Enhanced Antiproliferative Effects of Mitochondria-Targeted N-acetylcysteine

N-acetylcysteine (NAC) has been used as an antioxidant drug in tumor cells and preclinical mice tumor xenografts, and it improves adaptive immunotherapy in melanoma. However, NAC is not readily bioavailable and is used in high concentrations. Balaraman Kalyanaraman, PhD, professor of biophysics and the Harry R. & Angeline E. Quadracci Professor in Parkinson’s Research at MCW; Gang Cheng, PhD, assistant professor of biophysics at MCW; and Micael Hardy, PhD, of Aix-Marseille Université, France, synthesized and studied mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito₁₀-NAC) that is functionally similar to NAC to determine the effect of mitochondria-targeted thiol in cancer cell proliferation. They discuss their findings in their article, “Antiproliferative Effects of Mitochondria-Targeted N-acetylcysteine and Analogs in Cancer Cells,” published in Scientific Reports.

In this study, the investigators compared the relative antiproliferative potencies of NAC, Mito₁₀-NAC, and their methylated analogs in several cancer cells. Results show that Mito₁₀-NAC is nearly 1,500–2,000 times more potent than NAC, and that methylation of the free sulfhydryl group enhanced its antiproliferative effect. Typically, the free sulfydryl group (-SH) enhances the free radical detoxifying property of the molecule. Thus, Mito-NAC targeting mitochondria is considered as a mitochondria-targeted antioxidant. The team concludes that the antiproliferative effect of Mito₁₀-NAC is not related to the antioxidant or radical scavenging mechanism.