Faculty Collaboration Database

Antiproliferative effects of mitochondria-targeted N-acetylcysteine and analogs in cancer cells. Sci Rep 2023 May 04;13(1):7254

Date

05/05/2023

Pubmed ID

37142668

Pubmed Central ID

PMC10160116

DOI

10.1038/s41598-023-34266-w

Scopus ID

2-s2.0-85158068757 (requires institutional sign-in at Scopus site)   2 Citations

Abstract

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. NAC is not readily bioavailable and is used in high concentrations. The effects of NAC have been attributed to its antioxidant and redox signaling role in mitochondria. New thiol-containing molecules targeted to mitochondria are needed. Here, mitochondria-targeted NAC with a 10-carbon alkyl side chain attached to a triphenylphosphonium group (Mito₁₀-NAC) that is functionally similar to NAC was synthesized and studied. Mito₁₀-NAC has a free sulfhydryl group and is more hydrophobic than NAC. Mito₁₀-NAC is nearly 2000-fold more effective than NAC in inhibiting several cancer cells, including pancreatic cancer cells. Methylation of NAC and Mito₁₀-NAC also inhibited cancer cell proliferation. Mito₁₀-NAC inhibits mitochondrial complex I-induced respiration and, in combination with monocarboxylate transporter 1 inhibitor, synergistically decreased pancreatic cancer cell proliferation. Results suggest that the antiproliferative effects of NAC and Mito₁₀-NAC are unlikely to be related to their antioxidant mechanism (i.e., scavenging of reactive oxygen species) or to the sulfhydryl group-dependent redox modulatory effects.

Author List

Cheng G, Hardy M, Kalyanaraman B

Authors

Gang Cheng PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin
Micael Joel Hardy PhD Visiting Assistant Professor in the Biophysics department at Medical College of Wisconsin
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acetylcysteine
Animals
Antioxidants
Humans
Mice
Mitochondria
Pancreatic Neoplasms
Reactive Oxygen Species