sepantronium and Carcinoma

The imidazolium compound YM155, first discovered as a potent inhibitor of Survivin, effectively kills many carcinomas in preclinical models. However, the upstream signaling mechanism triggered by YM155 remains unclear. Here we studied early signaling responses in vitro in prostate and renal cancer cell lines in a dose-dependent manner. We found that YM155 rapidly activates the retinoblastoma protein, correlating with the loss of expression of all three Cyclin Ds. Using Western blot, various selective chemical inhibitors and q-PCR, we show that YM155-mediated decrease in protein levels of Cyclin Ds, Survivin and Mcl-1 is independent of transcription or proteasomal control mechanisms. Moreover, we provide the first evidence that YM155 changes the phosphorylation status of known mTOR-target proteins involved in translational control, namely ribosomal protein S6 (rS6) and 4E-BP1. Our data support that YM155 achieves this by blocking mTORC1 via the phosphorylation of Raptor at S792 through activated AMPKα (T172). Furthermore, we also used a polysome profile, supporting that YM155 markedly suppresses cap-dependent translation of mRNAs which include Survivin, Cyclin D1 and Mcl-1. We provide the first evidence that YM155 functions as a potent activator of AMPKα, a robust suppressor of mTORC1 and an attenuator of global protein synthesis.

Topics: Adaptor Proteins, Signal Transducing; AMP-Activated Protein Kinase Kinases; Apoptosis; Carcinoma; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin D; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Male; Mechanistic Target of Rapamycin Complex 1; Naphthoquinones; Prostate; Prostatic Neoplasms; Protein Kinases; Signal Transduction; Survivin

Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2-related proteins. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations approximately 20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach.

Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Carcinoma; CHO Cells; Cricetinae; Cricetulus; Drug Evaluation, Preclinical; Drug Resistance, Neoplasm; HeLa Cells; Humans; Imidazoles; Inhibitor of Apoptosis Proteins; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Microtubule-Associated Proteins; Models, Biological; Naphthoquinones; Neoplasm Proteins; Prostatic Neoplasms; Remission Induction; Survivin; Treatment Failure; Tumor Burden; Tumor Cells, Cultured; Xenograft Model Antitumor Assays