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.