Clinical significance of metallothioneins in cell therapy and nanomedicine

Abstract

Sushil Sharma,1 Afsha Rais,1 Ranbir Sandhu,1 Wynand Nel,1 Manuchair Ebadi21Saint James School of Medicine, Bonaire, The Netherlands; 2Department of Pharmacology, Physiology, and Therapeutics, Center of Excellence in Neuroscience, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND, USAAbstract: Mammalian metallothioneins (MTs) are low molecular weight (6–7 kDa) cysteine-rich proteins that are specifically induced by metal nanoparticles (NPs). MT induction in cell therapy may provide better protection by serving as antioxidant, anti-inflammatory, antiapoptotic agents, and by augmenting zinc-mediated transcriptional regulation of genes involved in cell proliferation and differentiation. Liposome-encapsulated MT-1 promoter has been used extensively to induce growth hormone or other genes in culture and gene-manipulated animals. MTs are induced as a defensive mechanism in chronic inflammatory conditions including neurodegenerative diseases, cardiovascular diseases, cancer, and infections, hence can serve as early and sensitive biomarkers of environmental safety and effectiveness of newly developed NPs for clinical applications. Microarray analysis has indicated that MTs are significantly induced in drug resistant cancers and during radiation treatment. Nutritional stress and environmental toxins (eg, kainic acid and domoic acid) induce MTs and aggregation of multilamellar electron-dense membrane stacks (Charnoly body) due to mitochondrial degeneration. MTs enhance mitochondrial bioenergetics of reduced nicotinamide adenine dinucleotide–ubiquinone oxidoreductase (complex-1), a rate-limiting enzyme complex involved in the oxidative phosphorylation. Monoamine oxidase-B inhibitors (eg, selegiline) inhibit α-synuclein nitration, implicated in Lewy body formation, and inhibit 1-methyl 4-phenylpyridinium and 3-morpholinosydnonimine-induced apoptosis in cultured human dopaminergic neurons and mesencephalic fetal stem cells. MTs as free radical scavengers inhibit Charnoly body formation and neurodegenerative α-synucleinopathies, hence Charnoly body formation and α-synuclein index may be used as early and sensitive biomarkers to assess NP effectiveness and toxicity to discover better drug delivery and surgical interventions. Furthermore, pharmacological interventions augmenting MTs may facilitate the theranostic potential of NP-labeled cells and other therapeutic agents. These unique characteristics of MTs might be helpful in the synthesis, characterization, and functionalization of emerging NPs for theranostic applications. This report highlights the clinical significance of MTs and their versatility as early, sensitive biomarkers in cell-based therapy and nanomedicine.Keywords: metallothioneins, free radicals, Charnoly body, α-synuclein index, nanomedicine, toxicity, stem cells, theranostics