Survivin selective inhibitor YM155 promotes cisplatin-induced apoptosis in embryonal rhabdomyosarcoma

Abstract

Abstract. Survivin, a member of the inhibitor of apoptosis protein family, functions as a key regulator of programmed cell death. YM155 is a small molecule that selectively inhibits survivin. We investigated the effect of YM155 on survivin suppression in the human rhabdomyosarcoma (RMS) cell line RD. The efficacy of YM155 in combination with cisplatin was also determined in a xenograft model. The effect of YM155 on survivin expression in the RD cell line was examined at both mRNA and protein levels using real-time PCR and western blot analysis. RD cells were cultured with various concentrations of YM155, then cisplatin was added to the medium and the anti-proliferation response was determined. Cell growth was evaluated by WST-8 assay. Finally, the efficacy of YM155 combined with cisplatin was examined in an established xenograft model. Survivin mRNA levels in the RD cell line were decreased to 72 and 24% at 24 and 48 h, respectively, after 10 nM of YM155 was added. YM155 also decreased the levels of survivin protein. YM155 treatment (10 nM) inhibited cell proliferation of RD in a dose-dependent manner in vitro, with 58% of cells viable at 48 h. When cultured with 10 nM of YM155 and 10 µM cisplatin, RD cells demonstrated only 25% of the growth observed when cultured with cisplatin alone. YM155 in combination with cisplatin significantly inhibited tumor growth by 13% compared with control (P<0.0001) in RD xenograft tumors. YM155 increased the sensitivity of cisplatin by suppressing survivin in the embryonal RMS cell line RD. Further studies should investigate the use of YM155 as an apoptosis inducer, either alone or in combination with cisplatin, for the treatment of malignant RMS.

Multifaceted Mechanisms of Cisplatin Resistance in Long-Term Treated Urothelial Carcinoma Cell Lines

“…YM155 inhibits transcription of Survivin by binding to the transcription factor ILF3/NF110 or disrupting the ILF3/p54 nrb complex [ 37 ] and has been demonstrated to significantly diminish BIRC5 /Survivin mRNA and protein expression without affecting other inhibitors of apoptosis (IAPs) or the BCL2 family member MCL-1 [ 38 ]. In this fashion, YM155 reverted resistance in cells from different cancer types [ 38 , 39 , 40 ]. In the UC LTTs, combined treatment with YM155 and cisplatin decreased clonogenic potential and further increased apoptosis, albeit not in a synergistic manner.…”

A five‐gene signature may predict sunitinib sensitivity and serve as prognostic biomarkers for renal cell carcinoma

“…BIRC5 (also called survivin) is a nodal protein which regulated cell division, involved in both apoptosis and autophagy, related to stress response and influenced tumor‐associated angiogenesis (Altieri, ; Ueno, Uehara, Nakahata, & Okuyama, ). As a result, BIRC5 was correlated with high‐grade and tumor progression, poor survival, high recurrence rate, and chemotherapy and radiation resistance in numerous cancers, such as head and neck squamous cell carcinoma (HNSCC), oral squamous cell carcinoma, breast cancer, and so on (Nestal de Moraes et al, ; Sun, Zheng, & Yan, ; Zhang et al, ).…”

Effects of Sepantronium Bromide (YM-155) on the Whole Transcriptome of MDA-MB-231 Cells: Highlight on Impaired ATR/ATM Fanconi Anemia DNA Damage Response

“…(22-24) YM-155 has been reported to overcome drug resistance (e.g. statins (16,(25)(26)(27) docetaxel (28)), improve efficacy of diverse therapies including hypericin-mediated photodynamic therapies (29) and on its own merit, induces apoptosis, reduces colony formation, attenuates invasion and growth of xenograft tumors in nude mice (30)(31)(32)(33). While reduction of survivin by YM-155 is believed to be a foremost mechanism of action, other biochemical targets for this drug are continually being reported in the literature.…”