Small-molecule Survivin Suppressant Research Articles

YM155: A Small Molecule Survivin Suppressant with Potent Antitumor Effect in Human Breast Cancer Models.

Abstract Background: Survivin, a member of the inhibitor of apoptosis (IAP) gene family, is a key regulator of apoptosis and mitosis. Aberrant expression of survivin is detected in various clinical tumors, but not in normal adult tissues. Increased survivin expression in cancer patients is an unfavorable prognostic marker correlating with decreased overall survival in several malignancies. Also, survivin expression has been implicated in tumor growth, progression, and resistance to conventional and targeted anticancer agents. YM155 is a novel small molecule survivin suppressant which has demonstated potent antitumor activity against a wide range of cancer cells and is currently in clinical development in a number of tumor types including breast cancer. In this study, we evaluated the therapeutic potential of YM155 against human breast cancer models.Material and Methods: Antiproliferative effect was evaluated by sulforhodamine B assay. In an assessment of gene expression changes, cell viability and caspase activation, cells were analyzed 48-96h post transfection of survivin siRNA or treatment with YM155. For antitumor experiments, three human triple negative breast cancer (TNBC), MRK-nu-1, MDA-MB-231 and MDA-MB-435 cells were subcutaneously or orthotopically implanted into female BALB/c nu/nu mice. After the tumors were established, YM155 was administered as a 7-day continuous sc infusion. Docetaxel was administered IV bolus.Results: In in vitro panel screening derived from human breast tumors, YM155 showed potent antiproliferative activity against breast cancer cell lines with GI50 values ranging from 0.64 to 32 nM, regardless of ER-alpha, PR, HER-2 expression status. In MRK-nu-1 TNBC cells, YM155 resulted in suppression of survivin expression, caspase-3/7 activation, induction of spontaneous apoptosis, and growth inhibition in the same way that survivin siRNA did. In addition, 7-day continuous infusion of YM155 resulted in the complete regression without body weight loss in an MRK-nu-1 subcutaneous xenograft model, indicating that MRK-nu-1 cells highly depend on survivin for survival. In an MDA-MB-231 human TNBC orthotopic xenograft model, YM155 also induced more durable tumor regression compared with that of the docetaxel treatment group. In the combination study using an MDA-MB-435 orthotopic model, concomitant administration of YM155 and docetaxel showed substantial tumor regression more potently and for longer periods than each single compound administration alone without enhancement of body weight loss.Conclusions: YM155 plus docetaxel showed enhanced antitumor activity as compared to each compound alone without increase in weight loss in breast cancer models, suggesting that survivin suppression may constitute a valuable supplement to current treatment strategies in breast cancer. Since taxanes are commonly utilized in the treatment of breast cancer, these results support evaluating this combination in patients with advanced breast cancer. A phase 2 study of YM155 in combination with docetaxel in women with metastatic HER2 negative breast cancer is planned. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3140.

YM155, a Novel Survivin Suppressant, Improves the Antitumor Effect of Rituximab and Rituximab-Containing Regimens in Diffuse Large B Cell Lymphoma (DLBCL) Xenograft Mouse Models.

Abstract 2718Poster Board II-694 Introduction:Survivin is a member of the inhibitor of apoptosis (IAP) family of proteins, and is highly expressed in many tumor types. Given its preferential expression in tumor cells, and its ability to block apoptosis and regulate cancer cell proliferation, survivin appears to be an attractive novel target for cancer therapy. YM155 is a novel, small molecule survivin suppressant (Nakahara et al., Cancer Research. 2007;67:8014–21). In this study, we evaluated the antitumor activity of YM155 alone and in combination with rituximab, R-ICE (rituximab + ifosfamide + carboplatin + etoposide), or [rituximab + cytarabin + cisplatin] in DLBCL xenograft models. Methods:Antiproliferative effect of YM155 in a panel of human DLBCL cell lines (DB, Pfeiffer, SU-DHL5, SU-DHL8, WSU-DLCL-2, and RL) was evaluated by sulforhodamine B assay. In in vivo studies, WSU-DLCL-2 and DB were subcutaneously implanted into male BALB/c nu/nu mice. When tumors reached a volume of 300 to 600 mm3, YM155 was administered as a 7-day continuous sc infusion, and the other drugs were administered via iv bolus. Dose and schedule of each drug were adjusted to clinical equivalent dose. PET imaging studies were performed using a Inveon PET/CT system (Siemens Medical Solusion). WSU-DLCL-2 xenografted mice were intravenously injected with [18F] FLT, and five-minute static PET scans were accqiured at 1h after injection. For each small-animal PET scan, region of interest was drawn over each tumor and over normal tissue on decay-corrected whole-body sagittal imagies. Results:In in vitro proliferation assays, YM155 showed potent antiproliferative activity against all six DLBCL cell lines, with GI50 values of 0.35 to 3.9 nM. In in vivo studies using WSU-DLCL2 xenograft model, YM155 at 1 and 3 mg/kg induced tumor regression without body weight loss. In combination studies using WSU-DLCL2 xenograft model, YM155 2 mg/kg enhanced antitumor effects of rituximab, R-ICE and [rituximab + cytarabin + cisplatin] without enhancement of the body weight loss. Tumor regression in the combination groups was sustained longer than single treatment groups, and even complete regressions were achievable. Moreover, combination of YM155 1 mg/kg and rituximab induced strong tumor regression in the DB xenograft model, while single-agent treatments did not show significant antitumor effect compared to vehicle control. In [18F]FLT-PET imaging, a significant reduction of FLT uptake in tumor was observed in rituximab combination group, which was more sensitive than the reduction in tumor volume. Conclusions:YM155 improves the antitumor effect of rituximab and rituximab-containing regimens in diffuse large B cell lymphoma (DLBCL) xenograft mouse models. Disclosures:Nakata:Astellas Pharma Inc.: Employment. Nakahara:Astellas Pharma Inc.: Employment. Kita:Astellas Pharma Inc.: Employment. Mitsuoka:Astellas Pharma Inc.: Employment. Yamanaka:Astellas Pharma Inc.: Employment. Kaneko:Astellas Pharma Inc.: Employment. Miyoshi:Astellas Pharma Inc.: Employment. Mori:Astellas Pharma Inc.: Employment. Koutoku:Astellas Pharma Inc.: Employment. Sasamata:Astellas Pharma Inc.: Employment.

