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

Abstract

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, which reduces oxidative stress, 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 (IV) at a dose of 150mg/kg and 600mg twice daily orally on the days not receiving NAC IV. Histochemistry (HC) 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.

Quercetin induced NUPR1-dependent autophagic cell death by disturbing reactive oxygen species homeostasis in osteosarcoma cells

“…Great attention has been paid to the anti-tumor effects of NAC. Recently, Monti et al (32) reported that NAC as a single agent reduced MCT4 stromal expression, which is a marker of glycolysis in breast cancer with reduced carcinoma cell proliferation in a clinical trial. However, other previous studies confirmed NAC inhibited anti-tumor effect of some chemical agents isolated from the plant, such as britannin, (33) Umbilicaria esculenta, (34) and cryptotanshinone.…”

Metabolic Reprogramming of Cancer Associated Fibroblasts: The Slavery of Stromal Fibroblasts

“…In fact, Monti et al demonstrated in a clinical trial that NAC, reducing MCT-4 expression in the tumour stroma of cancer patients, decreases carcinoma cell proliferation rates in women with stages 0 and I breast cancer. This pilot clinical trial showed NAC effectiveness and safety in breast cancer treatment [ 91 ]. Moreover, NAC in combination with topotecan underwent a phase 2 clinical trial in ovarian cancer patients, based on their role in the regulation of Cav-1, MCT-4, and HIF-1 α expression [ 20 ].…”

Fructose 2,6-Bisphosphate in Cancer Cell Metabolism

“…In the same clinical trial, metformin was shown to induce CAV1 expression in CAFs, preventing the metabolic coupling between stromal and cancer cells ( 240 , 241 ). Another example of effective anti-metabolic cancer therapies is the use of N-acetyl cysteine (NAC), whose antioxidant potential reduced both the proliferation of cancer cells and the expression of the metabolic coupling monocarboxylate transporter 4 (MCT4) in stromal cells in a clinical trial in breast cancer ( 242 ). In summary, inhibiting oxidative metabolism or altering the redox state of tumors appear as promising approaches for the treatment of cancer.…”