The combination of Curcumin and Doxorubicin on targeting PI3K/AKT/mTOR signaling pathway: an in vitro and molecular docking study for inhibiting the survival of MDA-MB-231

The process of tumorigenesis is highly associated with the disruption of cell-cycle regulators and derangement of various signaling pathways, which end up with the inhibition of apoptosis and hyper-activation of survival pathways. The PI3K medicated AKT/mTOR pathway is the widely explained mechanism for cancer cell survival which causes the overexpression of MDM2 and downregulates the p53-BAX mediated apoptotic pathway. Curcumin (CUR), the phyto-compound, derived from Curcuma longa is currently being focused on for its anticancer activities against breast cancer cells, MDA-MB-231, not only because of its minimal cytotoxicity against healthy cells (HEK293) but also because it synergistically sensitizes the activity of Doxorubicin (DOXO) in lower doses, which can be a promising source for complementary drug development. This study aims to investigate the combinatorial effect of CUR and DOXO on PI3K/AKT/mTOR pathway proteins by sequential molecular docking analysis and MD simulation studies. The lower binding affinity of the sequentially docked protein–ligand complex proves the increasing binding affinity of CUR and DOXO in the combinatorial dose. The mRNA expressions of different genes of this pathway are observed and quantified using rt-qPCR, where the decreasing fold change (2^−∆∆Ct) indicates the suppression of the AKT/mTOR pathway after co-treatment of CUR and DOXO against MDA-MB-231 cells. These in silico and in vitro findings can be a new horizon for further in vitro and clinical trials of breast cancer treatment.