Cancer drugs, genetic variation and the glutathione-S-transferase gene family

Abstract

The glutathione-S-transferase (GST) super family comprises multiple isozymes (Alpha, Mu, Pi, Omega, Theta, and Zeta) with compelling evidence of functional polymorphic variation. Over the last two decades, a significant body of data has accumulated linking aberrant expression of GST isozymes with the development and expression of resistance to cancer drugs. Clinical correlation studies show that genetic differences within the human GST isozymes may play a role in cancer susceptibility and treatment. The initial confusion was presented by the fact that not all drugs used to select for resistance were substrates for thioether bond catalysis by GSTs. However, recent evidence that certain GST isozymes possess the capacity to regulate mitogen activated protein kinases presents an alternative explanation. This dual functionality has contributed to the recent efforts to target GSTs with novel small molecule therapeutics. While the ultimate success of these attempts remains to be shown, at least one drug is in late-stage clinical testing. In addition, the concept of designing new drugs that might interfere with protein:protein interactions between GSTs and regulatory kinases provides a novel approach to identify new targets in the search for cancer therapeutics.

Fig. 1.

Drug discovery has frequently involved the targeting of a specific protein with small molecules that act as antagonists or agonists either at active or allosteric sites. Whether resultant drugs act competitively or non-competitively depends upon the actual site and avidity of binding. The impact on a target enzyme is usually interference with substrate-to-product conversion. More recently, the principle of interference with protein:protein interaction as a viable drug discovery approach has gained credibility. Shown in the figure is the concept of targeting an endogenous inhibitory protein (in context of this review, for example GSTP1*A). The outcome is to disassociate this protein from its partner (e.g. c-Jun N-terminal kinase) producing the agonist effect and concomitant activation of the kinase.