An Endogenous Reactive oxygen species (ROS)-activated HDAC inhibitor prodrug for cancer chemotherapy.

An Endogenous Reactive oxygen species (ROS)-activated HDAC inhibitor prodrug for cancer chemotherapy. ChemMedChem. 2018 Aug 02;: Authors: Srivastava A, Bhagat SD, Singh U, Mishra RK Abstract Suberoylanilide hydroxamic acid (SAHA) is a potent small molecule pan-inhibitor of histone deacetylases (HDACi) approved for treatment of Cutaneous T-cell Lymphoma (CTCL). However, SAHA exhibits poor selectivity for cancer cells over non-cancer cells. Towards improving its selectivity for cancer cells, we exemplify a novel SAHA prodrug (SAHA-OBP) that gets activated in the presence of H2O2, a reactive oxygen species (ROS) known to be overexpressed in cancer cells. The high endogenous ROS content in cancer cells triggers rapid removal of the OBP cap to release active SAHA. The SAHA-OBP prodrug demonstrates selective activity against multiple cancer cell lines such as HeLa, MCF-7, MDA-MB-231 and B16-F10, while remaining benign to non-cancer cells. The downstream effects of SAHA released from SAHA-OBP in cancer cells is the induction of apoptosis. SAHA-OBP was also effective on multicellular tumor spheroids (MCTS). Thus, the SAHA-prodrug designed here undergoes a rapid, ROS-dependent activation and imparts the much-needed selectivity to SAHA towards cancer cells. PMID: 30070768 [PubMed - as supplied by publisher]
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research