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/...

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Main Authors:	Inaba, Kanako, Oda, Katsutoshi, Aoki, Kazuhiro, Sone, Kenbun, Ikeda, Yuji, Miyasaka, Aki, Kashiyama, Tomoko, Fukuda, Tomohiko, Makii, Chinami, Arimoto, Takahide, Wada-Hiraike, Osamu, Kawana, Kei, Yano, Tetsu, Osuga, Yutaka, Fujii, Tomoyuki
Format:	Online
Language:	English
Published:	Impact Journals LLC 2016
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045418/

id	pubmed-5045418
recordtype	oai_dc
spelling	pubmed-50454182016-10-13 Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging Inaba, Kanako Oda, Katsutoshi Aoki, Kazuhiro Sone, Kenbun Ikeda, Yuji Miyasaka, Aki Kashiyama, Tomoko Fukuda, Tomohiko Makii, Chinami Arimoto, Takahide Wada-Hiraike, Osamu Kawana, Kei Yano, Tetsu Osuga, Yutaka Fujii, Tomoyuki Research Paper 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. Impact Journals LLC 2016-04-18 /pmc/articles/PMC5045418/ /pubmed/27102436 http://dx.doi.org/10.18632/oncotarget.8807 Text en Copyright: © 2016 Inaba et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Inaba, Kanako Oda, Katsutoshi Aoki, Kazuhiro Sone, Kenbun Ikeda, Yuji Miyasaka, Aki Kashiyama, Tomoko Fukuda, Tomohiko Makii, Chinami Arimoto, Takahide Wada-Hiraike, Osamu Kawana, Kei Yano, Tetsu Osuga, Yutaka Fujii, Tomoyuki
spellingShingle	Inaba, Kanako Oda, Katsutoshi Aoki, Kazuhiro Sone, Kenbun Ikeda, Yuji Miyasaka, Aki Kashiyama, Tomoko Fukuda, Tomohiko Makii, Chinami Arimoto, Takahide Wada-Hiraike, Osamu Kawana, Kei Yano, Tetsu Osuga, Yutaka Fujii, Tomoyuki Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging
author_facet	Inaba, Kanako Oda, Katsutoshi Aoki, Kazuhiro Sone, Kenbun Ikeda, Yuji Miyasaka, Aki Kashiyama, Tomoko Fukuda, Tomohiko Makii, Chinami Arimoto, Takahide Wada-Hiraike, Osamu Kawana, Kei Yano, Tetsu Osuga, Yutaka Fujii, Tomoyuki
author_sort	Inaba, Kanako
title	Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging
title_short	Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging
title_full	Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging
title_fullStr	Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging
title_full_unstemmed	Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging
title_sort	synergistic antitumor effects of combination pi3k/mtor and mek inhibition (sar245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging
description	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.
publisher	Impact Journals LLC
publishDate	2016
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045418/
_version_	1613668709406081024

Synergistic antitumor effects of combination PI3K/mTOR and MEK inhibition (SAR245409 and pimasertib) in mucinous ovarian carcinoma cells by fluorescence resonance energy transfer imaging

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