Pro-apoptotic genes as new targets for single and combinatorial treatments with resveratrol and curcumin in colorectal cancer.

Abstract

Colorectal cancer (CRC) represents the third most diagnosed type of cancer worldwide with high mortality and an increased incidence rate. Bioactive dietary components such as curcumin and resveratrol have great therapeutic potential as they can modulate a plethora of signaling pathways related to colorectal carcinogenesis. Previous data have demonstrated that curcumin and resveratrol can induce apoptosis in different types of cancer cells. Considering the lack of data on the combinatorial effect of curcumin and resveratrol associated with the induction of apoptosis in colorectal pathology, the main objective of this study is to investigate the impact of single vs. combinatorial treatment of resveratrol and curcumin on their cytotoxic effects, as well as the modulation of several essential pro-apoptotic genes, on two colorectal cancer cell lines (DLD-1 and Caco-2) different in terms of chromosomal stability (MSI and MSS). The cytotoxic effects were evaluated by the MTT assay, the nature of the interaction between curcumin and resveratrol was assessed by the combination index method and the expression levels of key genes involved in the modulation of pro-apoptotic mechanisms were evaluated by RT-qPCR. Our data indicate that the combination treatment of curcumin and resveratrol is more effective in inhibiting the proliferation in a dose-dependent manner, with a synergistic effect for the DLD-1 cell line (CI < 1) and an additive effect for the Caco-2 cell line (CI ≥ 1). The IC50 values for the combination treatment were 71.8 μM (20.5 μM curcumin + 51.3 μM resveratrol) for the DLD-1 cell line and 66.21 μM (18.9 μM curcumin + 47.3 μM resveratrol) for the Caco-2 cell line, respectively. Our data pointed out, for the first time, that several genes involved in the modulation of apoptosis, including PMAIP1, BID, ZMAT3, CASP3, CASP7, and FAS, represent new targets of both singular and combinatorial treatments with resveratrol and curcumin, and also the combinatorial approach of curcumin and resveratrol exhibits a more powerful gene regulating effect compared to single treatment. Considering the beneficial aspects of the combinatorial approach with curcumin and resveratrol on colorectal cancer cells further studies should address the possible pharmacological benefits of using a combination of both dietary agents with different chemotherapeutic drug approaches.