Abstract
BackgroundThe apoptosis (a cascade of biochemical reactions leading to suicide of damaged biological cells) is blocked in the cancer cells because of impossibility of cytochrome c (cytC) go out from the mitochondria. However, the apoptosis can be started by introducing of exogenous cytC into cytoplasm using colloid particles as a protein carrier due to ability of the cancer cells to phagocytize extracellular particles with submicron size.ResultsThe clay mineral montmorillonite (MM) were used to prepare aqueous suspension of protein/mineral composite particles by electrostatic adsorption of the positively charged cytC globules on the negatively charged MM colloid plates, and then added to colon cancel culture. The results shows out that separately cytC and MM have no effect but the composite cytC-MM particles kill 95% of the cancer cells after 96 h treatment using equine cytC which is 97% structurally identical with the human cytC. To reach this high cytotoxicity we have formulated requirements to: (a) bare colloid particles (electric charge, form and size), (b) conditions for protein adsorption (concentrations, pH, ionic strength), and (c) suspension with the composite particles (positive total charge and optimal concentration). Due to satisfying these requirements we have reached cytotoxicity which is 1/3 higher than the reached by other authors using different artificial particles. The cytotoxicity rapidly increases with concentration of the cytC-MM particles but further it shows tendency to saturation.MethodsThe optimal pH 6.5 and the 10:3 mg/mg cytC/MM concentration ratio at adsorption were found out by employing computer (protein electrostatics) and physicochemical methods (microelectrophoresis and colloid electrooptics) to prepare cytC-MM suspension. The anticancer capability of cytC-MM nanoplates were investigated using cell culture of metastasizing colon cancer.ConclusionThe in vitro experiments with colon cancer cell culture disclose that cytC-MM composite particles have potential for application in anticancer therapy of superficial neoplasms of the skin and the alimentary system (mouth cavity, esophagus, stomach, jejunum and colon).Graphic abstract
Highlights
Cytochrome c is a water-soluble haem-containing globular protein (104 aminoacid residues, 12.4 kg/mol molecular mass, 3 nm size) associated to the electrontransport macromolecule complex of the internal mitochondrial membrane, where it works as F e2+/Fe3+ electron carrier in the normal eukaryotic cells
The in vitro experiments with colon cancer cell culture disclose that cytochrome c (cytC)-MM composite particles have potential for application in anticancer therapy of superficial neoplasms of the skin and the alimentary system
The pH-dependence of the net charge suggests that the protein/mineral electrostatic attraction between cytC globules and MM surface is stronger at pH ≤ 5 due to the higher positive net charge
Summary
Cytochrome c (cytC) is a water-soluble haem-containing globular protein (104 aminoacid residues, 12.4 kg/mol molecular mass, 3 nm size) associated to the electrontransport macromolecule complex of the internal mitochondrial membrane, where it works as F e2+/Fe3+ electron carrier in the normal eukaryotic cells. In case of cancer cells the mitochondrial oxygen metabolism is replaced by anaerobic utilization of glucose with accumulation of lactate in the cytoplasm (Warburg effect) (Warburg et al 1926; Vander Heiden et al 2009; Gatenby and Gillies 2004), and that leads to impossibility of cytC to go out from the mitochondria; as result the apoptosis is blocked, and a resistance appears to chemotherapeutics that should start this process (Gogvadze et al 2009; Shannon et al 2003; Bhattacharya et al 2016). The apoptosis (a cascade of biochemical reactions leading to suicide of damaged biological cells) is blocked in the cancer cells because of impossibility of cytochrome c (cytC) go out from the mitochondria. The apoptosis can be started by introducing of exogenous cytC into cytoplasm using colloid particles as a protein carrier due to ability of the cancer cells to phagocytize extracellular particles with submicron size
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