Abstract
Gold nanoparticles (AuNPs) are used enormously in different cancers but very little is known regarding their molecular mechanism and surface charge role in the process of cell death. Here, we elucidate the molecular mechanism by which differentially charged AuNPs induce cytotoxicity in triple negative breast cancer (TNBC) cells. Cytotoxicity assay revealed that both negatively charged (citrate-capped) and positively charged (cysteamine-capped) AuNPs induced cell-death in a dose-dependent manner. We provide first evidence that AuNPs-induced oxidative stress alters Wnt signalling pathway in MDA-MB-231 and MDA-MB-468 cells. Although both differentially charged AuNPs induced cell death, the rate and mechanism involved in the process of cell death were different. Negatively charged AuNPs increased the expression of MKP-1, dephosphorylated and deacetylated histone H3 at Ser10 and K9/K14 residues respectively whereas, positively charged AuNPs decreased the expression of MKP-1, phosphorylated and acetylated histone H3 at Ser 10 and K9/K14 residues respectively. High-resolution transmission electron microscopy (HRTEM) studies revealed that AuNPs were localised in cytoplasm and mitochondria of MDA-MB-231 cells. Interestingly, AuNPs treatment makes MDA-MB-231 cells sensitive to 5-fluorouracil (5-FU) by decreasing the expression of thymidylate synthetase enzyme. This study highlights the role of surface charge (independent of size) in the mechanisms of toxicity and cell death.
Highlights
Breast cancer is the most common invasive cancer worldwide and for triple negative breast cancer, no targeted effective therapy is available till date[1,2]
Synthesized AuNPs were characterised by several means such as zeta size, zeta potential analysis and Transmission Electron Microscope (TEM)
Cytotoxicity assay of citrate-capped AuNPs (-vely charged) was performed in human mammary epithelial (MCF-10A) and triple negative breast cancer (MDA-MB-231 and MDA-MB-468) cells using concentrations ranging from 25 μg/mL to 1 mg/mL for 24 h
Summary
Breast cancer is the most common invasive cancer worldwide and for triple negative breast cancer, no targeted effective therapy is available till date[1,2]. Gold nanoparticles (AuNPs) are being used successfully till as versatile, selective and highly multifunctional anti-cancer therapeutics due to their unique physicochemical properties, therapeutic payload efficiency of drugs, biological compatibility, theranostic applications and radiation sensitizer effects[6,7,8]. Their surface can be functionalised with various biomolecules, thereby inciting specific functions, selectivity to the targets and stability in biological environments. Understanding of this will be of profound clinical significance for AuNPs either as stand-alone therapeutics or in combination with anti-cancer drugs
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