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An Endogenous Reactive Oxygen Species (ROS)‐Activated Histone Deacetylase Inhibitor Prodrug for Cancer Chemotherapy
Author(s) -
Bhagat Somnath D.,
Singh Usha,
Mishra Ram Kumar,
Srivastava Aasheesh
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800367
Subject(s) - vorinostat , prodrug , reactive oxygen species , histone deacetylase inhibitor , cancer cell , chemistry , cancer research , histone deacetylase , apoptosis , cancer , hela , pharmacology , biochemistry , histone , cell , biology , genetics , gene
Suberoylanilide hydroxamic acid (SAHA, vorinostat) is a potent small‐molecule pan‐inhibitor of histone deacetylases (HDACs) approved for treatment of cutaneous T‐cell lymphoma (CTCL). However, SAHA exhibits poor selectivity for cancer cells over noncancer cells. With an aim to improving its selectivity for cancer cells, we generated a novel SAHA prodrug (SAHA‐OBP) that is activated in the presence of hydrogen peroxide, 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 4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)benzyl carbonyl (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 toward noncancer cells. The downstream effects of SAHA released from SAHA‐OBP in cancer cells is the induction of apoptosis. SAHA‐OBP was also found to be effective on multicellular tumor spheroids (MCTS). The SAHA prodrug designed in this study undergoes rapid ROS‐dependent activation and imparts much‐needed selectivity to SAHA for cancer cells.