to target breast tumor cell migration during
late-stage tumor progression.
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28
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Shoaib S, Tufail S, Sherwani MA, Yusuf N, Islam N. Phenethyl Isothiocyanate Induces Apoptosis Through ROS Generation and Caspase-3 Activation in Cervical Cancer Cells. Front Pharmacol 2021; 12:673103. [PMID: 34393773 PMCID: PMC8358204 DOI: 10.3389/fphar.2021.673103] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 06/14/2021] [Indexed: 01/19/2023] Open
Abstract
The latest research shows that current chemotherapeutics are ineffective because of the development of resistance in cervical cancer cells, and hence, their scope of use is limited. The main concern of researchers at the moment is the discovery of safe and effective antiproliferative plant chemicals that can aid in the battle against cervical cancer. Previous studies have shown the possible anticancer potential of phenethyl isothiocyanate obtained from cruciferous plants for many cancers, which targets various signaling pathways to exercise chemopreventive and therapeutic effects. This provides the basis for studying phenethyl isothiocyanate's therapeutic potential against cervical cancer. In the present study, cervical cancer cells were treated with various doses of phenethyl isothiocyanate, alone and in combination with cisplatin. Phenethyl isothiocyanate alone was sufficient to cause nucleus condensation and fragmentation and induce apoptosis in cervical cancer cells, but evident synergistic effects were observed in combination with cisplatin. In addition, phenethyl isothiocyanate treatment increased the production of intracellular ROS in a dose-dependent manner in cervical cancer cells. Furthermore, investigation of phenethyl isothiocyanate induced mitochondrial reactive oxygen species production, and activation of caspases showed that phenethyl isothiocyanate significantly activated caspase-3.
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Affiliation(s)
- Shoaib Shoaib
- Department of Biochemistry, J.N.M.C, Aligarh Muslim University, Aligarh, India
| | - Saba Tufail
- Department of Biochemistry, J.N.M.C, Aligarh Muslim University, Aligarh, India
| | - Mohammad Asif Sherwani
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Nabiha Yusuf
- Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Najmul Islam
- Department of Biochemistry, J.N.M.C, Aligarh Muslim University, Aligarh, India
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29
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Bo S, Lai J, Lin H, Luo X, Zeng Y, Du T. Purpurin, a anthraquinone induces ROS-mediated A549 lung cancer cell apoptosis via inhibition of PI3K/AKT and proliferation. J Pharm Pharmacol 2021; 73:1101-1108. [PMID: 33877317 DOI: 10.1093/jpp/rgab056] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 03/13/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVES In this study, we sought to evaluate purpurin, a natural biomedicine and a potential inhibitor in decreasing the growth rate of lung cancer cells by modulating the role of PI3K/AKT signalling-associated proliferation and apoptosis. METHODS A549 cells were treated with purpurin (30 μM) for 24 and 48 h incubation, respectively, and it has been analysed for cytotoxicity, ROS-mediated apoptotic staining. Moreover, purpurin-mediated lipid peroxidation and GSH were measured by biochemical estimation. Furthermore, PI3K/AKT signalling-mediated cell proliferation and apoptotic gene expression done were by western blot. KEY FINDINGS In this study, we observed that purpurin could effectively kill A549 cancer cell lines and leads to cell death, thus conforming increased cytotoxicity, production of ROS-mediated enhancement of lipid peroxidation, nuclear fragmentation and apoptosis. Moreover, the GSH content of A549 cell lines was also diminished after treatment with purpurin. This study demonstrates that purpurin inhibits the phosphorylated PI3K/AKT molecules mediated cyclin-D1 and PCNA, thereby inducing apoptosis by observing increased proapoptotic mediators Bax, cleaved PARP, cytochrome-c, caspase-9 and caspase-3; and decreased Bcl-2 expression in the lung cancer cell lines. CONCLUSION This result concluded that purpurin eliminates the A549 lung cancer cells by blocking the PI3K/AKT pathway thereby inducing apoptosis.
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Affiliation(s)
- Su Bo
- Department of Cardiothoracic Surgery, Xiangyang No. 1 People's Hospital, Hubei University of Medicine, Xiangyang, Hubei 441000, China
| | - Jing Lai
- Nursing Department, The First People's Hospital of Longquanyi District, Chengdu, Sichuan 610100, China
| | - Honyu Lin
- The Third Affiliated Teaching Hospital of Xinjiang Medical University (Affiliated Cancer Hospital), Urumqi, Xinjiang 830011, China
| | - Xue Luo
- Nursing Department, The First People's Hospital of Longquanyi District, Chengdu, Sichuan 610100, China
| | - Yiqiong Zeng
- Nursing Department, The First People's Hospital of Longquanyi District, Chengdu, Sichuan 610100, China
| | - Tianying Du
- Department of Thoracic Oncology, Jilin Cancer Hospital, Jilin, Changchun 130000, China
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Current Perspectives on the Beneficial Effects of Soybean Isoflavones and Their Metabolites for Humans. Antioxidants (Basel) 2021; 10:antiox10071064. [PMID: 34209224 PMCID: PMC8301030 DOI: 10.3390/antiox10071064] [Citation(s) in RCA: 126] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 06/27/2021] [Accepted: 06/28/2021] [Indexed: 12/13/2022] Open
Abstract
Soybeans are rich in proteins and lipids and have become a staple part of the human diet. Besides their nutritional excellence, they have also been shown to contain various functional components, including isoflavones, and have consequently received increasing attention as a functional food item. Isoflavones are structurally similar to 17-β-estradiol and bind to estrogen receptors (ERα and ERβ). The estrogenic activity of isoflavones ranges from a hundredth to a thousandth of that of estrogen itself. Isoflavones play a role in regulating the effects of estrogen in the human body, depending on the situation. Thus, when estrogen is insufficient, isoflavones perform the functions of estrogen, and when estrogen is excessive, isoflavones block the estrogen receptors to which estrogen binds, thus acting as an estrogen antagonist. In particular, estrogen antagonistic activity is important in the breast, endometrium, and prostate, and such antagonistic activity suppresses cancer occurrence. Genistein, an isoflavone, has cancer-suppressing effects on estrogen receptor-positive (ER+) cancers, including breast cancer. It suppresses the function of enzymes such as tyrosine protein kinase, mitogen-activated kinase, and DNA polymerase II, thus inhibiting cell proliferation and inducing apoptosis. Genistein is the most biologically active and potent isoflavone candidate for cancer prevention. Furthermore, among the various physiological functions of isoflavones, they are best known for their antioxidant activities. S-Equol, a metabolite of genistein and daidzein, has strong antioxidative effects; however, the ability to metabolize daidzein into S-equol varies based on racial and individual differences. The antioxidant activity of isoflavones may be effective in preventing dementia by inhibiting the phosphorylation of Alzheimer's-related tau proteins. Genistein also reduces allergic responses by limiting the expression of mast cell IgE receptors, which are involved in allergic responses. In addition, they have been known to prevent and treat various diseases, including cardiovascular diseases, metabolic syndromes, osteoporosis, diabetes, brain-related diseases, high blood pressure, hyperlipidemia, obesity, and inflammation. Further, it also has positive effects on menstrual irregularity in non-menopausal women and relieving menopausal symptoms in middle-aged women. Recently, soybean consumption has shown steep increasing trend in Western countries where the intake was previously only 1/20-1/50 of that in Asian countries. In this review, I have dealt with the latest research trends that have shown substantial interest in the biological efficacy of isoflavones in humans and plants, and their related mechanisms.
