Resveratrol improves the anticancer effects of doxorubicin in vitro and in vivo models. - GreenMedInfo Summary
Resveratrol improves the anticancer effects of doxorubicin in vitro and in vivo models: A mechanistic insight.
Phytomedicine. 2016 Mar 15 ;23(3):233-42. Epub 2016 Jan 27. PMID: 26969377
BACKGROUND: Resveratrol (RSVL), a well known dietary compound and in combination with doxorubicin (DOX) has gained a global importance for cancer prevention. However, mechanism of action by this combination is not well understood till date.
HYPOTHESIS: The synergistic combination of RSVL and DOX might be more effective in anti-cancer activity by modulating the diverse cancer signaling pathways as compared to their alone treatments.
METHODS: The cytotoxicity of alone and combination doses of RSVL and DOX were analyzed by colorimetric MTT(3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) cell proliferation assay. The migration and colony forming abilities were evaluated by wound healing and clonogenic assays. Apoptosis was detected by Annexin V/PI and DAPI stainings. The cell cycle and intracellular reactive oxygen species (ROS) generation were measured by flow cytometry. The differential expression of genes and proteins were measured by qRT-PCR and western blotting analyses. Finally, in-vivo studies were performed in Ehrlich ascitic carcinoma (EAC) mouse model.
RESULTS: The synergistic combination of DOX (IC20) and RSVL (IC30) was selected based on the combination index values in MCF-7 and MDA-MB-231 cell lines. This combination showed potent growth inhibition with∼2.5 fold of dose advantage and also significantly decreased the wound healing and clonogenic potential of breast cancer cells. The combination treatment was also found to inhibit the inflammatory response (NF-kB, COX-2), autophagic flux (LC3, Beclin-1), redox regulation (Nrf2) and induces apoptosis (BAX: BCL-2 ratio and Caspase-9) in breast cancer cells. Further, combined dosages of DOX (5mg/kg b.wt) and RSVL (10mg/kg b.wt) inhibited tumor volume with increased life span (139%, p value<0.05) in Ehrlich ascitic carcinoma (EAC) cells bearing mice.
CONCLUSION: In brief, our results suggested that resveratrol chemosensitizes doxorubicin in combination, through inhibiting breast cancer cells proliferation and invasion, and inducing apoptosis via suppression of chronic inflammation and autophagy.