Characterization of Human Organic Cation Transporter 1 (OCT1/SLC22A1)- and OCT2 (SLC22A2)-Mediated Transport of 1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)- 4,9-dihydro-1H-naphtho[2,3-d]imidazolium Bromide (YM155 Monobromide), a Novel Small Molecule Survivin Suppressant

1-(2-Methoxyethyl)-2-methyl-4,9-dioxo-3-(pyrazin-2-ylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazolium bromide (YM155 monobromide) is a novel small-molecule survivin suppressant that induces the down-regulation of survivin and exhibits potent antitumor activity in nude mice bearing human hormone refractory prostate carcinoma cell line PC-3. Although YM155, which has a cationic moiety in its structure, is influxed into its pharmacologically effective site (cancer cells) and one of its eliminating organs (hepatocytes) in a transporter-mediated manner, the mechanism seems to be different between the two cell types. The other eliminating organ is the kidney. In this study, the transport of [(14)C]YM155 was characterized by using human embryonic kidney 293 cells expressing organic cation transporter 1 (OCT1/SLC22A1), OCT2 (SLC22A2), and OCT3 (SLC22A3). YM155 inhibited the uptake of a typical substrate [(3)H]1-methyl-4-phenylpyridinium via OCT1, OCT2, and OCT3 with IC(50) values of 23.8, 15.9, and 108 microM, respectively. The time- and saturable concentration-dependent uptake of [(14)C]YM155 was observed in cells expressing OCT1 and OCT2 with K(m) values of 22.1 and 2.67 microM, respectively, but not in cells expressing OCT3. By taking into consideration the tissue distribution and localization of each transporter, these results suggest that, in humans, YM155 is taken up from the blood into hepatocytes and proximal tubular cells via OCT1 and OCT2, respectively. The comparison of the IC(50) values of OCT inhibitors and K(m) values for the uptake of YM155 into cells expressing OCTs with those into cancer cell lines indicated that transporter(s) other than OCT1 and OCT2 are involved in the uptake of YM155 into cancer cell lines.

Radiosensitizing Effect of YM155, a Novel Small-Molecule Survivin Suppressant, in Non–Small Cell Lung Cancer Cell Lines

Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effect of YM155, a small-molecule inhibitor of survivin expression, on the sensitivity of human non-small cell lung cancer (NSCLC) cell lines to gamma-radiation. The radiosensitizing effect of YM155 was evaluated on the basis of cell death, clonogenic survival, and progression of tumor xenografts. Radiation-induced DNA damage was evaluated on the basis of histone H2AX phosphorylation and foci formation. YM155 induced down-regulation of survivin expression in NSCLC cells in a concentration- and time-dependent manner. A clonogenic survival assay revealed that YM155 increased the sensitivity of NSCLC cells to gamma-radiation in vitro. The combination of YM155 and gamma-radiation induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Immunofluorescence analysis of histone gamma-H2AX also showed that YM155 delayed the repair of radiation-induced double-strand breaks in nuclear DNA. Finally, combination therapy with YM155 and gamma-radiation delayed the growth of NSCLC tumor xenografts in nude mice to a greater extent than did either treatment modality alone. These results suggest that YM155 sensitizes NSCLC cells to radiation both in vitro and in vivo, and that this effect of YM155 is likely attributable, at least in part, to the inhibition of DNA repair and enhancement of apoptosis that result from the down-regulation of survivin expression. Combined treatment with YM155 and radiation warrants investigation in clinical trials as a potential anticancer strategy.

YM155, a Novel Small-Molecule Survivin Suppressant, Induces Regression of Established Human Hormone-Refractory Prostate Tumor Xenografts

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.

377 POSTER YM155, a novel small molecule survivin suppressant, exhibits curative antitumor activities in experimental human malignant lymphoma models in vivo

377 POSTER YM155, a novel small molecule survivin suppressant, exhibits curative antitumor activities in experimental human malignant lymphoma models in vivo