YM155 exerts potent cytotoxic activity against quiescent (G0/G1) multiple myeloma and bortezomib resistant cells via inhibition of survivin and Mcl-1.

Miyuki Ookura,Tatsuya Fujii,Hideki Yagi,Takanori Ueda,Hiroko Shigemi,Shinji Kishi,Takuya Ogawa,Takahiro Yamauchi,Naoko Hosono,Akira Yoshida

doi:10.18632/oncotarget.22871

Miyuki Ookura, Tatsuya Fujii + Show 8 more

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https://doi.org/10.18632/oncotarget.22871

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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 (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.

Highlights

Multiple myeloma (MM) is characterized by the abnormal growth of malignant plasma cells in the bone marrow
Cells were treated with increasing concentrations of YM155 for 72 h, and cell viability was measured by the cell counting kit-8
We investigated the effects of YM155 on the induction of apoptosis

Summary

Introduction

Multiple myeloma (MM) is characterized by the abnormal growth of malignant plasma cells in the bone marrow. The introduction of new drugs such as bortezomib and lenalidomide for the treatment of MM patients has significantly improved the clinical outcome [1, 2]. Most of the patients relapse due to acquired drug resistance or expansion of residual clones that shows intrinsic resistance. MM is a low growth fraction tumor with only a small percentage of myeloma cells in the S phase of the cell cycle [3, 4]. The majority of myeloma cells are quiescent. Quiescent cells are www.impactjournals.com/oncotarget generally insensitive to conventional anticancer agents [7,8,9]. It is critical to search the drug, which efficiently kills the quiescent MM cells

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