Abstract 5109: Chemosensitization of tumor cells by fish oil involves regulation of cell proliferation and apoptotic pathway in experimentally induced colon carcinogenesis

Abstract

Abstract Introduction In CRC, 5-FU is a antineoplastic chemotherapeutic drug, however a major drawback of 5-FU is its toxicity and low therapeutic index. Recently fish oil (FO) rich in n-3 PUFAs has been reported to chemosensitize tumor cells to anticancer drugs through regulation of cell proliferation and apoptotic pathway. Therefore, the current study is designed to understand the alteration in underlying cell proliferation and apoptotic pathway on using FO alongwith 5-FU. Experimental methods Male Balb/c mice were divided into control and N,N'-dimethylhydrazine dihydrochloride/dextran sodium sulphate (DMH/DSS) groups. DMH/DSS treated animals were kept for 20wks for development of colon cancer and further subdivided based upon the treatment with 5-FU and/or FO. After treatment, survival rate, tumor volume and burden was determined. The colonocytes were isolated and subjected to different estimations. Cell proliferation index was estimated using propidium iodide staining and expression of Ras was determined through immunofluorescence and flowcytometric method. Apoptotic index was measured by annexinV-PI double staining, M-30cytodeath expression using flowcytometer and DNA damage by comet assay. The extrinsic apoptotic pathway was delineated by Fas, FasL, Caspase8 estimation and intrinsic by Bax, Bcl-2 expression in colonocytes using flowcytometric method. The modulators of redox signalling such as ROS and Ca2+ levels were estimated using flowcytometer. Summary In the current study, FO in combination with 5-FU led to a significant increase in survival rate and decrease in tumor volume, count in contrast to other groups. 5-FU treatment led to S phase arrest which was further potentiated on combination with FO in comparison to DMH group. Administration of 5-FU+DMH significantly decreased the expression of Ras in colonocytes but the decrease was more pronounced after treatment with 5-FU+FO, suggestive of decrease in cell proliferation. In carcinogen treated animals, a significant decrease in the percentage of early apoptotic cells, M-30cytodeath expression and DNA damage was observed whereas 5-FU in combination with FO resulted in a marked increase in the above mentioned parameters and hence, an increase in apoptotic index. A significant decline in the activation of both extrinsic and intrinsic pathways was observed in carcinogen treated animals as demonstrated by decrease in the expression of Fas, FasL, Caspase8, Bax and an increase in Bcl-2. In contrast, administration of 5-FU alongwith FO significantly enhanced the activation of both extrinsic and intrinsic apoptotic pathways as compared to other groups. A significant increment in the levels of ROS and Ca2+ was reported in 5-FU+FO+DMH as compared to other groups. Conclusion The suppression of cell proliferation and activation of apoptotic pathways by FO may increase the susceptibility of chemotherapy to tumors. Note: This abstract was not presented at the meeting. Citation Format: Isha Rani, Navneet Agnihotri. Chemosensitization of tumor cells by fish oil involves regulation of cell proliferation and apoptotic pathway in experimentally induced colon carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5109. doi:10.1158/1538-7445.AM2014-5109