Proscillaridin A as a multifaceted anticancer agent: Mechanistic insights and therapeutic prospects

Proscillaridin A (PSD-A) is a bufadienolide-type cardiac glycoside found in both plants, such as Drimia maritima, and animals, such as toads and snakes. It has been used to treat heart conditions due to its inhibition of the Na+/K+ ATPase pump. However, recent preclinical research in various cancer cell lines and in vivo studies suggests that it may possess anticancer activity through varied mechanisms of action. It acts by activating both intrinsic and extrinsic apoptotic pathways, inducing mitochondrial membrane depolarization, and causing cell cycle arrest. It also exerts its anti-tumor effects by inhibiting topoisomerases, inhibiting DNA synthesis, and inducing MYC degradation. PSD-A disrupts cancer cell survival by suppressing STAT3 activation through inhibition of upstream tyrosine kinases and by modulating the JNK and p38 MAPK signaling pathways. Furthermore, PSD-A induces endoplasmic reticulum stress and inhibits the antioxidant system by depleting glutathione and inhibiting thioredoxin reductase activity. Moreover, PSD-A reactivates tumor suppressor genes through the MeCP2 pathway. Although no dedicated clinical trials for PSD-A in cancer were identified, related cardiac glycosides are being evaluated for repurposing. A central challenge is the narrow therapeutic window of this compound class, since the cytotoxic concentrations reported in vitro may approach those associated with cardiotoxicity; the extent to which a cancer-selective window is clinically achievable remains to be established. This review highlights the complex mechanisms of action of PSD-A and its potential as a promising candidate for further investigation in cancer therapy.