naphthoquinones and tanespimycin

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.

Topics: Antineoplastic Agents; Benzoquinones; Drug Resistance, Neoplasm; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mitomycin; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Neoplasms; Polymorphism, Genetic; Quinones; Rifabutin

A hallmark of cancer cells is their ability to reprogram nutrient metabolism. Thus, disruption to this phenotype is a potential avenue for anti-cancer therapy. Herein we used a phenotypic chemical library screening approach to identify molecules that disrupted nutrient metabolism (by increasing cellular oxygen consumption rate) and were toxic to cancer cells. From this screen we discovered a 1,4-Naphthoquinone (referred to as BH10) that is toxic to a broad range of cancer cell types. BH10 has improved cancer-selective toxicity compared to doxorubicin, 17-AAG, vitamin K3, and other known anti-cancer quinones. BH10 increases glucose oxidation via both mitochondrial and pentose phosphate pathways, decreases glycolysis, lowers GSH:GSSG and NAPDH/NAPD

Topics: Benzoquinones; Cell Line, Tumor; Cell Survival; Doxorubicin; Glycolysis; Humans; Lactams, Macrocyclic; Mitochondria; Naphthoquinones; Oxidative Stress; Oxygen Consumption; Phenotype; Small Molecule Libraries; Vitamin K 3