Chaetoglobosin K induces apoptosis and G2 cell cycle arrest through p53-dependent pathway in cisplatin-resistant ovarian cancer cells

• Published in: Cancer letters Vol. 356; no. 2; pp. 418 - 433
• Main Authors: Li, Bo, Gao, Ying, Rankin, Gary O, Rojanasakul, Yon, Cutler, Stephen J, Tu, Youying, Chen, Yi Charlie
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 28.01.2015; Elsevier Limited
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Blotting, Western; Cell cycle; Cell cycle arrest; Cell growth; Cell Proliferation - drug effects; Chaetoglobosin K; Chemotherapy; Cisplatin - pharmacology; Drug Resistance, Neoplasm - drug effects; Female; Flow Cytometry; G2 Phase Cell Cycle Checkpoints - drug effects; Hematology, Oncology and Palliative Medicine; Humans; Immunoenzyme Techniques; Indole Alkaloids - pharmacology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; p38; p53; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Small Interfering - genetics; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Cell cycle arrest; Chaetoglobosin K; p38; Ovarian cancer; Apoptosis; p53
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2014.09.023

Abstract Adverse side effects and acquired resistance to conventional platinum based chemotherapy have become major impediments in ovarian cancer treatment, and drive the development of more selective anticancer drugs. Chaetoglobosin K (ChK) was shown to have a more potent growth inhibitory effect than cisplatin on two cisplatin-resistant ovarian cancer cell lines, OVCAR-3 and A2780/CP70, and was less cytotoxic to a normal ovarian cell line, IOSE-364, than to the cancer cell lines. Hoechst 33342 staining and Flow cytometry analysis indicated that ChK induced preferential apoptosis and G2 cell cycle arrest in both ovarian cancer cells with respect to the normal ovarian cells. ChK induced apoptosis through a p53-dependent caspase-8 activation extrinsic pathway, and caused G2 cell cycle arrest via cyclin B1 by increasing p53 expression and p38 phosphorylation in OVCAR-3 and A2780/CP70 cells. DR5 and p21 might play an important role in determining the sensitivity of normal and malignant ovarian cells to ChK. Based on these results, ChK would be a potential compound for treating platinum-resistant ovarian cancer.