Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer

Semin Oncol. 2017 Jun;44(3):226-232. doi: 10.1053/j.seminoncol.2017.10.001. Epub 2017 Oct 10.


Background: High oxidative stress as defined by hydroxyl and peroxyl activity is often found in the stroma of human breast cancers. Oxidative stress induces stromal catabolism, which promotes cancer aggressiveness. Stromal cells exposed to oxidative stress release catabolites such as lactate, which are up-taken by cancer cells to support mitochondrial oxidative phosphorylation. The transfer of catabolites between stromal and cancer cells leads to metabolic heterogeneity between these cells and increased cancer cell proliferation and reduced apoptosis in preclinical models. N-Acetylcysteine (NAC) is an antioxidant that reduces oxidative stress and reverses stromal catabolism and stromal-carcinoma cell metabolic heterogeneity, resulting in reduced proliferation and increased apoptosis of cancer cells in experimental models of breast cancer. The purpose of this clinical trial was to determine if NAC could reduce markers of stromal-cancer metabolic heterogeneity and markers of cancer cell aggressiveness in human breast cancer.

Methods: Subjects with newly diagnosed stage 0 and I breast cancer who were not going to receive neoadjuvant therapy prior to surgical resection were treated with NAC before definitive surgery to assess intra-tumoral metabolic markers. NAC was administered once a week intravenously at a dose of 150 mg/kg and 600 mg twice daily orally on the days not receiving intravenous NAC. Histochemistry for the stromal metabolic markers monocarboxylate transporter 4 (MCT4) and caveolin-1 (CAV1) and the Ki67 proliferation assay and TUNEL apoptosis assay in carcinoma cells were performed in pre- and post-NAC specimens.

Results: The range of days on NAC was 14-27 and the mean was 19 days. Post-treatment biopsies showed significant decrease in stromal MCT4 and reduced Ki67 in carcinoma cells. NAC did not significantly change stromal CAV1 and carcinoma TUNEL staining. NAC was well tolerated.

Conclusions: NAC as a single agent reduces MCT4 stromal expression, which is a marker of glycolysis in breast cancer with reduced carcinoma cell proliferation. This study suggests that modulating metabolism in the tumor microenvironment has the potential to impact breast cancer proliferation.

Keywords: Antioxidant; Breast Cancer; N-Acetylcysteine; Tumor Metabolism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetylcysteine / therapeutic use*
  • Adult
  • Apoptosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinoma, Ductal, Breast / drug therapy*
  • Carcinoma, Ductal, Breast / metabolism
  • Carcinoma, Ductal, Breast / pathology
  • Carcinoma, Intraductal, Noninfiltrating / drug therapy*
  • Carcinoma, Intraductal, Noninfiltrating / metabolism
  • Carcinoma, Intraductal, Noninfiltrating / pathology
  • Carcinoma, Papillary / drug therapy
  • Carcinoma, Papillary / metabolism
  • Carcinoma, Papillary / pathology
  • Caveolin 1 / metabolism
  • Cell Proliferation
  • Female
  • Free Radical Scavengers / therapeutic use*
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Ki-67 Antigen / metabolism
  • Mastectomy*
  • Middle Aged
  • Monocarboxylic Acid Transporters / metabolism
  • Muscle Proteins / metabolism
  • Neoadjuvant Therapy
  • Neoplasm Staging
  • Pilot Projects
  • Stromal Cells / metabolism
  • Treatment Outcome
  • Tumor Microenvironment


  • CAV1 protein, human
  • Caveolin 1
  • Free Radical Scavengers
  • Ki-67 Antigen
  • Monocarboxylic Acid Transporters
  • Muscle Proteins
  • SLC16A4 protein, human
  • Acetylcysteine