title: Theaflavin-3, 3'-digallate induces apoptosis and G2 cell cycle arrest through the Akt/MDM2/p53 pathway in cisplatin-resistant ovarian cancer A2780/CP70 cells.
abstract: Ovarian cancer is the most lethal gynecological cancer among women worldwide. Adverse side effects and acquired resistance to conventional platinum based chemotherapy are major impediments in ovarian cancer treatment, and drive the development of more selective anticancer drugs that target cancer-specific defects. In this study, theaflavin-3, 3'-digallate (TF3), the major theaflavin monomer in black tea, exhibited a potent growth inhibitory effect on the cisplatin-resistant ovarian cancer A2780/CP70 cells (IC50, 23.81 µM), and was less cytotoxic to a normal ovarian IOSE‑364 cells (IC50, 59.58 µM) than to the cancer cells. Flow cytometry analysis indicated that TF3 induced preferential apoptosis and G2 cell cycle arrest in A2780/CP70 cells with respect to IOSE‑364 cells. TF3 induced apoptosis through both the intrinsic and extrinsic apoptotic pathways, and caused G2 cell cycle arrest via cyclin B1 in A2780/CP70 cells. The p53 protein played an important role in TF3-induced apoptosis and G2 cell cycle arrest. TF3 might upregulate the p53 expression via the Akt/MDM2 pathway. Our findings help elucidate the mechanisms by which TF3 may contribute to the prevention and treatment of platinum-resistant ovarian cancer.
authors.affiliation: Department of Tea Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Youying
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Tea Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Eunhye
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Tea Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Gary O
authors.initials: GO
authors.lastname: Rankin
authors.affiliation: Department of Tea Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Tea Science, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
authors.forename: Yi Charlie
authors.initials: YC
authors.lastname: Chen
mesh_terms: D017209:Apoptosis; D044946:Biflavonoids / Q000494:pharmacology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D044946:Biflavonoids; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C585473:theaflavin-3,3'-digallate; D002392:Catechin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt; D002945:Cisplatin