Potent antitumor activity of Laccaic acid and Phenethyl isothiocyanate combination in colorectal cancer via dual inhibition of DNA methyltransferase-1 and Histone deacetylase-1

Highlights: • Laccaic acid plus Phenethyl isothiocyanate showed potent activity against colorectal cancer • This activity is due to dual inhibition of DNA methyltransferase-1 and Histone deacetylase-1 • Cell line studies in HT29 cell lines showed potent synergistic action with combination index 0.13 • In rat model of colon cancer, combination showed potent efficacy along with better safety • This combination can be a potent therapeutic approach in the treatment of colorectal cancer -- Abstract: Despite an incessant advancement in the treatment of Colorectal Cancer (CRC), 40% of individuals suffer from disease relapse which marks the need for new treatment options. In this study we report synergistic antitumor activity of Laccaic acid (LA) and Phenethyl isothiocyanate (PEITC) combination in colorectal cancer via dual inhibition of DNA methyltransferase-1 and Histone deacetylase-1. Efficacy of combination was evaluated in both in-vitro and in-vivo experiments using human colon carcinoma cell line HT29 and 1,2-dimethyl hydrazine induced colon cancer rat model, respectively. In the cell line studies treatment with combination showed reduced cell viability with apoptotic cell death compared to individual treatment groups which showed necrotic cell death. IC50 value for combination (0.478 μM) was much lower than LA (6.08 μM), PEITC (11.88 μM) and 5-Fluorouracil (9.88 μM). In the in-vivo study combination group significantly attenuated number of aberrant crypt foci, fecal consistency score, IL-6, TNF-α, DNMT1 and HDAC1 levels, histological findings and mortality as compared to negative control. Further, toxic effects produced by combination were significantly less. Results suggest potent synergistic efficacy of Laccaic acid and Phenethyl isothiocyanate combination in colorectal cancer.