Abstract
N-acetylcysteine (NAC) is a widely used antioxidant with therapeutic potential. However, the cancer-promoting effect of NAC observed in some preclinical studies has raised concerns regarding its clinical use. Reactive oxygen species (ROS) can mediate signaling that results in both cancer-promoting and cancer-suppressing effects. The beneficial effect of NAC may depend on whether the type of cancer relies on ROS signaling for its survival and metastasis. Triple-negative breast cancer (TNBC) has aggressive phenotypes and is currently treated with standard chemotherapy as the main systemic treatment option. Particularly, basal-like TNBC cells characterized by inactivated BRCA1 and mutated TP53 produce high ROS levels and rely on ROS signaling for their survival and malignant progression. In addition, the high ROS levels in TNBC cells can mediate the interplay between cancer cells and the tissue microenvironment (TME) to trigger the recruitment and conversion of stromal cells and induce hypoxic responses, thus leading to the creation of cancer-supportive TMEs and increased cancer aggressiveness. However, NAC treatment effectively reduces the ROS production and ROS-mediated signaling that contribute to cell survival, metastasis, and drug resistance in TNBC cells. Therefore, the inclusion of NAC in standard chemotherapy could probably provide additional benefits for TNBC patients.
Highlights
NAC (10 mM) could inhibit this radiation therapy-induced cell adhesion. These results demonstrate that gene expression changes leading to high NADPH oxidases (NOXs)-related Reactive oxygen species (ROS) generation increase cell survival and induce invasive and metastatic phenotypes in Triple-negative breast cancer (TNBC), and that the reduction of ROS via NAC treatment can suppress the invasive and migratory behavior of TNBC cells
ROS levels are generated by TNBC cells due to gene mutation/inactivation (e.g., breast cancer susceptibility gene 1 (BRCA1) and TP53), gene expression changes, and cancercell stem-like cell (CSC) enrichment
High ROS levels derived from TNBC cells can mediate interaction between cancer cell and the tissue microenvironment (TME) to induce the formation of permissive
Summary
N-acetylcysteine (NAC) is widely used as a medication and a dietary supplement. It functions as a mucolytic due to its ability to break the disulfide bonds in the glycoproteins of the mucus, resulting in a decrease in viscosity [1]. An alternative mechanism has recently been suggested involving its ability to break the disulfide bonds of the cysteinylated proteins to release free thiols and regenerate reduced proteins, which can have direct antioxidant activity in certain cases (e.g., mercaptoalbumin) [1,5]. Antioxidants 2021, 10, 169 example, a pilot study has encouragingly suggested that NAC may be effective as a single agent in the inhibition of cancer cell proliferation in breast cancer patients [7]. Antioxidants are thought to protect cancer cells from ROS-induced cell death, thereby promoting their proliferation and malignancy. These are the types of cancer that can potentially benefit from the use of NAC
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