TY  - EJOU
AU  - Akiyama, Makoto 
AU  - Sowa, Yoshihiro 
AU  - Taniguchi, Tomoyuki 
AU  - Watanabe, Motoki 
AU  - Yogosawa, Shingo 
AU  - Kitawaki, Jo 
AU  - Sakai, Toshiyuki 

TI  - Three Combined Treatments, a Novel HDAC Inhibitor OBP-801/YM753,  5-Fluorouracil, and Paclitaxel, Induce G<sub>2</sub> Phase Arrest Through the p38  Pathway in Human Ovarian Cancer Cells
T2  - Oncology Research

PY  - 2017
VL  - 25
IS  - 8
SN  - 1555-3906

AB  - 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 G<sub>2</sub> 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 G<sub>2</sub> phase arrest induced by the TCTs, we 
employed the p38 inhibitor SB203580. SB203580 inhibited G<sub>2</sub> phase arrest, suppression of CDC25C, and 
phosphorylation of CDC2 (Tyr15) induced by the TCTs. These results suggest that the TCTs can induce 
G<sub>2</sub> 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.
KW  - Histone deacetylase (HDAC) inhibitor; 5-Fluorouracil (5-FU); Paclitaxel (PTX);  G<sub>2</sub> phase arrest; p38; Ovarian cancer

DO  - 10.3727/096504017X14850164661097