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Udomwan P, Pientong C, Tongchai P, Burassakarn A, Sunthamala N, Roytrakul S, Suebsasana S, Ekalaksananan T. Proteomics Analysis of Andrographolide-Induced Apoptosis via the Regulation of Tumor Suppressor p53 Proteolysis in Cervical Cancer-Derived Human Papillomavirus 16-Positive Cell Lines. Int J Mol Sci 2021; 22:ijms22136806. [PMID: 34202736 PMCID: PMC8268713 DOI: 10.3390/ijms22136806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/22/2021] [Accepted: 06/22/2021] [Indexed: 12/22/2022] Open
Abstract
Regardless of the prophylactic vaccine accessibility, persistent infections of high-risk human papillomaviruses (hr-HPVs), recognized as an etiology of cervical cancers, continues to represent a major health problem for the world population. An overexpression of viral early protein 6 (E6) is linked to carcinogenesis. E6 induces anti-apoptosis by degrading tumor suppressor proteins p53 (p53) via E6-E6-associated protein (E6AP)-mediated polyubiquitination. Thus, the restoration of apoptosis by interfering with the E6 function has been proposed as a selective medicinal strategy. This study aimed to determine the activities of andrographolide (Androg) on the disturbance of E6-mediated p53 degradation in cervical cancer cell lines using a proteomic approach. These results demonstrated that Androg could restore the intracellular p53 level, leading to apoptosis-induced cell death in HPV16-positive cervical cancer cell lines, SiHa and CaSki. Mechanistically, the anti-tumor activity of Androg essentially relied on the reduction in host cell proteins, which are associated with ubiquitin-mediated proteolysis pathways, particularly HERC4 and SMURF2. They are gradually suppressed in Androg-treated HPV16-positive cervical cancer cells. Collectively, the restoration of p53 in HPV16-positive cervical cancer cells might be achieved by disruption of E3 ubiquitin ligase activity by Androg, which could be an alternative treatment for HPV-associated epithelial lesions.
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Affiliation(s)
- Pariyakorn Udomwan
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.U.); (C.P.); (P.T.); (A.B.)
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Chamsai Pientong
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.U.); (C.P.); (P.T.); (A.B.)
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Panwad Tongchai
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.U.); (C.P.); (P.T.); (A.B.)
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Ati Burassakarn
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.U.); (C.P.); (P.T.); (A.B.)
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen 40002, Thailand;
| | - Nuchsupha Sunthamala
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen 40002, Thailand;
- Department of Biology, Faculty of Science, Mahasarakham University, Mahasarakham 44150, Thailand
| | - Sittiruk Roytrakul
- Functional Ingredients and Food Innovation Research Group, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani 12120, Thailand;
| | - Supawadee Suebsasana
- Faculty of Pharmacy, Thammasat University (Rangsit campus), Pathum Thani 12120, Thailand;
| | - Tipaya Ekalaksananan
- Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; (P.U.); (C.P.); (P.T.); (A.B.)
- HPV & EBV and Carcinogenesis Research (HEC) Group, Khon Kaen University, Khon Kaen 40002, Thailand;
- Correspondence: ; Tel./Fax: +66-4334-8385
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32
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Ghaffari T, Hong JH, Asnaashari S, Farajnia S, Delazar A, Hamishehkar H, Kim KH. Natural Phytochemicals Derived from Gymnosperms in the Prevention and Treatment of Cancers. Int J Mol Sci 2021; 22:6636. [PMID: 34205739 PMCID: PMC8234227 DOI: 10.3390/ijms22126636] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/16/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
The incidence of various types of cancer is increasing globally. To reduce the critical side effects of cancer chemotherapy, naturally derived compounds have been considered for cancer treatment. Gymnosperms are a group of plants found worldwide that have traditionally been used for therapeutic applications. Paclitaxel is a commercially available anticancer drug derived from gymnosperms. Other natural compounds with anticancer activities, such as pinostrobin and pinocembrin, are extracted from pine heartwood, and pycnogenol and enzogenol from pine bark. Gymnosperms have great potential for further study for the discovery of new anticancer compounds. This review aims to provide a rational understanding and the latest developments in potential anticancer compounds derived from gymnosperms.
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Affiliation(s)
- Tayyebeh Ghaffari
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 15731, Iran; (T.G.); (S.F.)
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz 15731, Iran
| | - Joo-Hyun Hong
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea;
| | - Solmaz Asnaashari
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz 15731, Iran;
| | - Safar Farajnia
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 15731, Iran; (T.G.); (S.F.)
| | - Abbas Delazar
- Research Center for Evidence based Medicine, Tabriz University of Medical Sciences, Tabriz 15731, Iran;
| | - Hamed Hamishehkar
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz 15731, Iran; (T.G.); (S.F.)
