Antitumor activities of YM155, a novel small‐molecule survivin suppressant, were investigated in a wide variety of human cancer cell lines and xenograft models. YM155 inhibited the growth of 119 ...human cancer cell lines, with the greatest activity in lines derived from non‐Hodgkin’s lymphoma, hormone‐refractory prostate cancer, ovarian cancer, sarcoma, non‐small‐cell lung cancer, breast cancer, leukemia and melanoma. The mean log growth inhibition of 50% (GI50) value was 15 nM. The mean GI50 values of YM155 were 11 nM for p53 mut/null cell lines and 16 nM for p53 WT cell lines, suggesting that YM155 inhibits the growth of human tumor cell lines regardless of their p53 status. In non‐small‐cell lung cancer (Calu 6, NCI‐H358), melanoma (A375), breast cancer (MDA‐MB‐231) and bladder cancer (UM‐UC‐3) xenograft models, 3‐ or 7‐day continuous infusions of YM155 (1–10 mg/kg) demonstrated significant antitumor activity without showing significant bodyweight loss. Tumor regressions induced by YM155 were associated with reduced intratumoral survivin expression levels, increased apoptosis and decreased mitotic indices. The broad and potent antitumor activity presented in the present study is indicative of the therapeutic potential of YM155 in the clinical setting. (Cancer Sci 2011; 102: 614–621)
Sodium glucose cotransporter 2 (SGLT2) inhibitors improve hyperglycemia in patients with type 2 diabetes mellitus (T2DM) by increasing urinary glucose excretion. In addition to their ...antihyperglycemic effect, SGLT2 inhibitors also reduce body weight and fat mass in obese and overweight patients with T2DM. However, whether or not SGLT2 inhibitors similarly affect body composition of non-obese patients with T2DM remains unclear. In this study, we investigated the effect of the SGLT2 inhibitor ipragliflozin on body composition in a Goto–Kakizaki (GK) rat model of non-obese T2DM. GK rats were treated with ipragliflozin once daily for 9 weeks, starting at 23 weeks of age. Body composition was then analyzed using dual-energy X-ray absorptiometry. Treatment with ipragliflozin increased urinary glucose excretion, reduced hemoglobin A1c (HbA1c) levels and suppressed body weight gain as the dose increased. Body composition analysis revealed that body fat mass was lower in the ipragliflozin-treated groups than in the control group, while lean body mass and bone mineral contents were comparable between groups. Thus, an SGLT2 inhibitor ipragliflozin was found to promote preferential loss of fat mass in a rat model of non-obese T2DM. Ipragliflozin might also promote preferential loss of fat in non-obese patients with T2DM.
The immune status of the tumor microenvironment is a key indicator in determining the antitumor effectiveness of immunotherapies. Data support the role of activation and expansion of ...tumor-infiltrating lymphocytes (TILs) in increasing the benefit of immunotherapies in patients with solid tumors. We found that intratumoral injection of a tumor-selective oncolytic vaccinia virus encoding interleukin-7 (IL-7) and IL-12 into tumor-bearing immunocompetent mice activated the inflammatory immune status of previously poorly immunogenic tumors and resulted in complete tumor regression, even in distant tumor deposits. Mice achieving complete tumor regression resisted rechallenge with the same tumor cells, suggesting establishment of long-term tumor-specific immune memory. Combining this virotherapy with anti-programmed cell death-1 (PD-1) or anti-cytotoxic T lymphocyte antigen 4 (CTLA4) antibody further increased the antitumor activity as compared to virotherapy alone, in tumor models unresponsive to either of the checkpoint inhibitor monotherapies. These findings suggest that administration of an oncolytic vaccinia virus carrying genes encoding for IL-7 and IL-12 has antitumor activity in both directly injected and distant noninjected tumors through immune status changes rendering tumors sensitive to immune checkpoint blockade. The benefit of intratumoral IL-7 and IL-12 expression was also observed in humanized mice bearing human cancer cells. These data support further investigation in patients with non-inflamed solid tumors.
Chemotherapy using anticancer drugs induces serious the problem of multidrug resistance (MDR) in the cancer cells. In contrast, endothelial cells so rarely acquire MDR that antiangiogenesis therapy ...has recently been considered as an effective means for cancer chemotherapy. We screened compounds in the chemical library to find a novel and orally active antitumor agent with vascular endothelial growth factor receptor-2 tyrosine kinase (VEGF-R2 TK) inhibition. The result was YM-231146 (IC50=0.080 μM). YM-231146 inhibited VEGF-stimulated proliferation, VEGF-R2 autophosphorylation, and vessel sprout formation of human vascular endothelial cells at concentrations between 0.15—0.30 μM. However, YM-231146 did not inhibit cancer cell proliferation at these concentrations (IC50>5 μM). In the in vivo studies, once-daily oral dosing of YM-231146 to human cancer xenografts elicited antitumor activity at doses of 3—100 mg/kg. Moreover, YM-231146 completely inhibited tumor growth of paclitaxel-resistant cancer cells without decreasing body weight at a dose of 100 mg/kg. These results suggest that YM-231146 is a novel orally bioavailable inhibitor of VEGF-R2 that would be useful for the treatment of multidrug resistant tumors.
The vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase has been implicated in the pathologic angiogenesis associated with tumor growth. YM-359445 was a ...(3Z)-3-quinolin-2(1H)-ylidene-1,3-dihydro-2H-indol-2-one derivative found while screening based on the inhibition of VEGFR2 tyrosine kinase. The aim of this study was to analyze the efficacy of this compound both in vitro and in vivo.
We tested the effects of YM-359445 on VEGFR2 tyrosine kinase activity, cell proliferation, and angiogenesis. The antitumor activity of YM-359445 was also tested in nude mice bearing various established tumors and compared with other VEGFR2 tyrosine kinase inhibitors (ZD6474, CP-547632, CGP79787, SU11248, and AZD2171), a cytotoxic agent (paclitaxel), and an epidermal growth factor receptor tyrosine kinase inhibitor (gefitinib).
The IC50 of YM-359445 for VEGFR2 tyrosine kinase was 0.0085 micromol/L. In human vascular endothelial cells, the compound inhibited VEGF-dependent proliferation, VEGFR2 autophosphorylation, and sprout formation at concentrations of 0.001 to 0.003 micromol/L. These concentrations had no direct cytotoxic effect on cancer cells. In mice bearing various established tumors, including paclitaxel-resistant tumors, once daily oral administration of YM-359445 at doses of 0.5 to 4 mg/kg not only inhibited tumor growth but also reduced its vasculature. YM-359445 had greater antitumor activity than other VEGFR2 tyrosine kinase inhibitors. Moreover, in human lung cancer A549 xenografts, YM-359445 markedly regressed the tumors (73%) at a dose of 4 mg/kg, whereas gefitinib caused no regression even at 100 mg/kg.
Our results show that YM-359445 is more potent than orally bioavailable VEGFR2 tyrosine kinase inhibitors, which leads to great expectations for clinical applicability.
There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to evaluate the therapeutic potential of ...sepantronium bromide (YM155), a survivin suppressant, in combination with either bendamustine or both bendamustine and rituximab using DLBCL models.
Human DLBCL cell lines, DB, SU-DHL-8, and WSU-DLCL2, were treated with YM155 in combination with bendamustine. Cell viability, apoptosis induction, protein expression, and cell-cycle distribution were evaluated. Furthermore, antitumor activities of YM155, in combination with bendamustine or both bendamustine and rituximab, were evaluated in mice bearing human DLBCL xenografts.
The combination of YM155 with bendamustine showed greater cell growth inhibition and sub-G1 population than either agent alone. YM155 inhibited bendamustine-induced activation of the ATM pathway and accumulation of survivin at G2-M phase, with greater DNA damage and apoptosis than either single agent alone. In a DLBCL DB murine xenograft model, YM155 enhanced the antitumor activity of bendamustine, resulting in complete tumor regression without affecting body weight. Furthermore, YM155 combined with bendamustine and rituximab, decreased FLT-PET signals in lymph nodes and prolonged overall survival of mice bearing disseminated SU-DHL-8, an activated B-cell-like (ABC)-DLBCL xenografts when compared with the combination of either rituximab and bendamustine or YM155 with rituximab.
These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL.
The tumor microenvironment (TME) is thought to influence the antitumor efficacy of immuno-oncology agents through various products of both tumor and stromal cells. One immune-suppressive factor is ...prostaglandin E2 (PGE2), a lipid mediator whose biosynthesis is regulated by ubiquitously expressed cyclooxygenase- (COX-) 1 and inducible COX-2. By activating its receptors, PGE2 induces immune suppression to modulate differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) rather than dendritic cells (DCs). Pharmacological blockade of prostaglandin E receptor 4 (EP4) causes a decrease in MDSCs, reprogramming of macrophage polarization, and increase in tumor-infiltrated T cells, leading to enhancement of antitumor immunity in preclinical models. Here, we report the effects of the highly potent EP4 antagonist ASP7657 on the DC population in tumor and antitumor immune activation in an immunocompetent mouse tumor model. Oral administration of ASP7657 inhibited tumor growth, which was accompanied by an increase in intratumor DC and CD8+ T cell populations and a decrease in the M-MDSC population in a CT26 immunocompetent mouse model. The antitumor activity of ASP7657 was dependent on CD8+ T cells and enhanced when combined with an antiprogrammed cell death-1 (PD-1) antibody. Notably, ASP7657 also significantly enhanced the antitumor efficacy of radiotherapy in an anti-PD-1 antibody refractory model. These results indicate that the therapeutic potential of ASP7657 arises via upregulation of DCs and subsequent CD8+ T cell activation in addition to suppression of MDSCs in mouse models and that combining EP4 antagonists with radiotherapy or an anti-PD-1 antibody can improve antitumor efficacy.
