YM155 exerts potent cytotoxic activity against quiescent (G0/G1) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1
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Miyuki Ookura1, Tatsuya Fujii1, Hideki Yagi2, Takuya Ogawa2, Shinji Kishi1, Naoko Hosono1, Hiroko Shigemi1, Takahiro Yamauchi1, Takanori Ueda1 and Akira Yoshida3
1Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan
2Department of Pharmaceutical Sciences, International University of Health and Welfare, Otawara, Tochigi 324-8501, Japan
3Department of Hematology, International University of Health and Welfare Hospital, Iguchi, Nasushiobara, Tochigi, 329-2763, Japan
Akira Yoshida, email: email@example.com
Keywords: YM155; survivin; Mcl-1; quiescent cells; multiple myeloma
Abbreviations: MM: multiple myeloma; PBS: phosphate-buffered saline; CSC: cancer stem cell; IC50: the half maximal inhibitory concentration
Received: January 17, 2017 Accepted: November 13, 2017 Published: December 04, 2017
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 (G0/G1) cells and bortezomib resistant cells. YM155 strongly inhibited the growth of MM cell lines with the IC50 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 G0 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 (G0/G1) 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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