NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones

Abstract

Quinones represent a large and diverse class of antitumor drugs and many quinones are approved for clinical use or are currently undergoing evaluation in clinical trials. For many quinones reduction to the hydroquinone has been shown to play a key role in their antitumor activity. The two-electron reduction of quinones by NQO1 has been shown to be an efficient pathway to hydroquinone formation. NQO1 is expressed at high levels in many human solid tumors making this enzyme ideally suited for intracellular drug activation. Cellular levels of NQO1 are influenced by the NQO1*2 polymorphism. Individuals homozygous for the NQO1*2 allele are NQO1 null and homozygous NQO1*2*2 cell lines have been shown to be more resistant to antitumor quinones when compared to isogenic cell lines overexpressing NQO1. In this review we will discuss the role of NQO1 in the sensitivity and resistance of human cancers to the quinone antitumor drugs mitomycin C, β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors including 17-AAG. The role of NQO1 in the bioreductive activation of mitomycin C remains controversial but pre-clinical data strongly suggests a role for NQO1 in the activation of β-lapachone and the benzoquinone ansamycin class of Hsp90 inhibitors. Despite a large volume of preclinical data demonstrating that NQO1 is an important determinant of sensitivity to these antitumor quinones there is little information on whether the clinical response to these agents is influenced by the NQO1*2 polymorphism. The availability of simple assays for the determination of the NQO1*2 polymorphism should facilitate clinical testing of this hypothesis.

Figure 1

Chemical structures of mitomycin C, β-lapachone and 17-AAG The quinone moiety is highlighted in red. 17-AAG, 17-N-allylamino-17-demethoxygeldanamycin.

Figure 2

Pathways for bioreductive activation of antitumor quinones by NQO1 (ROS, reactive oxygen species).

Figure 3

The role of NQO1 in the bioactivation of mitomycin C and β-lapachone. (A) Reduction of MMC by NQO1 generates leucomitomycin C (MMC hydroquinone) which under basic conditions alkylates NQO1 in the active site preventing further metabolism. Under acidic conditions, the leucomitomycin C escapes the active site in NQO1 and can alkylate important biomolecules such as DNA or form the major metabolite 2,7-diaminomitosene (2,7-DAM); (B) Reduction of β-lapachone by NQO1 forms an unstable hydroquinone which interacts with molecular oxygen to generate reactive oxygen species leading to apoptosis.

Figure 4

The Role of NQO1 in potentiating the antitumor activity of benzoquinone ansamycins. Solid lines represent major pathways. Dashed lines represent minor pathways. BQA, benzoquinone ansamycin quinone; BQAH₂, benzoquinone ansamycin hydroquinone; BQA-GS, benzoquinone ansamycin quinone-glutathione conjugate; Hsp90, heatshock 90 protein.