Exploiting Novel-Calcium-Mediated Apoptotic Processes for the Treatment of Human Breast Cancers with Elevated NQO1 Levels
Abstract
Beta-lapachone (beta-lap; a.k.a. ARQ 501) is currently in Phase II clinical trials for the treatment of pancreatic adenocarcinoma in combination with gemcitabine. Beta-Lap is a novel antitumor agent that is bio-activated by the two-electron oxidoreductase NAD(P)H quinone oxidoreductase-1 (NQO1) (E.C. 1.6.99.2). Since NQO1 is highly expressed in many human cancers (e.g. breast, lung, pancreatic, and prostate cancer) it is an attractive target for selective cancer chemotherapy by beta-lap alone or in combination with IR (1-3). We previously reported that the initiation of beta-lap-induced cell death is triggered by the NQO1-dependent oxidoreduction of beta-lap (1). NQO1-mediated metabolism of beta-lap results in a futile cycling event wherein beta-lap is reduced to an unstable hydroquinone that reverts spontaneously back to its parent structure, using two molecules of oxygen (4). As a result, ROS are generated causing DNA damage, beta-H2AX foci formation, poly(ADP-ribose) polymerase-1 (PARP-1) hyperactivation, and subsequent loss of ATP and NAD+ (5). This loss of ATP and NAD+ was proposed to be the mechanism by which beta-lap could enhance the sensitivities of a variety of chemotherapeutic therapies as well as IR (6). B-lap-induced cell death was unique in that PARP-1 and p53 were cleaved concomitant with -calpain activation, consistent with the fact that global caspase inhibitors had little effect on beta-lap-induced proteolysis and lethality (1, 7). Interestingly, beta-lap-mediated cell death exhibited classical features of apoptosis (e.g. DNA condensation, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells), but was not dependent on standard apoptotic mediators such as p53, Bax/Bak, or caspases (8).
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2007
- Accession Number
- ADA469426
Entities
People
- David A. Boothman
- Melissa S. Bentle
Organizations
- Case Western Reserve University