Targeted inhibition of CD47 expression in Human cancer cell lines on treatment with Cardiac Glycosides

Abstract The interest has grown in therapeutically targeting Hypoxia-inducible factor 1α (HIFα), which directly stimulates the expression of cluster of differentiation 47 (CD47) on the cell surface that suppresses phagocytosis in cancer cells. Increased expressions of CD47 and counter interaction with signal regulatory protein alpha (SIRPα) enable cancer cells to avoid cell-mediated cell destruction. On the other side, decreased expression of SIRPα was reported to promote growth. Thus, colossal concern and curiosity arise in identifying the molecular mechanism behind this suppressive effect of CGs in controlling cancer cells. We first report that cardiac glycosides (CGs) inhibit HIFα and CD47 in human breast, lung, and liver cancer cells. Furthermore, our analysis through TCGA (The Cancer Genome Atlas) data shows that these three potential genes correlate with poor survival in breast, lung, and liver cancers. Our molecular docking and molecular dynamic simulations studies demonstrated the interaction of the mentioned CGs with target proteins and identified the stability. Importantly, unlike any other anti-CD47 antibodies, the antitumor activity of CGs has been evaluated in many cancers with no hematologic toxicities. These findings would help to develop clear strategies to target CD47 and SIRPα interaction through HIF1-α inhibitors to promote phagocytosis.