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.
Diffuse large B-cell lymphoma (DLBCL) responds well to treatment with rituximab (RTX, an anti-CD20 antibody) based regimen, but a subset of patients still fail to achieve complete or durable ...responses and are not eligible for high-dose chemotherapy followed by autologous stem cell transplant. Therefore novel effective therapies with less toxicity for relapsed or refractory DLBCL patients are needed. Bendamustine (BEN) is a bifunctional alkylating agent for the treatment of multiple hematological tumors, including indolent and RTX-resistant NHL, and the combination of BEN with RTX showed clinical activity in patients with relapsed or refractory DLBCL in the Phase II study 1. Sepantronium bromide (YM155), a survivin suppressant, shows potent antitumor activities against a wide range of cancer cells, and NHL including DLBCL is one of the most sensitive tumor types to YM155. YM155 showed clinical activity when combined with RTX in patients with relapsed DLBCL 2. In the present study, we evaluated therapeutic potential of YM155, in combination with BEN or BEN and RTX using DLBCL models.
The combination of YM155 with BEN decreased cell viability to a greater extent than either single agent alone in DB, SU-DHL-8, and WSU-DLCL2 human DLBCL cell lines. Bliss additivism analysis revealed that the combined effects were synergistic. In addition The combination of YM155 with BEN induced a greater sub-G1 population, indicative of apoptosis, than either agent alone. The percentages of sub-G1 population induced by YM155, bendamustine, and combination of both were 5.9%, 6.5%, and 27% in DB cells; 19%, 32%, and 58% in SU-DHL-8 cells; and 46%, 30%, and 71% in WSU-DLCL2 cells, respectively. BEN induced γ-histone 2AX (γ-H2AX), a marker of DNA damage and phosphorylation of ATM substrates including p53, and check point kinase-2 (Chk2) which leads to phosphorylation of cdc2. Further BEN induced G2/M arrest associated with the increase of survivin. The combination of YM155 with BEN inhibited phosphorylation of p53, chk2, and cdc2 and accumulation of survivin at G2/M phase, and induced greater DNA damage and cleaved PARP than either single agent alone. In human DLBCL DB xenografts, 7-day continuous s.c. infusion of YM155 at 1 mg/kg/day enhanced antitumor activity of BEN at 50 mg/kg (i.v.) and induced complete regressions in 6 out of 8 mice without affecting body weight. Further, in an activated B-cell-like (ABC)-DLBCL disseminated xenograft model, the combination of YM155 with BEN and RTX significantly prolonged survival associated with the decrease in the FLT-PET signals in lymph node compare with either the combination of BEN with RTX and YM155 with RTX.
Our data indicates that YM155 enhances the antitumor activity of BEN against DLBCL models through inhibition of DNA damage responses as well as survivin accumulation at the G2/M phase. Further, triple combination of YM155 with BEN and RTX showed survival benefit in comparison with either BEN-RTX combination or YM155-RTX combination, supporting the further clinical investigation of this triple combination for the treatment of relapsed or refractory DLBCL.
1. Ohmachi et al. J Clin Oncol. 2013 Jun 10;31(17):2103-9
2. Papadopoulos et al. American Society of Hematology Annual meeting Abstract No. 2731. 2012.
No relevant conflicts of interest to declare.
We developed an oral administration-compatible, small molecular weight antitumor agent, YM-201627 by screening for the inhibition of the proliferation of VEGF-stimulated HUVECs. YM-201627 selectively ...inhibited the proliferation of various endothelial cell lines induced by VEGF, bFGF, and FBS (at IC
50
s of 0.0039–0.12
μM), that would not be expected to have any direct antiproliferative effect on other cell types. YM-201627 inhibited angiogenesis in vitro at a concentration of 0.01
μM. In the in vivo studies, it inhibited microvessel formation induced by human melanoma A375 cells suspended in Matrigel (86% with twice-daily doses of 30
mg/kg). Moreover, once-daily oral dosing of YM-201627 to mice bearing A375 xenografts elicited significant antitumor activity (73% with daily doses of 10
mg/kg). These results suggest that YM-201627 is a selective growth inhibitor of endothelial cells, which may be useful for treatment of solid tumors.
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