Restoration of paclitaxel resistance by CDK1 intervention in drug-resistant ovarian cancer.

Abstract

Epithelial ovarian cancer (EOC) commonly acquires resistance to chemotherapy, and this is the major obstacle to the better prognosis. Elucidating the molecular targets altered by chemotherapy is critically required to understand and overcome drug resistance. As a drug combination including paclitaxel is a prevalent prescription for treatment of EOC, to uncover gene expression altered in paclitaxel-resistant EOC, we analyzed multidirectional microarray profiles in both EOC cell lines and patients with paclitaxel resistance. Cyclin-dependent kinase 1 (CDK1) was found to be a potential target of transcription factors to regulate paclitaxel resistance. As a result of the subsequent pharmacogenomics analysis, CDK1 inhibitor alsterpaullone was also indicated as a promising chemical that may be used in combinatorial therapies to reverse paclitaxel-induced chemoresistance. Although a CDK1 inhibitor has the potential to kill cancer cells, short-term treatment over 2 weeks at sublethal doses effectively induced cell death only upon additional treatment with paclitaxel. A prominent reduction in the tumor growth rate was observed upon paclitaxel subsequent to alsterpaullone treatment in EOC xenograft model. Thus, we suggest that inhibition of CDK1 with alsterpaullone may be a novel therapeutic method to reverse paclitaxel-induced resistance in ovarian cancer cells.

• Authors: Taejeong Bae, Kwon-Yeon Weon, Jeong-Won Lee, Ki-Hwan Eum, Sungchul Kim, Jin Woo Choi
• Journal: Carcinogenesis (Carcinogenesis) Vol. 36 Issue 12 Pg. 1561-71 (Dec 2015) ISSN: 1460-2180 [Electronic] England
• PMID: 26442525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Antineoplastic Agents
• Benzazepines
• Indoles
• alsterpaullone
• CDC2 Protein Kinase
• CDK1 protein, human
• Cyclin-Dependent Kinases
• Paclitaxel

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Benzazepines (pharmacology)
• CDC2 Protein Kinase
• Carcinoma, Ovarian Epithelial
• Cell Line, Tumor
• Cyclin-Dependent Kinases (antagonists & inhibitors, metabolism)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Humans
• Indoles (pharmacology)
• Mice, Inbred C57BL
• Neoplasms, Glandular and Epithelial (drug therapy, enzymology)
• Ovarian Neoplasms (drug therapy, enzymology)
• Paclitaxel (pharmacology)
• Xenograft Model Antitumor Assays