ATP depletion by AG2034 mediates cell death or cytostasis in a hypoxanthine‐dependent manner in human prostate cancer cells

Abstract

AG2034 is a classical antifolate shown to be an excellent inhibitor of glycinamide ribonucleotide formyltransferase, ultimately inhibiting de novo purine synthesis. Previous studies investigating the efficacy of AG2034 against various cancer types concluded that AG2034 is cytotoxic to p53-null cells and caused cytostasis in cells with wild-type p53 due to the arrest in G1 phase of the cell cycle. In this study, we examine the effect of inhibiting de novo purine synthesis with AG2034 on proliferation and cell cycle distribution in two prostate cancer cell lines, when maintained in culture medium containing physiological concentrations of reduced folate supplemented with or without hypoxanthine. AG2034 was cytotoxic to both DU145 (with mutant p53) and PC-3 (p-53 negative) without exhibiting G1 arrest, when maintained in a hypoxanthine-deficient medium. Although total ATP was depleted to about the same level with drug treatment, the presence of hypoxanthine promoted cytostasis while its absence resulted in cell kill in both cell lines studied. Taken together, our results reveal that the prolonged effect of AG2034 at inhibiting the production of ATP, cell proliferation and cell cycle distribution is different depending on the cancer cell type and most importantly, independent of the residual level of total ATP quantified in these cells. Source: The Greenbaum Cancer Centre, Univ. of MD, Baltimore, MD 21201 and CINJ @ Cooper, Camden, NJ 08103.