Abstract 1596: Evaluation of radiosensitizing effects of KSP inhibition in cancer cells.

Abstract

Abstract Background: Several chemotherapeutic agents act as radiosensitizers, priming the cancer cells to the effects of ionizing radiation and resulting in increased tumor kill with radiotherapy. The combination of radiosensitizing chemotherapeutics and localized external beam radiation therapy is based on the scientific rationale derived from both preclinical and clinical observations of synergism between radiotherapy and chemotherapy. Recently, many kinesin spindle protein (KSP) inhibitors have undergone preclinical and clinical investigation as anticancer agents. The mitotic kinesin is an essential mitotic enzyme with no role outside of mitosis. KSP is essential for separation of spindle poles during mitosis; therefore its inhibition causes mitotic arrest and subsequent cell death. Amongst the various KSP inhibitors, SB-743921 is a highly potent second generation KSP inhibitor that has shown activity in a broad spectrum of tumor models and is now being investigated in clinical trials. We sought to investigate the radiosensitizing properties of SB-743921 in various cell lines in order to investigate its potential as a radiosensitizer for enhancing treatment efficacy in multiple cancers. Materials & Methods: We first assessed the inhibitory activity of SB-743921 in multiple cell models (hepatocellular carcinoma, colorectal cancer, breast cancer, pancreatic cancer). The half-maximal inhibitory concentrations (IC50) were determined by carrying out cell viability assays in each of these cell lines. Cancer cells were exposed to various concentrations of SB-743921 in growth medium for 72 hrs before cell viability was determined by colorimetric estimation of metabolic activity using XTT assay. Further, we evaluated the radiosensitizing effect of SB-743921 on hepatocellular carcinoma and colorectal cancer cells by performing clonogenic assays. Cells were first treated with SB-743921 for 24 hours at their respective IC50 values, followed by irradiation with 2-8 Gy doses. Post-treatment, the cells were plated at clonal density and incubated in growth medium for 10-14 days. Cells were fixed and stained, and colonies with 50 cells or more were counted. Results: The IC50 values of 4 cancer cell lines were between 0.5-2.5 nM. The results from the clonogenic assays indicate radiosensitization effect in the heptatocellular carcinoma cell line, whereas in the colorectal cancer cell line, radiosensitization was not observed. Conclusion and Future studies: From our results, it can be concluded that KSP inhibition with SB-743921 radiosensitizes some types of cancer, but not all. More cancer cell lines are currently being evaluated to demonstrate a relationship between cancer type and the radiosensitization effect by KSP inhibition. In future, in vivo chemoradiation experiments in mice will be performed in multiple cancer models to further assess the radiosensitization effect by KSP inhibition. Citation Format: Ripen Misri, Nelson Wong, Mohamed Khan. Evaluation of radiosensitizing effects of KSP inhibition in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1596. doi:10.1158/1538-7445.AM2013-1596