The Singh lab's research projects revolve around glutathione transferases (GSTs), which play an important role in drug metabolism and cellular defense against environmental and dietary chemical carcinogens (e.g., polycyclic aromatic hydrocarbons or PAHs). One of his research projects focuses on toxicological relevance of polymorphism at the GST Pi gene locus (a subclass of GSTs) in susceptibility to PAH induced cancers. These studies are based on his findings that allelic variants of GST Pi (hGSTP1-1) differ remarkably in their ability to detoxify PAH carcinogens. His colleagues are trying to generate knock-in mice for hGSTP1 variants to investigate the in vivo relevance of hGSTP1 polymorphism in defense against PAH carcinogens in an animal model. GST-catalyzed conjugation reactions are not always advantageous. For example, a number of clinically used alkylating anticancer drugs are substrates for hGSTP1-1, and its overexpression in cancer cells confers resistance to these drugs. Dr. Singh and his colleagues have shown that the allelic variants of hGSTP1-1 differ in their activity toward certain alkylating agents. Studies are in progress to test the hypothesis that individuals homozygous for high-activity allele of hGSTP1-1 may be at a greater risk for developing resistance to alkylating agents than heterozygotes or homozygotes for the low-activity allele. The Singh laboratory is also interested in investigating the anticarcinogenic effects of certain natural agents found in edible plants, including organosulfides from garlic and isothiocyanates from cruciferous vegetables such as broccoli. His more recent studies have revealed that these dietary phytochemicals can not only prevent chemically induced cancers but also inhibit the growth of tumor cells in vitro in culture and in vivo in nude mouse. Studies are in progress to elucidate the molecular mechanism for anti-neoplastic effects of these widely consumed dietary agents.
(c) identify biomarkers predictive of tissue exposure and possibly response. Some of the agents under active investigation in the Singh laboratory include: cruciferous vegetable-derived isothiocyanates, garlic-derived organosulides, and medicinal plant constituent withaferin A. As an example, recent published work from the Singh laboratory indicates suppression of glycolysis in mammary cancer prevention by withaferin A in a transgenic mouse model (JNCI, In Press, 2013). Likewise, complementary cellular and molecular biological, targeted proteomics, and molecular modeling techniques were used to identify beta-tubulin as a novel target of cancer cell growth arrest by withaferin A (WA).