Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging.
The aim of this study was to clarify the synergistic effects of dual inhibition of the PI3K/mTOR and MAPK pathways in ovarian mucinous carcinoma (OMC) cells, using fluorescence resonance energy transfer (FRET) imaging. We exposed 6 OMC cell lines to a PI3K/mTOR inhibitor (voxtalisib, SAR245409) and/or a MEK inhibitor (pimasertib), and evaluated synergistic effects using the Chou-Talalay method. Then, S6K (PI3K pathway) and ERK (MAPK pathway) kinase activities, and their individual proliferative or cytotoxic effects were calculated by time-lapse FRET imaging. In combination with SAR245409, pimasertib (30 nM) synergistically inhibited cell growth (combination indexes: 0.03-0.5) and induced apoptosis in all 6 OMC cell lines. FRET-imaging results demonstrated that ERK inhibition induced both anti-proliferation and apoptosis in a dose-dependent manner in both MCAS and OAW42 cells. However, S6K inhibition suppressed proliferation in a threshold manner in both cell lines, although apoptosis was only induced in OAW42 cells. These results demonstrated that combined PI3K/mTOR and MEK inhibition exhibited synergistic antitumor effects in OMC cells and that FRET imaging is useful for analyzing kinase activities in live cells and elucidating their cytostatic and cytotoxic effects.
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Kanako
K
Inaba
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Katsutoshi
K
Oda
Imaging Platform for Spatio-Temporal Information, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Kazuhiro
K
Aoki
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Kenbun
K
Sone
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Yuji
Y
Ikeda
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Aki
A
Miyasaka
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Tomoko
T
Kashiyama
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Tomohiko
T
Fukuda
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Chinami
C
Makii
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Takahide
T
Arimoto
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Osamu
O
Wada-Hiraike
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Kei
K
Kawana
Department of Obstetrics and Gynecology, National Center for Global Health and Medicine, Tokyo, Japan.
Tetsu
T
Yano
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Yutaka
Y
Osuga
Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
Tomoyuki
T
Fujii
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018282:Cystadenocarcinoma, Mucinous; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008962:Models, Theoretical; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010051:Ovarian Neoplasms; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011810:Quinoxalines; D013449:Sulfonamides; C576808:XL765; D009536:Niacinamide; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases
FRET imaging; MAPK pathway; PI3K/mTOR pathway; molecular target therapy; ovarian mucinous carcinoma