Ameliorated Chemotherapeutic Potential of Diverse Dose Flouropyrimidine Therapy By Etodolac via NF-?B Pathway, PPAR-? Expression and COX-II Inhibition in DMH Induced Colon Cancer Rats

Abstract

Background: 5-Flurorouracil (5-FU) chemotherapy has been one of the extensively employed standard therapies for the treatment of colon cancer. Various molecular interventions and dose modulations in the form of adjuvant therapies has been exploited for better therapeutic efficacy and low adverse effects to improve overall survival rate in advanced colorectal cancer. Non-steroidal anti-inflammatory drugs (NSAIDs) have shown huge potential to supplement the classical chemotherapeutic regimens in order to achieve better cytotoxic potency against cancer cells and specifically through targeting of multi apoptotic pathways and inflammatory markers. Methods: The present investigation was carried out to study the effect of etodolac (ETD) on the therapeutic spectrum of 5-FU in colon cancer in order to regress the dose related adverse potential by modulating the 5-FU dose in 1,2 dimethylhydrazine (DMH) induced colon cancer rats and to explore the molecular apoptotic pathways involved. Results: Diverse dose combination therapy of 5-FU plus ETD (FEC1; high dose combination of 5-FU and ETD in ratio of 4:1), FEC2; medium dose combination of 5-FU and ETD in ratio of 3:1) and (FEC3; low dose combination of 5-FU and ETD in ratio of 2:1) showed significant decrease in the tumor burden in a dose dependent manner (i.e. FEC1>FEC2>FEC3) in comparison to monotherapy. Further, the combination therapy also showed significantly enhanced apoptosis in DMH induced colon cancer rats in comparison to monotherapy. Conclusions: ETD could be a useful intervention as adjuvant therapy for increasing the cytotoxic potential of 5-FU at lower therapeutic dose. The present study showed the immense application and future role of ETD as an adjuvant agent in fluorouracil based combination strategy to widen therapeutic spectrum and increased apoptosis in cancer cells. To best of our knowledge, this report for the first time elucidates the enhanced therapeutic efficacy of low dose 5-FU in combination with ETD via nuclear factor kappa-B (NF-κB), peroxisome proliferator activator receptor-gamma (PPAR-γ), tumor necrosis factoralpha (TNF-α) and cyclooxygenase–II (COX-II) pathway in DMH induced colon cancer rats. Keywords: Colon cancer, DMH, ETD, 5-FU, COX-II inhibitor.