The data were analyzed using SPSS version 16

The data were analyzed using SPSS version 16.0. to investigate the effect of the combination on (24S)-MC 976 cell proliferation, cell migration, cell apoptosis and signaling pathways involved in molecular mechanism of drug(s). The antitumor effects of either of the drugs were compared to the combination using human colon carcinoma cell line HT-29 xenograft model. Treated vs untreated tumor sections were also compared for proliferation and angiogenesis markers by immunohistochemistry. Results The combination of dovitinib and oxaliplatin showed higher cytotoxicity in colon cell lines irrespective of their RAS-RAF status as compared to either of the drugs alone. Simultaneous inhibition of MAP kinase and AKT pathways and induction of apoptosis via activation of caspases 9/caspases 3 contributed to the synergistic effect of this combination therapy. In the xenograft model, the combination showed a significantly higher antitumor activity. Immunohistochemistry of post treatment tumors showed a significant decrease in proliferation and angiogenesis as compared to either of the treatments alone. Conclusions This study demonstrates the synergistic antitumor activity of combination of dovitinib and oxaliplatin against colon cancer with different RAS-RAF status. The combination also showed its antitumor efficacy in a multidrug resistant phenotype xenograft model. This provides a basis for further investigation for its potential in clinical setting for colorectal cancer. (31%) and (9.6%) are both thought to occur early in colorectal carcinogenesis and are associated with significantly poor survival [24,25]. Although majority studies show that these two mutations are rarely observed together, a recent study in Chinese patients with CRC showed approximately 25% of the population harboring both kRAS and bRAF mutations [26]. The presence of multiple mutations has usually posed potential limitations to the inhibitors. Since receptor tyrosine kinase activation initiates these effects, they are the key targets for inhibitors [22,27]. The majority of currently available tyrosine kinase inhibitors has provided a new approach for cancer therapy and has the potential for avoiding some of the drawbacks of cytotoxic chemotherapy [22]. Targeted brokers have also offered an opportunity to reverse chemotherapy resistance and enhance response in patients with localized or advanced cancer [28]. Along with holding a great promise, (24S)-MC 976 these inhibitors have also posed drawbacks, being beneficial to only certain subpopulations of patients and limiting resistance in patients who initially responded [29-31]. Dovitinib, or TKI258 (4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2 (1H)-one; formerly known as CHIR-258), is usually a small molecule adenosine 5-triphosphateCcompetitive inhibitor of class III, IV, and V receptor tyrosine kinases (RTKs), which include fibroblast growth factor receptor (FGFR), vascular endothelial growth factor (VEGFR), Tyrosine-protein kinase kit (c-KIT), and FMS-like tyrosine kinase 3 (FLT3) [32-35]. According to previous studies, dovitinib exhibits potent tumor growth inhibition and in a broad range of preclinical animal models [32,36-38]. For example, dovitinib induced apoptosis in Fibroblast growth factor receptor (FGFR) expressing mammary cells via inhibition of Phosphoinositide-3-kinase (PI3K)/Akt signaling pathway [39]. In addition, dovitinib specifically inhibited proliferation and survival of primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome [40]. There remains a need for not only novel regimens but also refinement of existing regimens to improve and extend survival and decrease treatment related toxicities. In the present study, we hypothesized that Dovitinib may attempt to boost therapeutic kill by employing combination regimen with oxaliplatin. Our results reveal (24S)-MC 976 that co- treatment of Dovitinib and Oxaliplatin in colon cancer cell lines induced superior cell killing in comparison to either of these drugs alone in all colon cancer cell lines regardless of their Cdc14A2 mutation status. The significantly enhanced antitumor activity that results from the combination of Oxaliplatin and Dovitinib offers promise as a novel treatment for patients with colon cancer. This combination will achieve a greater anticancer effect at a lower efficacious dose with a less chance of a cell developing resistance along with reduced injury to normal cells. Results Combination of Dovitinib and Oxaliplatin inhibits cell viability and migration in colorectal carcinoma cell lines We performed MTS assay to find out the combined effect of dovitinib and oxaliplatin in colon cancer cell lines. Several human colon cancer cell lines (HCT-116, HT-29, SW-480, Caco2 and LS174T) were tested for antiproliferative effects of individual drugs after 72 h of incubation. Table ?Table11 summarizes the half maximal inhibitory concentration (IC50) values (mean standard deviation) and mutation status for different cell lines. All cell lines showed sensitivity to dovitinib in low micro molar range (3-5 M) and sensitivity to oxaliplatin varied from 1.6 0.17 M to 8.0 2.0 M. HCT-116 cell line showed highest sensitivity to both the drugs among all five colorectal cancer cell lines tested. HT-29.