| | - Ki-Hyun Kim
- School of Pharmacy, Sungkyunkwan University, Suwon 16419, Korea;
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M R, Jose SP, IM K, S S, Saji S, S S. Curcumin-Galactomannoside Complex inhibits the Proliferation of Human Cervical Cancer Cells: Possible Role in Cell Cycle Arrest and Apoptosis. Asian Pac J Cancer Prev 2021; 22:1713-1720. [PMID: 34181325 PMCID: PMC8418838 DOI: 10.31557/apjcp.2021.22.6.1713] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 06/03/2021] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Cervical cancer is the most common cancer and has the highest morbidity rate of gynaecological malignancies in women worldwide. So, the development of effective anti-cancer agents to treat this condition is vital. Considering the recent interest in free (unconjugated) curcuminoids delivery, the present study investigated the efficacy of a novel food-grade, free-curcuminoids (curcumin-galactomannoside complex; CGM) on cervical cancer cells (HeLa) of human origin. In this study, we examined the anticancer potential of CGM as well as its effects on the cell cycle and the apoptosis of HeLa cancer cell. METHODS Determination of anti-proliferative and apoptosis validation of CGM on HeLa cells was performed by 3-(4,5-Dimethylthiazol-2-yl)-2, 5,-diphenyltetrazolium bromide (MTT), acridine orange/propidium iodide and annexin-V-fluorescein isothiocyanate assays. Measurement of Reactive Oxygen Species (ROS) production, Caspase activities and protein expression experiments were performed to investigate the potential mechanisms of action in the apoptotic process. RESULTS The cytotoxic assays revealed that the CGM showed inhibition of cell survival and exhibited high cytotoxic activity against HeLa cells at 25 μg/mL. Further studies on morphological changes were done in CGM-treated cervical cancer cells contributing to apoptosis. Flow cytometry analysis with Annexin V-FITC and PI staining precisely indicated that CGM induced apoptosis in HeLa cell lines at 25 μg/mL. By the supplementation of CGM showed an increase in Bax and cleaved caspase-8 protein in HeLa cells after 48 h exposure. CONCLUSION The evidence obtained from this study suggests that CGM is a potent and promising natural formulation against cervical cancer cells via induction of apoptosis through ROS mediated mitochondrial damage in HeLa cells. Hence, CGM could be further explored as a potential lead in treating cancer.
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Affiliation(s)
- Ratheesh M
- Department of Biochemistry, St. Thomas College, Pala, Kottayam, Kerala, India.
| | - Svenia P Jose
- Department of Biochemistry, St. Thomas College, Pala, Kottayam, Kerala, India.
| | - Krishnakumar IM
- R & D Center, Akay Natural Ingredients Pvt.Ltd, Cochin, India.
| | - Sandya S
- Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, Karnataka, India.
| | - Sangeeth Saji
- Department of Biochemistry, St. Thomas College, Pala, Kottayam, Kerala, India.
| | - Sheethal S
- Department of Biochemistry, St. Thomas College, Pala, Kottayam, Kerala, India.
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Michalkova R, Mirossay L, Gazdova M, Kello M, Mojzis J. Molecular Mechanisms of Antiproliferative Effects of Natural Chalcones. Cancers (Basel) 2021; 13:cancers13112730. [PMID: 34073042 PMCID: PMC8198114 DOI: 10.3390/cancers13112730] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/20/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Despite the important progress in cancer treatment in the past decades, the mortality rates in some types of cancer have not significantly decreased. Therefore, the search for novel anticancer drugs has become a topic of great interest. Chalcones, precursors of flavonoid synthesis in plants, have been documented as natural compounds with pleiotropic biological effects including antiproliferative/anticancer activity. This article focuses on the knowledge on molecular mechanisms of antiproliferative action of chalcones and draws attention to this group of natural compounds that may be of importance in the treatment of cancer disease. Abstract Although great progress has been made in the treatment of cancer, the search for new promising molecules with antitumor activity is still one of the greatest challenges in the fight against cancer due to the increasing number of new cases each year. Chalcones (1,3-diphenyl-2-propen-1-one), the precursors of flavonoid synthesis in higher plants, possess a wide spectrum of biological activities including antimicrobial, anti-inflammatory, antioxidant, and anticancer. A plethora of molecular mechanisms of action have been documented, including induction of apoptosis, autophagy, or other types of cell death, cell cycle changes, and modulation of several signaling pathways associated with cell survival or death. In addition, blockade of several steps of angiogenesis and proteasome inhibition has also been documented. This review summarizes the basic molecular mechanisms related to the antiproliferative effects of chalcones, focusing on research articles from the years January 2015–February 2021.
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Sharma J, Pandey A, Sharma S, Dixit A. Securinine Induces Differentiation of Human Promyelocytic Leukemic HL-60 Cells through JNK-Mediated Signaling Pathway. Nutr Cancer 2021; 74:1122-1137. [PMID: 33998358 DOI: 10.1080/01635581.2021.1925710] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Acute myeloid leukemia is characterized by abnormal differentiation of hematopoietic stem cells, leading to the accumulation of immature myeloid cells. Differentiation therapy has been a successful treatment option for acute promyelocytic leukemia but suffers from adverse effects. Therefore, search for novel differentiation-inducing agents with minimal side effects is desirable. Securinine, a naturally-occurring alkaloid, induces differentiation in various leukemic cells and apoptosis in other types of cancers. However, the underlying molecular mechanism(s) remain elusive. Our study aimed to elucidate the possible molecular mechanism(s) and signaling events involved in securinine-induced differentiation of HL-60 cells. Securinine inhibited proliferation in a time- and dose-dependent manner and triggered differentiation. A higher CD14+ population indicated maturation toward monocytic lineage. Securinine caused cell cycle arrest at the G0/G1 phase and enhanced ROS generation. Quantitative gene expression analysis showed significant down-regulation of C/EBP-α, C/EBP-ε, GAΤΑ, and c-myc and up-regulation of the PU.1 gene. The expression of distinct protein kinases Lyn, Chk-2, Yes, FAK, c-Jun, and JNK were enhanced. Use of specific inhibitors of crucial intracellular signaling proteins indicated that JNK and ERK blockade resulted in a significant decline in differentiation. These data thus confirm that securinine induces differentiation through the activation of the JNK-ERK signaling pathway in HL-60 cells.
