Novel carbamodithioate regulates cellular hypoxia through chemical activation of prolyl hydroxylase‐2 for breast cancer chemoprevention

Abstract

AbstractInhibition of prolylhydroxylase‐2 (PHD‐2) in both normoxic and hypoxic cells is a critical component of solid tumours. The present study aimed to identify small molecules with PHD‐2 activation potential. Virtually screening 4342 chemical compounds for structural similarity to R59949 and docking with PHD‐2. To find the best drug candidate, hits were assessed for drug likeliness, antihypoxic and antineoplastic potential. The selected drug candidate's PHD‐2 activation, cytotoxic and apoptotic potentials were assessed using 2‐oxoglutarate, MTT, AO/EtBr and JC‐1 staining. The drug candidate was also tested for its in‐vivo chemopreventive efficacy against DMBA‐induced mammary gland cancer alone and in combination with Tirapazamine (TPZ). Virtual screening and 2‐oxoglutarate assay showed BBAP‐6 as lead compound. BBAP‐6 exhibited cytotoxic and apoptotic activity against ER+ MCF‐7. In carmine staining and histology, BBAP‐6 alone or in combination with TPZ restored normal surface morphology of the mammary gland after DMBA produced malignant alterations. Immunoblotting revealed that BBAP‐6 reduced NF‐κB expression, activated PHD‐2 and induced intrinsic apoptotic pathway. Serum metabolomics conducted with 1H NMR confirmed that BBAP‐6 prevented HIF‐1α and NF‐κB‐induced metabolic changes in DMBA mammary gland cancer model. In a nutshell, it can be concluded that BBAP‐6 activates PHD‐2 and exhibits anticancer potential.