Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1783291666300403712 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5762341 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT ookuramiyuki ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT fujiitatsuya ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT yagihideki ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT ogawatakuya ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT kishishinji ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT hosononaoko ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT shigemihiroko ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT yamauchitakahiro ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT uedatakanori ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 AT yoshidaakira ym155exertspotentcytotoxicactivityagainstquiescentg0g1multiplemyelomaandbortezomibresistantcellsviainhibitionofsurvivinandmcl1 |