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Affiliation(s)
- Jeetesh Sharma
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Ankita Pandey
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Sapna Sharma
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Aparna Dixit
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
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Bhosale PB, Vetrivel P, Ha SE, Kim HH, Heo JD, Won CK, Kim SM, Kim GS. Iridin Induces G2/M Phase Cell Cycle Arrest and Extrinsic Apoptotic Cell Death through PI3K/AKT Signaling Pathway in AGS Gastric Cancer Cells. Molecules 2021; 26:2802. [PMID: 34068568 PMCID: PMC8126061 DOI: 10.3390/molecules26092802] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 01/03/2023] Open
Abstract
Iridin is a natural flavonoid found in Belamcanda chinensis documented for its broad spectrum of biological activities like antioxidant, antitumor, and antiproliferative effects. In the present study, we have investigated the antitumor potential of iridin in AGS gastric cancer cells. Iridin treatment decreases AGS cell growth and promotes G2/M phase cell cycle arrest by attenuating the expression of Cdc25C, CDK1, and Cyclin B1 proteins. Iridin-treatment also triggered apoptotic cell death in AGS cells, which was verified by cleaved Caspase-3 (Cl- Caspase-3) and poly ADP-ribose polymerase (PARP) protein expression. Further apoptotic cell death was confirmed by increased apoptotic cell death fraction shown in allophycocyanin (APC)/Annexin V and propidium iodide staining. Iridin also increased the expression of extrinsic apoptotic pathway proteins like Fas, FasL, and cleaved Caspase-8 in AGS cells. On the contrary, iridin-treated AGS cells did not show variations in proteins related to an intrinsic apoptotic pathway such as Bax and Bcl-xL. Besides, Iridin showed inhibition of PI3K/AKT signaling pathways by downregulation of (p-PI3K, p-AKT) proteins in AGS cells. In conclusion, these data suggest that iridin has anticancer potential by inhibiting PI3K/AKT pathway. It could be a basis for further drug design in gastric cancer treatment.
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Affiliation(s)
- Pritam-Bhagwan Bhosale
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (P.-B.B.); (P.V.); (S.-E.H.); (H.-H.K.); (C.-K.W.)
| | - Preethi Vetrivel
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (P.-B.B.); (P.V.); (S.-E.H.); (H.-H.K.); (C.-K.W.)
| | - Sang-Eun Ha
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (P.-B.B.); (P.V.); (S.-E.H.); (H.-H.K.); (C.-K.W.)
| | - Hun-Hwan Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (P.-B.B.); (P.V.); (S.-E.H.); (H.-H.K.); (C.-K.W.)
| | - Jeong-Doo Heo
- Biological Resources Research Group, Bioenvironmental Science & Toxicology Division, Korea Institute of Toxicology (KIT), 17 Jeigok-gil, Jinju 52834, Korea;
| | - Chung-Kil Won
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (P.-B.B.); (P.V.); (S.-E.H.); (H.-H.K.); (C.-K.W.)
| | - Seong-Min Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (P.-B.B.); (P.V.); (S.-E.H.); (H.-H.K.); (C.-K.W.)
| | - Gon-Sup Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Gazwa, Jinju 52828, Korea; (P.-B.B.); (P.V.); (S.-E.H.); (H.-H.K.); (C.-K.W.)
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Kotawong K, Chajaroenkul W, Roytrakul S, Phaonakrop N, Na-Bangchang K. The Proteomics and Metabolomics Analysis for Screening the Molecular Targets of Action of β-Eudesmol in Cholangiocarcinoma. Asian Pac J Cancer Prev 2021; 22:909-918. [PMID: 33773557 PMCID: PMC8286696 DOI: 10.31557/apjcp.2021.22.3.909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE β-eudesmol is the active compound isolated from Atractylodes lancea (Thunb) D.C. The actions of this compound against cholangiocarcinoma (CCA) cells include anti-angiogenesis and anti-cell proliferation and growth. For more understanding of the molecular targets of action of β-eudesmol, the CCA cells (CL-6) were exposed to β-eudesmol for 24 and 48 hours. METHODS Proteins and metabolites from the intra- and extra-cellular components of the CL-6 cells were extracted and identified by LC-MS/MS. Protein analysis was performed using the Venn diagram (protein grouping), PANTHER (gene ontology), and STITCH software (protein-protein interaction). Metabolite analysis including their interactions with proteins, was performed using MetaboAnalyst software. RESULTS The analysis showed that the actions of β-eudesmol were associated with various biological processes particularly apoptosis and cell cycle. These included blood coagulation, wound healing, DNA repair, PI3K-Akt signaling pathway, immune system process, MAPK cascade, urea cycle, purine metabolism, ammonia recycling, and methionine metabolism. CONCLUSION Possible molecular targets of action of β-eudesmol against CL-6 for cell apoptosis induction were TNFRSf6, cytochrome C, BAX3, DHCR24, CD29, and ATP. On the other hand, possible targets for cell cycle arrest induction were CDKN2B, MLF1, TFDP2, CDK11-p110, and nicotinamide.
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Affiliation(s)
- Kanawut Kotawong
- Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klonglung, Pathumthani Thailand
| | - Wanna Chajaroenkul
- Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klonglung, Pathumthani Thailand.,Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Paholyothin Road, Klonglung, Pathumthani Thailand
| | - Sittiruk Roytrakul
- Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand
| | - Narumon Phaonakrop
- Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand
| | - Kesara Na-Bangchang
- Graduate Program in Bioclinical Sciences, Chulabhorn International College of Medicine, Thammasat University, Paholyothin Road, Klonglung, Pathumthani Thailand.,Center of Excellence in Pharmacology and Molecular Biology of Malaria and Cholangiocarcinoma, Thammasat University, Paholyothin Road, Klonglung, Pathumthani Thailand
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Sun X, Liu X, Chen S. The Pharmacokinetics, Tissue Distribution, Metabolism, and Excretion of Pinostrobin in Rats: Ultra-High-Performance Liquid Chromatography Coupled With Linear Trap Quadrupole Orbitrap Mass Spectrometry Studies. Front Pharmacol 2020; 11:574638. [PMID: 33324207 PMCID: PMC7725875 DOI: 10.3389/fphar.2020.574638] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 10/21/2020] [Indexed: 11/25/2022] Open
Abstract
Pinostrobin is a natural flavonoid found in various plants, well known for its wide range of pharmacological activities. However, there are few reports regarding the pharmacokinetics, tissue distribution, metabolism, and excretion of pinostrobin in rats after oral administration as a single compound. Therefore, we established a method using ultra-high-performance liquid chromatography coupled with linear trap quadrupole orbitrap mass spectrometry (UPLC-LTQ orbitrap-MS/MS) to determine pinostrobin and its metabolites in rat plasma, urine, feces, bile, and tissue homogenates. Pharmacokinetic parameters were measured. The large apparent volume of distribution implied that pinostrobin preferentially bound to tissues and preferably remained within the body. Based on previous pharmacological studies of its antiulcer, anti-HP, anti-inflammatory, and antioxidant activities, pinostrobin is mostly distributed in the gastrointestinal tract, indicating its potential as an effective component of traditional Chinese medicines for the treatment of peptic ulcers. Furthermore, 30 flavonoid metabolites were screened using UPLC-LTQ orbitrap-MS/MS. The metabolism pathways (mainly hydroxylation, demethylation, glucuronidation, and sulfation) of pinostrobin in rats have also been proposed. A small amount of pinostrobin in its parent form is excreted through the urine, feces, and bile, indicating that it is mainly metabolized in vivo. In this study, we systemically investigated the pharmacokinetics, tissue distribution, metabolism, and excretion of pinostrobin in rats. Our results provide a significant basis for the clinical development and application of pinostrobin as well as traditional Chinese medicines containing pinostrobin.
