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YM155 exerts potent cytotoxic activity against quiescent (G(0)/G(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1

YM155, a novel small molecule inhibitor of survivin, shows broad anticancer activity. Here, we have focused on the cytotoxic activity of YM155 against multiple myeloma (MM) including cytokinetically quiescent (G(0)/G(1)) cells and bortezomib resistant cells. YM155 strongly inhibited the growth of MM...

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Autores principales: Ookura, Miyuki, Fujii, Tatsuya, Yagi, Hideki, Ogawa, Takuya, Kishi, Shinji, Hosono, Naoko, Shigemi, Hiroko, Yamauchi, Takahiro, Ueda, Takanori, Yoshida, Akira
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762341/
https://www.ncbi.nlm.nih.gov/pubmed/29340073
http://dx.doi.org/10.18632/oncotarget.22871
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author Ookura, Miyuki
Fujii, Tatsuya
Yagi, Hideki
Ogawa, Takuya
Kishi, Shinji
Hosono, Naoko
Shigemi, Hiroko
Yamauchi, Takahiro
Ueda, Takanori
Yoshida, Akira
author_facet Ookura, Miyuki
Fujii, Tatsuya
Yagi, Hideki
Ogawa, Takuya
Kishi, Shinji
Hosono, Naoko
Shigemi, Hiroko
Yamauchi, Takahiro
Ueda, Takanori
Yoshida, Akira
author_sort Ookura, Miyuki
collection PubMed
description YM155, a novel small molecule inhibitor of survivin, shows broad anticancer activity. Here, we have focused on the cytotoxic activity of YM155 against multiple myeloma (MM) including cytokinetically quiescent (G(0)/G(1)) cells and bortezomib resistant cells. YM155 strongly inhibited the growth of MM cell lines with the IC(50) value of below 10 nM. YM155 also showed potent anti-myeloma activity in mouse xenograft model. YM155 suppressed the expression of survivin and rapidly directed Mcl-1 protein for proteasome degradation. YM155 abrogated the interleukin-6-induced STAT3 phosphorylation, subsequently blocked Mcl-1 expression and induced apoptosis in MM cells. Triple-color flow cytometric analysis revealed that YM155 potently induced cell death of MM cells in G(0) phase. Quiescent primary MM cells were also sensitive to YM155. We established bortezomib-resistant MM cell line, U266/BTZR1, which possess a point mutation G322A. YM155 exhibited similar cytotoxic potency against U266/BTZR1 compared with parental cells. Interestingly, survivin expression was markedly elevated in U266/BTZR1 cells. Treatment with YM155 significantly down-regulated this increased survivin and Mcl-1 expression in U266/BTZR1 cells. In conclusion, our data indicate that YM155 exhibits potent cytotoxicity against quiescent (G(0)/G(1)) MM cells and bortezomib-resistant cells. These unique features of YM155 may be beneficial for the development of new therapeutic strategies to eliminate quiescent MM cells and overcome bortezomib resistance.
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spelling pubmed-57623412018-01-16 YM155 exerts potent cytotoxic activity against quiescent (G(0)/G(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1 Ookura, Miyuki Fujii, Tatsuya Yagi, Hideki Ogawa, Takuya Kishi, Shinji Hosono, Naoko Shigemi, Hiroko Yamauchi, Takahiro Ueda, Takanori Yoshida, Akira Oncotarget Research Paper YM155, a novel small molecule inhibitor of survivin, shows broad anticancer activity. Here, we have focused on the cytotoxic activity of YM155 against multiple myeloma (MM) including cytokinetically quiescent (G(0)/G(1)) cells and bortezomib resistant cells. YM155 strongly inhibited the growth of MM cell lines with the IC(50) value of below 10 nM. YM155 also showed potent anti-myeloma activity in mouse xenograft model. YM155 suppressed the expression of survivin and rapidly directed Mcl-1 protein for proteasome degradation. YM155 abrogated the interleukin-6-induced STAT3 phosphorylation, subsequently blocked Mcl-1 expression and induced apoptosis in MM cells. Triple-color flow cytometric analysis revealed that YM155 potently induced cell death of MM cells in G(0) phase. Quiescent primary MM cells were also sensitive to YM155. We established bortezomib-resistant MM cell line, U266/BTZR1, which possess a point mutation G322A. YM155 exhibited similar cytotoxic potency against U266/BTZR1 compared with parental cells. Interestingly, survivin expression was markedly elevated in U266/BTZR1 cells. Treatment with YM155 significantly down-regulated this increased survivin and Mcl-1 expression in U266/BTZR1 cells. In conclusion, our data indicate that YM155 exhibits potent cytotoxicity against quiescent (G(0)/G(1)) MM cells and bortezomib-resistant cells. These unique features of YM155 may be beneficial for the development of new therapeutic strategies to eliminate quiescent MM cells and overcome bortezomib resistance. Impact Journals LLC 2017-12-04 /pmc/articles/PMC5762341/ /pubmed/29340073 http://dx.doi.org/10.18632/oncotarget.22871 Text en Copyright: © 2017 Ookura et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Ookura, Miyuki
Fujii, Tatsuya
Yagi, Hideki
Ogawa, Takuya
Kishi, Shinji
Hosono, Naoko
Shigemi, Hiroko
Yamauchi, Takahiro
Ueda, Takanori
Yoshida, Akira
YM155 exerts potent cytotoxic activity against quiescent (G(0)/G(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1
title YM155 exerts potent cytotoxic activity against quiescent (G(0)/G(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1
title_full YM155 exerts potent cytotoxic activity against quiescent (G(0)/G(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1
title_fullStr YM155 exerts potent cytotoxic activity against quiescent (G(0)/G(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1
title_full_unstemmed YM155 exerts potent cytotoxic activity against quiescent (G(0)/G(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1
title_short YM155 exerts potent cytotoxic activity against quiescent (G(0)/G(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1
title_sort ym155 exerts potent cytotoxic activity against quiescent (g(0)/g(1)) multiple myeloma and bortezomib resistant cells via inhibition of survivin and mcl-1
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762341/
https://www.ncbi.nlm.nih.gov/pubmed/29340073
http://dx.doi.org/10.18632/oncotarget.22871
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