Simultaneous inhibition of the mitogen-activated protein kinase kinase and phosphatidylinositol 3'-kinase pathways enhances sensitivity to paclitaxel in ovarian carcinoma.
Paclitaxel (PTX), one of the key drugs used to treat ovarian cancer, activates the Raf-mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3'-kinase (PI3K) pathways, both considered to be proliferation and cell-survival pathways. The present study aimed to clarify whether and how MEK and PI3K inhibitors affect sensitivity to PTX in ovarian cancer cells. We treated five ovarian cancer cell lines using PTX combined with MEK inhibitor (PD98059 [PD]) and PI3K inhibitor (LY294002 [LY]), then assessed cell viability, apoptosis, and expression of phosphorylated (p) MEK and pAkt. We also investigated the effect of combined treatment on survival in a xenograft model. The protein expression levels of MEK, pMEK, Akt, and pAkt were confirmed in all cell lines. pMEK levels increased after PTX treatment in all five ovarian cancer cell lines. Combining PTX with either PD or LY had an additive effect on cell-growth inhibition. In contrast, we observed a synergistic effect when PTX was combined with both PD and LY. The number of apoptotic cells was significantly higher after treatment with PTX combined with PD and LY, compared with PTX alone or PTX with either PD or LY (P < 0.05). PD with PTX downregulated the protein expression level of pMEK and upregulated pAkt in all five cell lines. Treating nude mice with PTX and PD and LY prolonged survival in an ovarian cancer xenograft model (P < 0.005). These results indicate that further study is warranted for PTX combined with MEK inhibitor and PI3K inhibitor to treat ovarian carcinoma.
Kawaguchi
Wakae
W
Department of Obstetrics and Gynecology, Tottori University School of Medicine, 36-1 Nishicho, Yonago 683-8504, Japan.
Itamochi
Hiroaki
H
Kigawa
Junzo
J
Kanamori
Yasunobu
Y
Oishi
Tetsuro
T
Shimada
Muneaki
M
Sato
Sinya
S
Shimogai
Ruri
R
Sato
Seiya
S
Terakawa
Naoki
N
D000230:Adenocarcinoma; D017304:Annexin A5 / Q000032:analysis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors
D017304:Annexin A5; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; D017239:Paclitaxel