title: Checkpoint kinase 1 inhibitors as targeted molecular agents for clear cell carcinoma of the ovary.
abstract: In clear cell carcinoma of the ovary, chemoresistance frequently results in treatment failure. The present study aimed to review the potential association of transcription factor hepatocyte nuclear factor (HNF)-1β with cell cycle checkpoint machinery, as a mechanism for chemoresistance. The English-language literature on the subject was reviewed to identify genomic alterations and aberrant molecular pathways interacting with chemoresistance in clear cell carcinoma. Oxidative stress induced by repeated hemorrhage induces greater susceptibility of endometriotic cells to DNA damage, and subsequent malignant transformation results in endometriosis-associated ovarian cancer. Molecular changes, including those in HNF-1β and checkpoint kinase 1 (Chk1), may be a manifestation of essential alterations in cell cycle regulation, detoxification and chemoresistance in clear cell carcinoma. Chk1 is a critical signal transducer in the cell cycle checkpoint machinery. DNA damage, in turn, increases persistent phosphorylation of Chk1 and induction of G2/M phase cell cycle arrest in cells overexpressing HNF-1β. HNF-1β deletion induces apoptosis, suggesting that enhanced levels of HNF-1β may be associated with chemoresistance. Targeted therapy with Chk1 inhibitors may be explored as a potential treatment modality for patients with clear cell carcinoma. This provides a novel direction for combination therapy, including targeting of Chk1, which may overcome drug resistance and improve treatment efficacy.
authors.affiliation: Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.affiliation: Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shigetomi
authors.affiliation: Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634-8522, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Yoshimoto
keywords: cell cycle checkpoint; chemoresistance; clear cell carcinoma; targeted therapy