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Affiliation(s)
- Xiaoya Sun
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China.,Collaborative Innovation Center for Respiratory Disease Diagnosis and Treatment & Chinese Medicine Development of Henan Province, Henan University of Chinese Medicine, Zhengzhou, China
| | - Xiaojun Liu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Suiqing Chen
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China.,Collaborative Innovation Center for Respiratory Disease Diagnosis and Treatment & Chinese Medicine Development of Henan Province, Henan University of Chinese Medicine, Zhengzhou, China
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Kis B, Avram S, Pavel IZ, Lombrea A, Buda V, Dehelean CA, Soica C, Yerer MB, Bojin F, Folescu R, Danciu C. Recent Advances Regarding the Phytochemical and Therapeutic Uses of Populus nigra L. Buds. PLANTS 2020; 9:plants9111464. [PMID: 33138272 PMCID: PMC7693997 DOI: 10.3390/plants9111464] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/16/2020] [Accepted: 10/22/2020] [Indexed: 12/14/2022]
Abstract
Populus nigra L. (Salicaceae family) is one of the most popular trees that can be found in deciduous forests. Some particularities that characterize the Populus genus refer to the fact that it includes more than 40 species, being widespread especially in Europe and Asia. Many residues, parts of this tree can be used as a bioresource for different extracts as active ingredients in pharmaceuticals next to multiple benefits in many areas of medicine. The present review discusses the latest findings regarding the phytochemical composition and the therapeutic properties of Populus nigra L. buds. The vegetal product has been described mainly to contain phenolic compounds (phenols, phenolic acids and phenylpropanoids), terpenoids (mono and sesquiterpenoids), flavones (e.g., apigenol and crysin), flavanones (e.g., pinocembrin and pinostrombin), caffeic/ferulic acids and their derivates, and more than 48 phytocompounds in the essential oils. The resinous exudates present on the buds have been the major plant source used by bees to form propolis. Several studies depicted its antioxidant, anti-inflammatory, antibacterial, antifungal, antidiabetic, antitumor, hepatoprotective, hypouricemic properties and its effects on melanin production. All these lead to the conclusion that black poplar buds are a valuable and important source of bioactive compounds responsible for a wide range of therapeutic uses, being a promising candidate as a complementary and/or alternative source for a large number of health problems. The aim of the review is to gather the existing information and to bring an up to date regarding the phytochemical and therapeutic uses of Populus nigra L. buds.
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Affiliation(s)
- Brigitta Kis
- Department of Pharmacognosy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No.2, 300041 Timisoara, Romania; (B.K.); (S.A.); (I.Z.P.); (A.L.); (C.D.)
| | - Stefana Avram
- Department of Pharmacognosy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No.2, 300041 Timisoara, Romania; (B.K.); (S.A.); (I.Z.P.); (A.L.); (C.D.)
| | - Ioana Zinuca Pavel
- Department of Pharmacognosy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No.2, 300041 Timisoara, Romania; (B.K.); (S.A.); (I.Z.P.); (A.L.); (C.D.)
| | - Adelina Lombrea
- Department of Pharmacognosy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No.2, 300041 Timisoara, Romania; (B.K.); (S.A.); (I.Z.P.); (A.L.); (C.D.)
| | - Valentina Buda
- Department of Pharmacology and Clinical Pharmacy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No.2, 300041 Timisoara, Romania
- Correspondence: ; Tel.: +40-755-100-408
| | - Cristina Adriana Dehelean
- Department of Toxicology, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No.2, 300041 Timisoara, Romania;
| | - Codruta Soica
- Department of Pharmaceutical Chemistry, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No.2, 300041 Timisoara, Romania;
| | - Mukerrem Betul Yerer
- Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Melikgazi, 38039 Kayseri, Turkey;
| | - Florina Bojin
- Department of Functional Sciences, Victor Babeş University of Medicine and Pharmacy, 2, Eftimie Murgu Square, 300041 Timişoara, Romania;
| | - Roxana Folescu
- Department of Anatomy and Embryology, University of Medicine and Pharmacy Victor Babeş, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania;
| | - Corina Danciu
- Department of Pharmacognosy, Victor Babes University of Medicine and Pharmacy, Eftimie Murgu Square, No.2, 300041 Timisoara, Romania; (B.K.); (S.A.); (I.Z.P.); (A.L.); (C.D.)
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Balan DJ, Rajavel T, Das M, Sathya S, Jeyakumar M, Devi KP. Thymol induces mitochondrial pathway-mediated apoptosis via ROS generation, macromolecular damage and SOD diminution in A549 cells. Pharmacol Rep 2020; 73:240-254. [PMID: 33095436 DOI: 10.1007/s43440-020-00171-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 10/01/2020] [Accepted: 10/07/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Thymol is a monoterpene phenol found in thyme species plants. The present study was carried out to investigate the effect of thymol and its molecular mechanism on non-small lung cancer (A549) cells. METHODS The cytotoxic effect of thymol on A549 cells was assessed via MTT assay. ROS production, macromolecular damage, apoptosis were determined using DCF-DA, PI, AO/EtBr stains, respectively. ROS-dependent effect of thymol was confirmed using NAC. The expression of caspase-9, Bcl-2, Bax and cell cycle profile was analyzed via western blot and FACS, respectively. RESULTS The antiproliferative effect of thymol on A549 cells was found to be both dose and time dependent with IC50 values of 112 μg/ml (745 μM) at 24 h. Thymol treatment favored apoptotic cell death and caused G0/G1 cell cycle arrest. It mediated cellular and nuclear morphological changes, phosphatidylserine translocation, and mitochondrial membrane depolarization. Additionally, upregulation of Bax, downregulation of Bcl-2, and apoptotic fragmented DNA were also observed. Thymol induced ROS by reducing the SOD level which was confirmed via in vitro and in silico analysis. Furthermore, the levels of lipid peroxides and protein carbonyl content were elevated in thymol-treated groups. Notably, N-acetyl cysteine pretreatment reversed the efficacy of thymol on A549 cells. Moreover, thymol-treated human PBMC cells did not show any significant cytotoxicity. CONCLUSION Overall, our results confirmed that thymol can act as a safe and potent therapeutic agent to treat NSCLC.
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Affiliation(s)
- Devasahayam Jaya Balan
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi, Tamil Nadu, 630 003, India
| | - Tamilselvam Rajavel
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi, Tamil Nadu, 630 003, India.,Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Mamali Das
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi, Tamil Nadu, 630 003, India
| | - Sethuraman Sathya
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi, Tamil Nadu, 630 003, India
| | - Mahalingam Jeyakumar
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi, Tamil Nadu, 630 003, India
| | - Kasi Pandima Devi
- Department of Biotechnology, Alagappa University [Science Campus], Karaikudi, Tamil Nadu, 630 003, India.
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Magura J, Moodley R, Mackraj I. The effect of hesperidin and luteolin isolated from Eriocephalus africanus on apoptosis, cell cycle and miRNA expression in MCF-7. J Biomol Struct Dyn 2020; 40:1791-1800. [DOI: 10.1080/07391102.2020.1833757] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Judie Magura
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu–Natal, Durban, South Africa
| | - Roshila Moodley
- School of Chemistry and Physics, University of KwaZulu–Natal, Durban, South Africa
| | - Irene Mackraj
- School of Laboratory Medicine and Medical Sciences, University of KwaZulu–Natal, Durban, South Africa
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Yusof WNSW, Abdullah H. Phytochemicals and Cytotoxicity of Quercus infectoria Ethyl Acetate Extracts on Human Cancer Cells. Trop Life Sci Res 2020; 31:69-84. [PMID: 32963712 PMCID: PMC7485533 DOI: 10.21315/tlsr2020.31.1.5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Conventional and modern cancer treatment were reported to manifest adverse effects to the patients. More researches were conducted to search for selective cytotoxic agent of plant natural product on cancer cells. The presences of wide range phytochemicals in Quercus infectoria (QI) extract have been implicated with the cytotoxic effect against various types of cancer cell which remain undiscovered. This present study aimed to evaluate cytotoxic effect of QI extracts on selected human cancer cells and then, the most potent extract was further analysed for general phytochemical constituents. QI galls were extracted successively with n-hexane, ethyl acetate and methanol yielded three main extracts; n-hexane (QIH), ethyl acetate (QIEA) and methanol (QIM), respectively. The most potent extract was qualitatively analysed for the present of tannin, alkaloids, glycosides, saponins, terpenoids, flavonoids and phenolic compounds. Next, the extracts were tested to determine the cytotoxic activity against cervical cancer cells (HeLa), breast cancer cells (MDA-MB-231) and liver cancer cells (Hep G2) using MTT assay. Cytotoxic activity of QI extracts against normal fibroblast (L929) cell line was also evaluated to determine the cytoselective property. Meanwhile, DMSO-treated cells served as negative control while cisplatin-treated cells served as positive control. The most potent extract then chosen to be further investigated for DNA fragmentation as hallmark of apoptosis using Hoechst staining. Qualitative phytochemical analysis revealed the presence of tannin, alkaloids, glycosides, saponins, terpenoids, flavonoids and phenolic compounds. QIEA extract exhibited the most potent cytotoxic activity against HeLa cells with (IC50 value = 6.33 ± 0.33 μg/mL) and showed cytoselective property against L929 cells. DNA fragmentation revealed QIEA induced apoptosis in the treated cells. The richness of phytochemical constituents in QIEA extract might contribute to the potency of cytotoxic activity towards HeLa cells.
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Affiliation(s)
- Wan Nur Suzilla Wan Yusof
- School of Health Sciences, USM Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
| | - Hasmah Abdullah
- School of Health Sciences, USM Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
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Sharma S, Tripathi P, Sharma J, Dixit A. Flavonoids modulate tight junction barrier functions in hyperglycemic human intestinal Caco-2 cells. Nutrition 2020; 78:110792. [PMID: 32473529 DOI: 10.1016/j.nut.2020.110792] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 01/01/2020] [Accepted: 02/27/2020] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Diabetes mellitus is a chronic disease requiring lifelong medical attention. With hundreds of millions suffering worldwide and a rapidly rising incidence, diabetes mellitus poses a great burden on health care systems. Recent studies investigating the underlying mechanisms involved in disease development in diabetes point to the role of the dysregulation of the intestinal barrier. Hyperglycemia-mediated tight junction deformity is known to contribute to leaky gut in various metabolic disorders. The present study aimed to investigate the role of oxidative stress on intestinal epithelial tight junction (TJ) barrier functions in hyperglycemia. Because many flavonoids are known to influence the cellular redox state, exploring these flavonoids may help to understand the role of TJ barrier in hyperglycemia-mediated oxidative stress, which in turn might unfold the association of oxidative stress and dysfunction of barrier-forming TJs. METHODS Caco-2 cells were stimulated with high glucose (HG), with or without flavonoids (quercetin, morin, naringenin), for 24 h. We determined cellular viability, levels of reactive oxygen species, and mitochondrial membrane potential in flavonoids treated HG-Caco-2 cells. The levels of the proinflammatory cytokines, glucose uptake, and expression of glucose transporters were determined on flavonoids treatment. We investigated the effect of flavonoids on TJs functions by measuring transepithelial electrical resistance (a TJ integrity marker), membrane permeability using tracer compounds, and the expressions levels of TJs related molecules on hyperglycemic Caco-2 cell monolayers. RESULTS We found that high glucose treatment resulted in reduced cell viability, increased reactive oxygen species production, measurable mitochondrial dysfunction, and decreased transepithelial electrical resistance, with increased membrane permeability. Treatment with the test flavonoids produced increased cell viability and reduced glucose uptake of HG-Caco-2 cells. A concomitant decrease in reactive oxygen species production, proinflammatory cytokines, and Glut-associated genes and proteins were identified with flavonoid treatment. Flavonoids prevented derangement of TJs protein interaction and stabilized membrane permeability. CONCLUSIONS These findings indicate that flavonoids confer protection against hyperglycemia-mediated oxidative stress and enhance intestinal barrier functions by modulating underlying intracellular molecular mechanisms.
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Affiliation(s)
- Sapna Sharma
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Prabhanshu Tripathi
- Translational Health Science, and Technology Institute, NCR Biotech Science Cluster, Faridabad, India
| | - Jeetesh Sharma
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - Aparna Dixit
- Gene Regulation Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India.
