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

// Miyuki Ookura 1 , Tatsuya Fujii 1 , Hideki Yagi 2 , Takuya Ogawa 2 , Shinji Kishi 1 , Naoko Hosono 1 , Hiroko Shigemi 1 , Takahiro Yamauchi 1 , Takanori Ueda 1 and Akira Yoshida 3 1 Department of Hematology and Oncology, University of Fukui, Matsuoka, Fukui 910-1193, Japan 2 Department of Pharmaceutical Sciences, International University of Health and Welfare, Otawara, Tochigi 324-8501, Japan 3 Department of Hematology, International University of Health and Welfare Hospital, Iguchi, Nasushiobara, Tochigi, 329-2763, Japan Correspondence to: Akira Yoshida, email: akiyoshida@iuhw.ac.jp Keywords: YM155; survivin; Mcl-1; quiescent cells; multiple myeloma Abbreviations: MM: multiple myeloma; PBS: phosphate-buffered saline; CSC: cancer stem cell; IC 50 : the half maximal inhibitory concentration Received: January 17, 2017      Accepted: November 13, 2017      Published: December 04, 2017 ABSTRACT 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.