Naturally occurring benzoic acid derivatives retard cancer cell growth by inhibiting histone deacetylases (HDAC)

Histone deacetylases (HDACs), which modulate the expression of genes, are potential therapeutic targets in several cancers. Targeted inhibition of HDAC prevents the expression of oncogenes thereby help in the treatment of cancers. Hence, several pharmaceutical companies developed inhibitors of HDAC and tested them in preclinical models and in clinical trials. SAHA (suberanilohydroxamic acid) is one such HDAC inhibitor developed for treating breast and colorectal carcinomas. However, due to poor efficacy in clinical trials the utility of SAHA for treating cancers was discouraged. Similarly another HDAC inhibitor Trichostatin-A (TSA) also showed promising results in clinical trials but exhibited severe adverse effects, which dampened the interest of using this molecule for cancer treatment. Therefore, search for developing a potent HDAC inhibitor with minimal side effects still continues. Hence, in this study we have screened benzoic acid and benzoic acid derivatives with hydroxylic (-OH) groups and methoxy (-OCH3) groups for their efficacy to bind to the TSA binding site of HDAC using molecular docking studies. Molecules that showed much stronger affinity (than TSA) to HDAC were tested for inhibiting HDAC expressing cultured cancer cells. DHBA but not Dimethoxy Benzoic Acid (DMBA) inhibited HDAC activity, leading to cancer cell growth inhibition through the induction of ROS and cellular apoptosis mediated by Caspase-3. In addition, DHBA arrested cells in G2/M phase of the cell cycle and elevated the levels of sub-G0-G1 cell population. In summary, results of this study report that DHBA could be a strong HDAC inhibitor and inhibit cancer cell growth more effectively.