Natural Small Molecules as Stabilizers and Activators of Cancer-Associated NQO1 Polymorphisms

quinone oxidoreductase 1 (NQO1) is an antioxidant and detoxifying enzyme involved in the two-electron reduction of a wide variety of quinones. As a non-enzymatic function, it is involved in the stabilization of several tumour suppressors such as p53, p33 and p73α. NQO1 is overexpressed in several types of tumours, and two common polymorphisms are associated with increased cancer risk, making NQO1 a potential target for new cancer treatments. Here we review the structural and enzymological properties of NQO1, as well as its roles in cancer development and treatment. Particularly, we focus on recent developments on the understanding of the molecular basis leading to loss-of-function in cancer-associated polymorphisms, and propose new approaches to target these molecular defects to develop new pharmacological agents to rescue them. We will focus on pharmacological therapies aimed at correcting the abnormal properties of polymorphic proteins (such as protein stability and dynamics) and modulating intracellular factors leading to loss-of-function (such as accelerated proteasomal degradation).