YM155 Reverses Statin Resistance in Renal Cancer by Reducing Expression of Survivin

Abstract

Abstract. Aim: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reverses statin resistance in statinresistant renal cell cancer (RCC). Materials and Methods:We induced simvastatin resistance in a renal clear cell carcinoma cell line Statins are a family of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors that are used to treat hyperlipidemia. Statins have recently been reported to exert anticancer effects on various cancer cells, including breast (1-3), hepatic (4), colon (5, 6), and renal (7) cancer. We previously reported that simvastatin inhibited insulin-like growth factor 1 (IGF1)/insulin-like growth factor 1 receptor (IGF1R) signaling in prostate cancer by reducing the expression of IGF1R in PC-3 cells, which resulted in inhibition of cell proliferation in vitro (8). Although a large number of patients with cancer receive therapeutic agents, the development of resistance ultimately results in treatment failure. Accordingly, the molecular mechanisms contributing to drug resistance need to be elucidated in greater detail in order to identify novel therapeutic targets for cancer.Survivin, a member of the inhibitors of apoptosis protein family (9), is selectively expressed in most common human neoplasms (10). The up-regulation of survivin has been correlated with an advanced grade of carcinoma (11) and poor patient survival in several cancer types, including colorectal (12) and non-small cell lung cancer (13). Furthermore, increasing evidence suggests that the expression of survivin is associated with drug resistance in cancer cells and cancer-associated endothelial cells (14-19).YM155, a novel small-molecule inhibitor of survivin, was identified by cell-based high-throughput screening (20). YM155 suppresses the transactivation of survivin by directly binding to its promoter (21). Cheng et al. reported that YM155 inhibited the expression of survivin at least in part through its inhibition of survivin transcription via the disruption of SP1 interaction with the region of -149 to -71 in the survivin core promoter (22). YM155 exhibited potent antitumor activity in vitro and induced tumor regression in established xenografts of hormone-refractory prostate cancer (20), non-Hodgkin's lymphoma (23), non-small cell lung cancer (24) and melanoma (25). Furthermore, the safety and tolerability of YM155 have been demonstrated in phase I and phase II trials on patients with advanced refractory non-small cell lung carcinoma (26) and unresectable melanoma (27). In xenograft models, the anticancer efficacy of YM155 in combination with docetaxel (28) or platinum compounds (29) was found to be superior to that of monotherapy (20,30). We previously reported that YM155 reversed rapamycin resistance in renal cancer by reducing survivin expression in vitro and in vivo (31).This study was intended as an investigation of the efficacy of YM155 and of whether treatment with YM155 reverses statin resistance in a statin-resistant renal clear c...

YM155 Reverses Cabazitaxel Resistance in Castration-resistant Prostate Cancer by Reducing Survivin Expression

“…Furthermore, YM155 significantly enhanced the antitumor effects of rapamycin in these cells. Additionally, we found that, in the statin-resistant renal cell clear cell carcinoma cell line, Caki-1-StaR, survivin knockdown by siRNA or YM155 significantly reversed simvastatin resistance in vitro (17). These findings prompted us to confirm the effects of survivin inhibition in a CRPC model.…”

Inhibition of Survivin by Adenovirus Vector Enhanced Paclitaxel-induced Apoptosis in Breast Cancer Cells

“…Several approaches, including the use of the transcriptional inhibitor sepantronium bromide (YM155), have been designed to target survivin (15)(16)(17). However, recent studies have revealed that an improvement in the response rate was not observed when YM155 was added to the combination therapy of carboplatin and paclitaxel for progressive nonsmall cell lung cancer in Phase I/II trials (18).…”

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.…”