No abstract

Autophagy is a dynamic process, conserved in all eukaryotes. It is responsible for the degradation of cytoplasmic content. Autophagy is crucial in cell survival and cell death. It plays a significant role in the cell response to stress, nutrient deficiencies, embryonic development, tumor suppression, response to pathogens and aging. The process of autophagy is also involved in the pathology of human diseases, such as cancer, diabetes, cardiomyopathy, and neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Autophagy is a mechanism that involves degradation of cells, proteins, damaged organelles and pathogens through the lysosomal mechanisms, thus autophagy supports cell survival during starvation, hypoxia and metabolic stress. However, if extensive and/or excessive, autophagy can promote apoptosis (type I) or function as an alternative cell-death pathway, called autophagic cell death (type II). Autophagy can either promote cancer cell death, or serve as a survival mechanism against apoptosis or necrosis induced by various anticancer treatments. Given the contradictory role of autophagy during tumor initiation and progression, the use of autophagy in therapy depends on the context and must be approached individually

<p> </p> <p>Regardless of the fascinating progress of humanity, biotechnology and medicine, the outbreak of the global pandemic of the SARS-CoV-2 virus has shown us that we are just as vulnerable as in previous eras when communicable diseases decimated the world’s population. But the discoveries made so far at the molecular level allow us to connect knowledge interdisciplinary and find solutions and therapeutic strategies where there seems to be no link. It was the previous coronavirus infections that served as a homologous model for finding the connection between the SARS-CoV-2 virus and autophagy. Autophagy, a conserved universal process of all eukaryotic cells responsible for cell survival under stressful circumstances, has been shown to play a significant role in viral invasions. It contributes to both direct and indirect antiviral responses such the elimination of viruses, the presentation of their antigens, and the reduction of inflammatory responses. The autophagy machinery of host cells can, however, be suppressed, evaded, or used by viruses to their benefit. Therefore, autophagy has an ambiguous role in coronavirus-related infections, especially in COVID-19.</p> <p> </p>

Halogenated boroxine K2(B3O3F4OH), (HB) has effectively inhibited growth of several carcinoma cell lines. Because of the growing interest in autophagy induction as therapeutic approach in bladder carcinoma (BC), we aimed to assess the effects of HB on metabolic phenotype and autophagy levels in 5637 human bladder carcinoma cells (BC). Cytotoxicity was evaluated using alamar blue assay, and degree of autophagy was determined microscopically. Mitochondrial respiration and glycolysis were measured simultaneously. The relative expression of autophagy related genes BECN1, P62, BCL-2, and DRAM1 were determined by real time PCR. HB inhibited cell growth in concentration dependent manner. Starvation significantly increased level of autophagy in positive control compared to the basal level of autophagy in negative control. In HB treated cultures, the degree of autophagy was higher compared to the basal level and metabolic phenotype altered: both glycolysis and oxidative phosphorylation (OXPHOS) were decreased by HB at 0.2 and 0.4 mg/ml. Genes expression was deregulated towards autophagy induction and expansion. These findings suggest that HB disrupts the bioenergetic metabolism, and reduces intracellular survival potential of BC cells. Further molecular studies are needed to confirm and potentially apply these findings.

Anti-proliferative effects of halogenated boroxine – K2(B3O3F4OH) (HB) – have been confirmed in multiple cancer cell lines, including melanoma, but the exact mechanism of action is still unknown. This study aimed to determine its cytotoxic effects on human Caucasian melanoma (GR-M) cell growth in vitro as well as on the expression of cell death-related genes BCL-2, BECN1, DRAM1, and SQSTM1. GR-M and peripheral blood mononuclear (PBM) cells were treated with different HB concentrations and their growth inhibition and relative gene expression profiles were determined using the Alamar blue assay and real-time PCR. HB significantly inhibited cell growth of both GR-M and PBM cells but was even more effective in GR-M melanoma cells, as significant inhibition occurred at a lower HB concentration of 0.2 mg/mL. GR-M BCL-2 expression was significantly downregulated (P=0.001) at HB concentration of 0.4 mg/mL, which suggests that HB is a potent tumour growth inhibitor. At the same time, it upregulated BCL-2 expression in normal (PBM) cells, probably by activating protective mechanisms against induced cytotoxicity. In addition, all but the lowest HB concentrations significantly upregulated SQSTM1 (P=0.001) in GR-M cells. Upregulated BECN1 expression suggests early activation of autophagy at the lowest HB concentration in SQSTM1 cells and at all HB concentrations in PBM cells. Our findings clearly show HB-associated cell death and, along with previous cytotoxicity studies, reveal its promising anti-tumour potential.