title: Time-staggered inhibition of JNK effectively sensitizes chemoresistant ovarian cancer cells to cisplatin and paclitaxel.
abstract: Ovarian cancer is the most lethal gynecological malignancy, for which platinum- and taxane-based chemotherapy plays a major role. Chemoresistance of ovarian cancer poses a major obstacle to the successful management of this devastating disease; however, effective measures to overcome platinum and taxane resistance are yet to be established. In the present study, while investigating the mechanism underlying the chemoresistance of ovarian cancer, we found that JNK may have a key role in the resistance of ovarian cancer cells to cisplatin and paclitaxel. Importantly, whereas simultaneous application of a JNK inhibitor and either of the chemotherapeutic agents had contrasting effects for cisplatin (enhanced cytotoxicity) and paclitaxel (decreased cytotoxicity), JNK inhibitor treatment prior to chemotherapeutic agent application invariably enhanced the cytotoxicity of both drugs, suggesting that the basal JNK activity is commonly involved in the chemoresistance of ovarian cancer cells to cisplatin and paclitaxel in contrast to drug‑induced JNK activity which may have different roles for these two drugs. Furthermore, we confirmed using non-transformed human and rodent fibroblasts that sequential application of the JNK inhibitor and the chemotherapeutic agents did not augment their toxicity. Thus, our findings highlight for the first time the possible differential roles of the basal and induced JNK activities in the chemoresistance of ovarian cancer cells and also suggest that time‑staggered JNK inhibition may be a rational and promising strategy to overcome the resistance of ovarian cancer to platinum- and taxane-based chemotherapy.
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Seino
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Sakaki
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Hikaru
authors.initials: H
authors.lastname: Watarai
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Shizuka
authors.initials: S
authors.lastname: Seino
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kuramoto
authors.affiliation: Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ohta
authors.affiliation: Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Nagase
authors.affiliation: Department of Obstetrics and Gynecology, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata 990‑9585, Japan.
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
mesh_terms: D000873:Anthracenes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; C432165:pyrazolanthrone; D017239:Paclitaxel; D002945:Cisplatin