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Mishra RC, Kumari R, Yadav S, Yadav JP. Target Based Virtual Screening of New Leads Inhibitor against Bacterial Cell Division Protein FtsZ for the Discovery of Antibacterial Agents. Med Chem 2020; 16:169-175. [DOI: 10.2174/1573406415666190206233448] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Revised: 11/14/2018] [Accepted: 01/07/2019] [Indexed: 01/06/2023]
Abstract
Background:
Staphylococus epidermidis coagulase negative and gram positive streptococci
have emerged as major nosocomial pathogens associated with the infection of implanted
medical devices and dandruff on human scalp. S. epidermidis filamenting temperature-sensitive
mutant Z (FtsZ) gene encoded FtsZ protein that assembles at future bacterial cell division site that
forms Z-ring structure. FtsZ is a tubulin homolog protein with low sequence similarity; this makes
it possible to inhibit bacterial FtsZ protein without affecting the eukaryote cell division.
Objective:
In the present study, phytochemicals of Cinnamomum zeylanicum, Punica granatum
and Glycyrrhiza glabra were virtually screened for their antibacterial activity against Staphylococcus
epidermidis cell division protein, FtsZ.
Methods:
Molecular docking method was used to investigate new lead inhibitor against bacterial
cell division protein FtsZ. SwissADME and ProTox tool were used to evaluate the toxicity of the
lead molecule.
Results:
Molecular docking based screening confirmed that among 122 phytochemicals, β-
sitosterol and glabrol showed the highest inhibitory activity against FtsZ. SwissADME tool
showed β-sitosterol and glabrol as the ideal antibacterial agents.
Conclusion:
Structure based drug design strategy has been broadly used to optimize antimicrobial
activity of small molecule/ligand against large protein receptor of disease, causing pathogens
which gives a major breakthrough in pharmaceuticals industries. The molecular docking and SwissADME
tool showed that β-sitosterol and glabrol may be developed to be potential topical and
sublingual antibacterial agents, respectively.
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Affiliation(s)
- Ratish C. Mishra
- Department of Genetics, Maharshi Dayanand University, Rohtak-124001, Haryana, India
| | - Rosy Kumari
- Department of Genetics, Maharshi Dayanand University, Rohtak-124001, Haryana, India
| | - Shivani Yadav
- Department of Computer Science and Applications, Maharshi Dayanand University, Rohtak-124001, Haryana, India
| | - Jaya P. Yadav
- Department of Genetics, Maharshi Dayanand University, Rohtak-124001, Haryana, India
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Narayanankutty A, Job JT, Narayanankutty V. Glutathione, an Antioxidant Tripeptide: Dual Roles in Carcinogenesis and Chemoprevention. Curr Protein Pept Sci 2020; 20:907-917. [PMID: 30727890 DOI: 10.2174/1389203720666190206130003] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 01/14/2019] [Accepted: 01/25/2019] [Indexed: 12/12/2022]
Abstract
Glutathione (GSH or reduced glutathione) is a tripeptide of gamma-Glutamyl-cysteinylglycine and the predominant intracellular antioxidant in many organisms including humans. GSH and associated enzymes are controlled by a transcription factor-nuclear factor-2 related erythroid factor-2 (Nrf2). In cellular milieu, GSH protects the cells essentially against a wide variety of free radicals including reactive oxygen species, lipid hydroperoxides, xenobiotic toxicants, and heavy metals. It has two forms, the reduced form or reduced glutathione (GSH) and oxidized form (GSSG), where two GSH moieties combine by sulfhydryl bonds. Glutathione peroxidase (GPx) and glutathione-s-transferase (GST) essentially perform the detoxification reactions using GSH, converting it into GSSG. Glutathione reductase (GR) operates the salvage pathway by converting GSSG to GSH with the expense of NADPH and restores the cellular GSH pool. Hence, GSH and GSH-dependent enzymes are necessary for maintaining the normal redox balance in the body and help in cell survival under stress conditions. In addition, GST removes various carcinogenic compounds offering a chemopreventive property, whereas the GSH system plays a significant role in regulating the cellular survival by offering redox stability in a variety of cancers including prostate, lung, breast, and colon cancer. Studies have also indicated that GSH inhibitors, such as buthionine sulfoximine, improve the chemo-sensitivity in cancer cells. In addition, GSH and dependent enzymes provide a survival advantage for cancer cells against chemotherapeutic drugs and radiotherapy.
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Affiliation(s)
- Arunaksharan Narayanankutty
- Postgraduate & Research Department of Zoology, St. Joseph's College (Autonomous), Devagiri (Affiliated to University of Calicut), Calicut- 673 019, Kerala, India
| | - Joice Tom Job
- Postgraduate & Research Department of Zoology, St. Joseph's College (Autonomous), Devagiri (Affiliated to University of Calicut), Calicut- 673 019, Kerala, India
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Khandia R, Munjal A. Interplay between inflammation and cancer. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 119:199-245. [DOI: 10.1016/bs.apcsb.2019.09.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Pratama MRF, Poerwono H, Siswodiharjo S. ADMET properties of novel 5-O-benzoylpinostrobin derivatives. J Basic Clin Physiol Pharmacol 2019; 30:/j/jbcpp.ahead-of-print/jbcpp-2019-0251/jbcpp-2019-0251.xml. [PMID: 31851612 DOI: 10.1515/jbcpp-2019-0251] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 10/06/2019] [Indexed: 06/10/2023]
Abstract
Background Prediction of the properties of absorption, distribution, metabolism, excretion, and toxicity (ADMET) from a compound is essential, especially for modified novel compounds. Previous research has successfully designed several modified compounds of 5-O-benzoyl derivatives from pinostrobin, a flavanone that has cytotoxic activity. This study aims to describe the properties of ADMET from the 5-O-benzoylpinostrobin derivative. Methods Prediction of the properties of ADMET was carried out using three web servers consisting of SwissADME, pkCSM, and ProTox-II. The observed parameters are divided into ADMET parameters. Results In general, absorption parameters indicate that the 5-O-benzoylpinostrobin derivative has lower water solubility than the parent pinostrobin. Distribution parameters show mixed results for distribution through the blood-brain barrier. Metabolism parameters showed different results with generally inhibitory activity shown in CYP2C19, CYP2C9, and CYP3A4. The excretion parameters showed a higher total clearance than pinostrobin except in the trifluoromethyl derivative. The toxicity parameters showed both pinostrobin and the 5-O-benzoylpinostrobin derivatives, including the class IV toxicity category with the lowest LD50 value indicated by the nitro derivative of 1500, with the possible target of the androgen receptor and prostaglandin G/H synthase 1. Conclusions Overall, the 5-O-benzoylpinostrobin derivative has the predicted ADMET profile that is relatively similar to pinostrobin, with the most noticeable difference being shown in the absorption parameters where all 5-O-benzoylpinostrobin derivatives have lower water solubility than pinostrobin.
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Affiliation(s)
- Mohammad Rizki Fadhil Pratama
- Universitas Airlangga, Doctoral Program of Pharmaceutical Science, Faculty of Pharmacy, Kampus C UNAIR, Jl. Dr. Ir. Soekarno Mulyorejo Surabaya, East Java, Indonesia
| | - Hadi Poerwono
- Universitas Airlangga, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kampus C UNAIR, Jl. Dr. Ir. Soekarno Mulyorejo Surabaya, East Java, Indonesia
| | - Siswandono Siswodiharjo
- Universitas Airlangga, Department of Pharmaceutical Chemistry, Faculty of Pharmacy,, Kampus C UNAIR, Jl. Dr. Ir. Soekarno Mulyorejo Surabaya, East Java, Indonesia
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Vetrivel P, Kim SM, Saralamma VVG, Ha SE, Kim EH, Min TS, Kim GS. Function of flavonoids on different types of programmed cell death and its mechanism: a review. J Biomed Res 2019; 33:363. [PMCID: PMC6891872 DOI: 10.7555/jbr.33.20180126] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 06/04/2019] [Indexed: 08/18/2023] Open
Abstract
Cell death in the living system plays a vital role in maintaining the homeostasis and balancing the cell count in the body. Programmed cell death (PCD) is a crucial component of several development and defense mechanisms. PCD is also important in terms of aging which avoids the accumulation of cellular damage by maintaining cell division. Depending on the execution of cell death and its role in destruction, PCD is categorized into several subtypes. The major different forms of PCD in animals are apoptosis, autophagy and necrosis, which can be distinct in morphological terms. More intense investigations of cell death have given close insight showing other important types of cellular destruction and their pivotal roles in treating disease conditions like cancer. Flavonoids have been acquired a great interest for disease therapies and chemoprevention through activation of several PCD mechanisms. The significant potential of natural flavonoids in the induction of distinct signaling cascades is being a massive approach for targeting uncontrolled cell growth. For these reasons, understanding PCD mechanisms is a promising approach for the interventions in treating cancer. Thus, it is intriguing that understanding the different forms of PCD mechanism induced by flavonoids with more accurate descriptions on the biochemical and cellular processes are gaining more significance in cancer research. Here, we provide a brief overview on the different types of PCD and aim to discuss the functional role of flavonoids in promoting different types of cell death as well as an extensive brief review on their mechanism of action has been highlighted.
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Affiliation(s)
- Preethi Vetrivel
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea
| | - Seong Min Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea
| | - Venu Venkatarame Gowda Saralamma
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea
| | - Sang Eun Ha
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea
| | - Eun Hee Kim
- Department Institute of Women's Health Care, Jinju, Gyeongsangnam-do 52818, Republic of Korea
| | - Tae Sun Min
- Faculty of Biotechnology, Sustainable Agriculture Research Institute, Jeju National University, Jeju 63243, Republic of Korea
| | - Gon Sup Kim
- Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, Jinju, Gyeongsangnam-do 52828, Republic of Korea
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Sánchez-Mendoza M, Santiago-Cruz J, Arrieta J, García-Machorro J, Arrieta-Baez D. Cytotoxic activity of Rauvolfia tetraphylla L. on human cervical cancer (HeLa) cells. Pharmacogn Mag 2019. [DOI: 10.4103/pm.pm_106_19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Su EY, Chu YL, Chueh FS, Ma YS, Peng SF, Huang WW, Liao CL, Huang AC, Chung JG. Bufalin Induces Apoptotic Cell Death in Human Nasopharyngeal Carcinoma Cells through Mitochondrial ROS and TRAIL Pathways. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2019; 47:237-257. [DOI: 10.1142/s0192415x19500125] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
The aim of this study was to investigate the effects of bufalin on human nasopharyngeal carcinoma NPC-TW 076 cells in vitro. Bufalin is a cardiotonic steroid and a key active ingredient of the Chinese medicine ChanSu. The extracts of Chansu are used for various cancer treatments in China. In the present study, bufalin induced cell morphological changes, decreased total cell viability and induced G2/M phase arrest of cell cycle in NPC-TW 076 cells. Results also indicated that bufalin induced chromatin condensation (cell apoptosis) and DNA damage by DAPI staining and comet assay, respectively. The induced apoptotic cell death was further confirmed by annexin-V/PI staining assay. In addition, bufalin also increased ROS and Ca[Formula: see text] production and decreased the levels of [Formula: see text]. Furthermore, the alterations of ROS, ER stress and apoptosis associated protein expressions were investigated by Western blotting. Results demonstrated that bufalin increased the expressions of ROS associated proteins, including SOD (Cu/Zn), SOD2 (Mn) and GST but decreased that of catalase. Bufalin increased ER stress associated proteins (GRP78, IRE-1[Formula: see text], IRE-1[Formula: see text], caspase-4, ATF-6[Formula: see text], Calpain 1, and GADD153). Bufalin increased the pro-apoptotic proteins Bax, and apoptotic associated proteins (cytochrome c, caspase-3, -8 and -9, AIF and Endo G) but reduced anti-apoptotic protein Bcl-2 in NPC-TW 076 cells. Furthermore, bufalin elevated the expressions of TRAIL-pathway associated proteins (TRAIL, DR4, DR5, and FADD). Based on these findings, we suggest bufalin induced apoptotic cell death via caspase-dependent, mitochondria-dependent and TRAIL pathways in human nasopharyngeal carcinoma NPC-TW 076 cells.
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Affiliation(s)
- En-Yun Su
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Yung-Lin Chu
- Department of Food Science, International College, National Pingtung University of Science and Technology, Pingtung, Taiwan
| | - Fu-Shin Chueh
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Yi-Shih Ma
- School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan
- Department of Chinese Medicine, E-Da Hospital, Kaohsiung, Taiwan
| | - Shu-Fen Peng
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Wen-Wen Huang
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
| | - Ching-Lung Liao
- College of Chinese Medicine, School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung, Taiwan
| | - An-Cheng Huang
- Department of Nursing, St. Mary’s Junior College of Medicine, Nursing and Management, Taiwan
| | - Jing-Gung Chung
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
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