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

Abstract

Background/Aim: The purpose of the present study was to clarify whether treatment with YM155, a novel small-molecule inhibitor of survivin, reversed cabazitaxel resistance in castration-resistant prostate cancer (CRPC). Materials and Methods: Cabazitaxel resistance was induced in the castration-resistant prostate cancer cell line, 22Rv1-CR. In vitro and in vivo models were used to test the efficacy of YM155 and cabazitaxel. Results: Survivin gene expression was significantly higher in 22Rv1-CR than its parent cells (22Rv1). In 22Rv1-CR cells, YM155 significantly reduced expression of the survivin gene in a concentration-dependent manner. YM155 alone was poorly effective; however, it significantly enhanced the anticancer effects of cabazitaxel on 22Rv1-CR in vitro and in vivo. Conclusion: Inhibition of survivin by YM155 overcomes cabazitaxel resistance in CRPC cells.Cabazitaxel was more efficacious in terms of producing a significant difference in patients with castration-resistant prostate cancer (CRPC) compared with the control group in the TROPIC trial (1). Hence, cabazitaxel is now employed as the standard treatment for most patients with CRPC. However, treatment outcomes are not always completely successful. Thus, the development of a new therapeutic regimen is required.Survivin is a member of a family of eight different proteins that function as inhibitors of apoptosis (2). In 1997, Altieri et al. reported, for the first time, that survivin controlled apoptosis in cancer cells (3). It was also reported that survivin is overexpressed in several kinds of cancer and is involved in the survival of cancer cells and cell division.Conversely, cancer cell apoptosis is induced when the function of survivin is restrained. Additionally, because survivin expression level correlates with malignant disease prognosis and drug resistance, it is considered a potential target of future cancer therapeutics.A novel small-molecule inhibitor of survivin, YM155, was identified by cell-based high-throughput screening (4). YM155 suppresses the transactivation of survivin by directly binding to its promoter (5). Subsequently, Cheng et al. reported that YM155-mediated inhibition of survivin expression occurs, at least in part, through inhibition of survivin transcription by disrupting Sp1 interaction with the -149 to -71 region in the survivin core promoter (6).YM155 exhibits potent antitumor activity in vitro, and induces tumor regression in established non-small cell lung cancer, non-Hodgkin lymphoma, melanoma, and hormonerefractory prostate cancer xenografts (4, 7-9). The anticancer efficacy of YM155 as monotherapy or in combination with docetaxel (10) or platinum compounds, such as cisplatin and carboplatin (11) has been shown in Xenograft models (4,12).The purpose of this study was to determine the efficacy of YM155 and whether YM155 treatment could reverse acquired cabazitaxel resistance in the prostate cancer cell line 22Rv1-CR both in vitro and in vivo. Materials and MethodsCells and chemicals. The human prostate cancer cell l...

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“…The first confirmed survivin inhibitor, YM155, can target the survivin promoter, inhibit the transactivation of survivin, and reduce the expression of survivin protein. 25 , 26 We have confirmed that the proliferation activity and survivin expression of cells were most significant for 10 ng/mL TGF-β1 ( Fig. 3 A).…”

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“…As a sort of next-generation cancer biomarker, survivin mRNA can offer potential diagnostic information for cancer care, and thus, exploring an efficient analytical approach to accomplish a monitoring task at the cellular level is of great necessity. 27 To this aim, two groups of HeLa cells are treated in turn with different concentrations of the survivin inhibitor [sepantronium bromide (YM155)] 33 to realize a target downregulation phenomenon. In comparison to the untreated cells (top images in Figure S18A), the incremental additions of YM155 give rise to a dramatically decreased Cy5 fluorescence (middle and bottom images in Figure S18A), and such a finding can be explained by the fact that the reduced survivin mRNA lessens the walking frequency.…”

L‐type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel‐resistant prostate cancer by inhibiting cyclin‐dependent kinase activity

“…4 Cabazitaxelresistant 22Rv1-CR cells were also generated previously. 5 Cell culturing was basically performed as previously reported. 14 PC-3-TxR/CxR and DU145-TxR/CxR cells were cultured in RPMI-1640 medium (Fujifilm Wako, Osaka, Japan) with 3 nM cabazitaxel (Fujifilm Wako) to maintain their drug resistance.…”

“…3 We previously cultured PC cells in medium containing cabazitaxel for an extended time and established a cabazitaxel-resistant cell line as a tool to search for effective drugs. 4,5 L-type amino acid transporter 1 (LAT1, SLC7A5) is an amino acid transporter expressed on the plasma membrane of various types of cancer cells. 6 Our group has demonstrated that LAT1 plays a pivotal role in cancer cell proliferation through the activation of the mammalian target of rapamycin (mTOR) pathway in urologic cancers, including PC.…”