Pilot study demonstrating metabolic and anti-proliferative effects of in vivo anti-oxidant supplementation with N-Acetylcysteine in Breast Cancer.
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.
['Monti|Daniel|D|', 'Sotgia|Federica|F|', 'Whitaker-Menezes|Diana|D|', 'Tuluc|Madalina|M|', 'Birbe|Ruth|R|', 'Berger|Adam|A|', 'Lazar|Melissa|M|', 'Cotzia|Paolo|P|', 'Draganova-Tacheva|Rossitza|R|', 'Lin|Zhao|Z|', 'Domingo-Vidal|Marina|M|', 'Newberg|Andrew|A|', 'Lisanti|Michael P|MP|', 'Martinez-Outschoorn|Ubaldo|U|']
D000111:Acetylcysteine D000328:Adult D017209:Apoptosis D001943:Breast Neoplasms D018270:Carcinoma, Ductal, Breast D002285:Carcinoma, Intraductal, Noninfiltrating D002291:Carcinoma, Papillary D051242:Caveolin 1 D049109:Cell Proliferation D005260:Female D016166:Free Radical Scavengers D006801:Humans D007150:Immunohistochemistry D020287:In Situ Nick-End Labeling D019394:Ki-67 Antigen D008408:Mastectomy D008875:Middle Aged D027501:Monocarboxylic Acid Transporters D009124:Muscle Proteins D020360:Neoadjuvant Therapy D009367:Neoplasm Staging D010865:Pilot Projects D017154:Stromal Cells D016896:Treatment Outcome D059016:Tumor Microenvironment
N-Acetylcysteine Breast Cancer Antioxidant Tumor Metabolism