Sunitinib Malate Synergistically Potentiates Anti-Tumor Effect of Gemcitabine in Human Bladder Cancer Cells

Abstract

PurposeSunitinib malate (Sutent; Pfizer, New York, NY, USA) is a highly selective multi-targeted agent and has been reported to have potent anti-tumor effects against various tumors, including renal cell carcinoma and gastrointestinal stromal tumors. In this study, we explored in vitro the anti-tumor effect and related molecular mechanisms of sunitinib malate against human bladder cancer cell lines. We also determined the synergistic anti-tumor effect between sunitinib and conventional cytotoxic drugs, cisplatin and gemcitabine, in bladder cancer cells.Materials and MethodsSix human cancer cell lines (HTB5, HTB9, T24, UMUC14, SW1710, and J82) were exposed to an escalating dose of sunitinib alone or in combination with cisplatin/gemcitabine, and the cytotoxic effect of the drugs was examined by CCK-8 assay. The synergistic effect between sunitinib and cisplatin/gemcitabine was determined by the combination index (CI) and clonogenic assay. Alterations in cell cycle (cyclin D, B1), survival (p-Akt, t-Akt), and apoptosis (Bax, Bad) regulator expression were analyzed by Western blotting.ResultsLike cisplatin and gemcitabine, sunitinib exerted a dose- and time-dependent anti-tumor effect in bladder cancer cells. However, sunitinib exhibited entirely different sensitivity profiles from cisplatin and gemcitabine. Sunitinib suppressed the expression of cyclin B1, p-Akt, and t-Akt while augmenting the expression of cyclin D and pro-apoptotic Bax and Bad in HTB5 cells. Analysis of the drug combination by the isobolic method and clonogenic assay revealed that sunitinib acts in synergy with gemcitabine in HTB5 cells.ConclusionsThese results indicate that sunitinib malate has a potent anti-tumor effect and may synergistically enhance the anti-tumor effect of gemcitabine in human bladder cancer cells.

5-fluorouracil enhances the antitumor effect of sorafenib and sunitinib in a xenograft model of human renal cell carcinoma

“…Several studies have addressed the combination therapy of sorafenib/sunitinib and chemotherapeutic reagents, such as platinum, taxane, and gemcitabine (9)(10)(11)(12)(13)(14), whereas only a small number of studies have evaluated the combination with fluorinated pyrimidine (11,22). The present findings are consistent with the result reported by Takeuchi et al (22), who examined the combination effect of S-1 (an oral fluorinated pyrimidine) and sorafenib for RCC treatment in vitro and in tumor-bearing murine models.…”

“…In addition to promising preclinical and clinical data culminating in the approval of sorafenib and sunitinib, their mechanism of action, good safety and tolerability indicate that they may be a useful treatment option in combination with conventional chemotherapy for advanced solid cancers. Several studies have evaluated the effect of sorafenib or sunitinib in combination with a variety of anticancer agents in various types of tumor (9)(10)(11)(12)(13)(14).…”

Synergistic interaction between sunitinib and docetaxel is sequence dependent in human non–small lung cancer with EGFR TKIs-resistant mutation

“…These data suggest that sunitinib is efficacious for growth inhibition in EGFR TKIs-resistant NSCLC cell lines. However, the IC50 values of sunitinib to A549 and H1975 cell lines ranged from 0.4 to 24 lmol/l were 3.6 ± 0.41 lM and 3.13 ± 0.09 lM, respectively, indicating a lower sensitivity to sunitinib, as previously reported in small cell lung cancer, nasopharyngeal carcinoma, and bladder cancer Hui et al 2010;Yoon et al 2011). Hence, underlying in vitro mechanism to sunitinib sensitivity is still unclear.…”

Therapeutic potential of sepantronium bromide YM155 in gemcitabine-resistant human urothelial carcinoma cells

“…Very low IC 50 s of gemcitabine (usually <100 nM) have been reported for many TCC cell lines (26,27) except one gemcitabine-resistant TCC cell line UM-UC-3R (8). IC 50 s of gemcitabine for T24 and TSGH8301 cells in our experiments were >100 nM, and we suppose the variation may result from different cytotoxic assays and protocols.…”