Ribonucleotide reductase, the rate-limiting enzyme for de novo DNA synthesis, is an excellent target for chemotherapy. Its increased activity in cancer cells is associated with malignant transformation and proliferation. 3-AP is a ribonucleotide reductase inhibitor and iron chelator with antitumor activity. At 5 μM it can enhance DU145, U251, and PSN1 tumor cell radiosensitivity in vitro, inhibiting DNA synthesis and repair. It destroys the tyrosine free radical in the R2/p53R2 subunits of ribonucleotide reductase by forming a redox active complex with iron, thus producing reactive oxygen species. Furthermore, 3-AP has been shown to activate an endoplasmic reticulum stress pathway, leading to the unfolded protein response and apoptosis.
