Inactivation of ribonucleotide reductase in tumour cells and inhibition of tumour cell growth by p-alkoxyphenols.

Abstract

A significant correlation between the inactivation of the growth-regulating enzyme ribonucleotide reductase (RR) with the growth inhibition of four different tumour cell lines has been found for seven different p-alkoxyphenol derivatives with varying lengths of alkyl side chain. In Novikoff hepatoma and human leukaemia cells, inactivation of RR by p-alkoxyphenols was monitored by electron paramagnetic resonance (EPR) spectroscopy of the catalytically essential tyrosyl radical in the subunit R2 of RR. A significant inhibition of cellular growth of Novikoff hepatoma cells, human leukaemia cells and two human melanoma cell lines (MeWo and M5) by p-alkoxyphenols was also observed by growth inhibition assays. Inactivation of RR in whole tumour cells as well as inhibition of cellular growth of tumour cell lines by p-alkoxyphenols both show an increase in inhibition with increasing length of the alkyl side chain; the most effective inhibitors are p-isobutoxyphenol, p-butoxyphenol and p-propoxyphenol. The enzyme RR, and in particular the catalytically essential tyrosyl radical in the active site, is recognized as an important cellular target for growth inhibition of Novikoff hepatoma cells, human leukaemia cells and melanoma cells by p-alkoxyphenols. Thus, the most potent RR inhibitors-p-isobutoxyphenol, p-butoxyphenol and p-propoxyphenol-may be considered as future antiproliferative drugs for the systemic treatment of melanoma as well as leukaemia and possibly other malignancies.