A minireview on N -acetylcysteine: An old drug with new approaches

Dhouib, Ines El-Bini; Jallouli, Manel; Annabi, Alya; Gharbi, N.; El-Fazaâ, Saloua; Lasram, Mohamed Montassar

doi:10.1016/j.lfs.2016.03.003

Cited by 167 publications

(95 citation statements)

References 49 publications

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“…A limitation of the present study, however, is that only a single strain of each bacterial species was used and it is possible that other strains will behave differently. NAC is a potent thiol-containing antioxidant that serves as a precursor of glutathione synthesis and is used in the treatment of many diseases (41). Moreover, NAC efficiently reduces disulfide bonds in proteins and alters their structure, leading to a reduction in the viscosity of secretions and to the inhibition/ inactivation of the proteins involved in biofilm synthesis and maintenance.…”

Section: Discussionmentioning

confidence: 99%

N -Acetyl- l -Cysteine and Cysteamine as New Strategies against Mixed Biofilms of Nonencapsulated Streptococcus pneumoniae and Nontypeable Haemophilus influenzae

Domenech

Garcı́a

2017

Antimicrob Agents Chemother

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Acute otitis media, a polymicrobial disease of the middle ear cavity of children, is a significant public health problem worldwide. It is most frequently caused by encapsulated Streptococcus pneumoniae and nontypeable Haemophilus influenzae, although the widespread use of pneumococcal conjugate vaccines is apparently producing an increase in the carriage of nonencapsulated S. pneumoniae. Frequently, pneumococci and H. influenzae live together in the human nasopharynx, forming a self-produced biofilm. Biofilms present a global medical challenge since the inherent antibiotic resistance of their producers demands the use of large doses of antibiotics over prolonged periods. Frequently, these therapeutic measures fail, contributing to bacterial persistence. Here, we describe the development of an in vitro nonencapsulated S. pneumoniae-nontypeable H. influenzae biofilm system with polystyrene or glass-bottom plates. Confocal laser scanning microscopy and specific fluorescent labeling of pneumococcal cells with Helix pomatia agglutinin revealed an even distribution of both species within the biofilm. This simple and robust protocol of mixed biofilms was used to test the antimicrobial properties of two well-known antioxidants that are widely used in the clinical setting, i.e., N-acetyl-L-cysteine and cysteamine. This repurposing approach showed the high potency of N-acetyl-Lcysteine and cysteamine against mixed biofilms of nonencapsulated S. pneumoniae and nontypeable H. influenzae. Decades of clinical use mean that these compounds are safe to use, which may accelerate their evaluation in humans. KEYWORDS Haemophilus influenzae, Streptococcus pneumoniae, antioxidants, biofilmsA cute otitis media (AOM) is defined as the presence of inflammation in the middle ear accompanied by the rapid onset of signs and symptoms of an ear infection. Frequent suppurative complications of AOM are mastoiditis, hearing loss, and meningitis. AOM is a significant public health problem worldwide (incidence rate, ϳ11%) (1). Indeed, Ͼ80% of children suffer at least one episode of AOM by their third birthday and 40% will suffer six or more recurrences by the age of 7 years (2). Pediatric AOM, which is often treated with antibiotics (56 to 95% of cases, depending on the country) (3), represents a significant health care burden, annually accounting for some $2.88 billion in medical costs in the United States (4). A polymicrobial disease, AOM is typically caused by colonization of the middle ear space by opportunistic bacteria that normally form part of the nasopharyngeal microbiota. The most frequently involved bacterial pathogens are Streptococcus pneumoniae, nontypeable (nonencapsulated) Haemophilus influenzae (NT H. influenzae), and, to a lesser extent, Moraxella catarrhalis and other species (5). Several respiratory viruses may also cause AOM (6).

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Section: Discussionmentioning

confidence: 99%

N -Acetyl- l -Cysteine and Cysteamine as New Strategies against Mixed Biofilms of Nonencapsulated Streptococcus pneumoniae and Nontypeable Haemophilus influenzae

Domenech

Garcı́a

2017

Antimicrob Agents Chemother

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“…NAC is directly an antioxidant and is also a precursor of reduced glutathione (GSH), which is the main intracellular antioxidant 5 . NAC reduces disfulfide bonds in proteins, which alters their structures and disrupts their ligand bonding, competing with larger reducing molecules in sterically less accessible spaces and ultimately altering signal transduction.…”

Section: Discussionmentioning

confidence: 99%

“…NAC is a precursor for reduced glutathione (GSH), which is the main intracellular antioxidant 5 . GSH is a water-soluble molecule found in millimolar concentration in cells.…”

Section: Introductionmentioning

confidence: 99%

“…GSH is a water-soluble molecule found in millimolar concentration in cells. It is a low molecular weight peptide containing a thiol group, which provides its antioxidant activity 5 . The physiological roles of GSH include being a scavenger of free radical and reactive oxygen species, forming conjugates with metabolites and xenobiotics, being a thiol buffer for many cellular proteins such as metallothioneins and thioredoxins, altering protein structures by reducing disulfide bonds, being an essential cofactor for many enzymes, and allowing the regeneration of other antioxidants such as tocopherols and ascorbate 64 .…”

Section: Introductionmentioning

confidence: 99%

“…NAC’s ability to limit tumor growth in some in vivo models is dependent on its antioxidant properties 28 . NAC also reduces catabolism, glycolysis, mitochondrial dysfunction and inflammatory mediators by reducing oxidative stress 572425 . However, NAC has not been investigated systematically in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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

Monti

Sotgia

Whitaker‐Menezes

et al. 2017

Seminars in Oncology

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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.

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