Comparative Study of Curcumin, All-Trans Retinoic Acid and Resveratrol: Therapeutic Targeting of Breast Cancer Signalling

Abstract

Aims: Breast cancer is the most prevalent cancer affecting women worldwide. Aberrant signalling through the phosphatidylinositol 3’ kinase (PI3K) and extracellular signal regulated kinase (ERK) pathways promotes metastatic spread of breast carcinomas. As prevalent chemotherapeutic treatments can cause toxic side effects, exploring the anti-tumorigenic potential of natural phytochemicals as inhibitors of these pathways is important. Methodology: In our study we analyzed binding efficacy and patterns of interactions of the phytochemicals curcumin, resveratrol and all-trans retinoic acid (ATRA) with PI3K and ERK using molecular docking and computer based analysis. Results and Discussion: Molecular docking showed curcumin, ATRA and resveratrol to have very good binding affinity and interactions with PI3K-α and ERK2 indicating their excellent potential as inhibitors of these signalling cascades with ATRA showing the highest binding affinity (ΔG = -7.73 kcal/mole) to PI3K-α and curcumin showing the highest binding affinity (ΔG = -8.10 kcal/mole) to ERK2. Analysis showed that curcumin, ATRA and resveratrol interact at a similar site on PI3K-α while for ERK2, ATRA and curcumin interact at a similar site while resveratrol interacts with a different site. While most synthetic inhibitors target a single signalling pathway, curcumin, ATRA and resveratrol all show excellent potential for targeting both signalling pathways which may prevent cancer cells from circumventing treatment by activating alternative pathways. Using these phytochemicals for therapy may also help in reducing side effects. Conclusion: Our study highlights the excellent potential of curcumin, ATRA and resveratrol for targeting both PI3K and ERK signalling pathways which could lead to inhibition of breast cancer progression and metastasis and, following further in vitro and in vivo studies, pave a pathway for therapies with less side effects and better clinical outcomes.