title: Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753, 5-Fluorouracil, and Paclitaxel, Induce G₂ Phase Arrest Through the p38 Pathway in Human Ovarian Cancer Cells.
abstract: Ovarian cancer is the most lethal disease among gynecological malignancies. More effective therapy is required to counter high recurrence rates and chemotherapy resistance. We investigated the efficacy and molecular mechanisms of three combined treatments (TCTs)-a novel histone deacetylase (HDAC) inhibitor OBP-801/YM753, 5-fluorouracil (5-FU), and paclitaxel (PTX)-in human ovarian cancer SKOV-3 and OVCAR-3 cells. The inhibition of cell growth was stronger with TCTs than with each single agent and with two combined treatments. The TCTs significantly induce G2 phase arrest in both cell lines. We then analyzed the molecular mechanisms and found that the TCTs increased the phosphorylation of p38 (Thr180/Tyr182), decreased the expression of CDC25C, and increased the phosphorylation of CDC2 (Tyr15), an inactive form of CDC2. To examine the responsibilities of the p38 pathway for G2 phase arrest induced by the TCTs, we employed the p38 inhibitor SB203580. SB203580 inhibited G2 phase arrest, suppression of CDC25C, and phosphorylation of CDC2 (Tyr15) induced by the TCTs. These results suggest that the TCTs can induce G2 phase arrest through activation of the p38 signaling pathway. We therefore believe that this combination is promising as a novel therapeutic strategy against ovarian cancer.
authors.forename: Makoto
authors.initials: M
authors.lastname: Akiyama
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sowa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Taniguchi
authors.forename: Motoki
authors.initials: M
authors.lastname: Watanabe
authors.forename: Shingo
authors.initials: S
authors.lastname: Yogosawa
authors.forename: Jo
authors.initials: J
authors.lastname: Kitawaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakai
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010456:Peptides, Cyclic / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D047630:Depsipeptides
chemical_list: D005472:Fluorouracil; D017239:Paclitaxel; D010456:Peptides, Cyclic; D048051:p38 Mitogen-Activated Protein Kinases; C528967:YM753 compound; D047630:Depsipeptides