Abstract 1188: Sodium phenylbutyrate has an antineoplastic effect and enhances the cytotoxicity of 5-fluorouracil and irinotecan in colorectal cancer cell lines

Abstract

Abstract Colorectal cancer is the third most common cancer in the world and it is the second leading cause of cancer-related deaths in the United States. About 25% of colorectal cancer cases present with metastases at time of diagnosis and 50% of patients who undergo surgery will ultimately develop metastatic disease. Consequently, adjuvant chemotherapy is required in many cases and it aims to prevent tumor progression and metastasis. Resistance to chemotherapy is the biggest obstacle in the treatment path of advanced colorectal cancer. Thus, highlighting the urgent need for the identification of new therapeutic agents that can enhance the cytotoxicity of the currently approved anticancer drugs. Sodium phenylbutyrate (NaPB), a salt of a short chain fatty acid that is used for treatment of urea cycle disorders, is under investigation for its antineoplastic potential. NaPB acts as a histone deacetylase inhibitor and it has been shown to be associated with reduced ER stress and enhanced JNK signaling pathway. This indicates that NaPB may enhance the cytotoxicity of the currently approved agents for colorectal cancer including oxaliplatin, 5-fluorouracil, and irinotecan. The aims of this study were to identify the antineoplastic potential of NaPB in colorectal cell lines, and to identify its effect on the cytotoxicity of oxaliplatin, 5-fluorouracil, and irinotecan. MTT proliferation assay showed that NaPB possessed a concentration dependent killing effect against HCT-116 and HT-29 colorectal cancer cell line (IC50 values were 5 and 10 mM respectively). Moreover, at clinically achievable and nontoxic concentration (2.5 mM), NaPB showed a synergistic effect in HCT-116 on 5-fluorouracil (R=14.176, p=0.006), on irinotecan (R=53.86, p=0.0117), and on oxaliplatin (R=20, p=0.004), but resulted in extensive cytotoxicity when used at 5 mM and 10 mM. In HT-29 cells, NaPB at concentrations 5 mM and 10 mM, showed a synergistic effect on 5-fluorouracil (R=5.5, p<0.001; and R=125, p<0.001 respectively), on irinotecan (R=5.7, p=0.016; and R=21.3, p=0.018 respectively), and on oxaliplatin (R=2.4, p=0.003; and R=3, p=0.002 respectively). The addition of NaPB at concentration of 20 mM to the previous drugs resulted in profound cytotoxic effect toward HT-29 cells. As a conclusion, NaPB is a promising new adjuvant antineoplastic agent that can be used to enhance the cytotoxicity of 5-fluorouracil, irinotecan, and oxaliplatin in colorectal cancer. Citation Format: Maha Al-Keilani, Ruba Darweesh. Sodium phenylbutyrate has an antineoplastic effect and enhances the cytotoxicity of 5-fluorouracil and irinotecan in colorectal cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1188. doi:10.1158/1538-7445.AM2017-1188