Withaferin A downregulates NDRG1 to overcome hypoxia mediated EMT and chemoresistance in lung adenocarcinoma and glioma cells

One of the important hurdles to be overcome in the management of cancers is the acquired resistance to therapy. There is a crucial need to not only understand molecular pathways underpinning resistance to therapy but to find better and more effective therapeutic avenues to overcome such acquired resistance. Tumor microenvironmental conditions such as hypoxia have long been known to result in chemoresistance in various cancers that become unresponsive to standard-of-care drugs such as cisplatin. Although many new compounds are screened for their anticancer properties, the recalcitrant tumor microenviroenment has not been given due importance in many potential drugs. In this study, we examine the efficacy of Withaferin A (WA), a bioactive compound isolated from Withania somnifera, in overcoming hypoxia-induced metabolic adaptation, chemoresistance, and epithelial-to-mesenchymal transition (EMT) in both lung adenocarcinoma and glioma cells. Our results reveal that WA significantly inhibits hypoxia-induced increased migration, EMT, and metabolic reprogramming, leading to enhanced cytotoxicity in otherwise chemoresistant cancer cells. WA treatment suppressed the expression of markers of EMT, glucose metabolism, and bonafide hypoxia markers, particularly NDRG1 thereby inducing cell death in these cancer cells. WA showed significant cytotoxic effects in chemoresistant lung adenocarcinoma and glioma cells, both alone or in combination with cisplatin, highlighting its potential as a therapeutic agent for overcoming chemoresistance in these cancers. Our results provide new insights into the anti-cancer mechanisms of WA especially under hypoxic conditions, and support its further investigation as a promising adjunctive therapy for the treatment against hypoxia-induced chemoresistance in cancers.