title: 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.forename: Taejeong
authors.initials: T
authors.lastname: Bae
authors.affiliation: College of Pharmacy, Catholic University of Daegu, Gyeongbuk 712-702, Republic of Korea.
authors.forename: Kwon-Yeon
authors.initials: KY
authors.lastname: Weon
authors.affiliation: Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea, Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul 135-710, Republic of Korea.
authors.forename: Jeong-Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Wonkwang Institute of Integrative Biomedical Science and Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk 570-711, Republic of Korea.
authors.forename: Ki-Hwan
authors.initials: KH
authors.lastname: Eum
authors.affiliation: Wonkwang University Oriental Medical Hospital, Department of Acupuncture and Moxibustion, Gwangju, 503-832, South Korea and.
authors.forename: Sungchul
authors.initials: S
authors.lastname: Kim
authors.affiliation: Wonkwang Institute of Integrative Biomedical Science and Dental Research Institute, School of Dentistry, Wonkwang University, Iksan, Chonbuk 570-711, Republic of Korea, Advanced Institute of Convergence Technology, Seoul National University Suwon, Gyeonggi-do 443-270, South Korea jinwoochoi@wku.ac.kr.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001552:Benzazepines / Q000494:pharmacology*; D016203:CDC2 Protein Kinase; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000201:enzymology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D017239:Paclitaxel / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001552:Benzazepines; D007211:Indoles; C120793:alsterpaullone; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel