3-AP

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.¹ 3-AP is a ribonucleotide reductase inhibitor and iron chelator with antitumor activity.² At 5 μM it can enhance DU145, U251, and PSN1 tumor cell radiosensitivity in vitro, inhibiting DNA synthesis and repair.² 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.³ Furthermore, 3-AP has been shown to activate an endoplasmic reticulum stress pathway, leading to the unfolded protein response and apoptosis.⁴

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1. Szekeres, T., Fritizer, M., Strobl, H., et al. Synergistic growth inhibitory and differentiating effects of trimidox and tiazofurin in human promyelocytic leukemia HL-60 cells. Blood 84(12), 4316-4321 (1994).

2. Barker, C.A., Burgan, W.E., Carter, D.J., et al. In vitro and in vivo radiosensitization induced by the ribonucleotide reductase inhibitor triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone). Clin. Cancer Res. 12(9), 2912-2918 (2006).

3. Chapman, T.R., and Kinsella, T.J. Ribonucleotide reductase inhibitors: A new look at an old target for radiosensitization. Front. Oncol. 1, 56 (2012).

4. Trondl, R., Flocke, L.S., Kowol, C.R., et al. Triapine and a more potent dimethyl derivative induce ER stress in cancer cells. Mol. Pharmacol. 85(3), 451-459 (2013).