acriflavine and Necrosis

Antiangiogenic therapy is a promising strategy for cancer therapy. However, antiangiogenic therapy can induce intratumor hypoxia and hypoxia-inducible factor-1 (HIF-1) expression, which slows cancer progression. In our present study, we found that antiangiogenic therapy with sunitinib plus HIF-1 dimerization inhibitor acriflavine retarded tumor growth in a murine model of breast cancer. The combination of sunitinib with acriflavine significantly decreased vascular endothelial growth factor and TGF-β expression and reduced tumor vasculature followed by increased intratumor necrosis and apoptosis. Moreover, decreased accumulation of myeloid-derived suppressor cells in the spleen was observed after the combinational therapy. In conclusion, the combination of HIF-1 inhibition and antiangiogenic therapy may represent a novel strategy for cancer patients.

Topics: Acriflavine; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Female; Hypoxia-Inducible Factor 1; Indoles; Mammary Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Myeloid Cells; Necrosis; Neovascularization, Pathologic; Protein Multimerization; Pyrroles; Spleen; Sunitinib; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Acriflavine is an antiseptic, fungicide, and effective agent against parasitic infections, inducing petite mutation in the yeast Saccharomyces cerevisiae and kinetoplast loss in Trypanosomidae. Here we showed that acriflavine caused both apoptosis and necrosis in the yeast Candida utilis. Cells were cultured in minimal medium, with 1.5% ethanol as substrate, in the presence of 30-180 micromol/L acriflavine. Fluorescence measurements showed a linear concentration-dependence flux of the drug into the cells. Acriflavine induced a decrease in cell number, an increase in trypan blue-positive cells, and a decrease in cell viability. Cells cultured in the presence of acriflavine showed an alteration in their respiratory control ratio and a decrease in their cytochrome content. Fluorescence microscopy, after acridine orange staining, revealed the presence of apoptotic cells in cultures conducted in the presence of acriflavine. Electron microscopy of cells grown in the presence of acriflavine showed apoptotic cells exhibiting chromatin condensation, cytoplasmic lysis, but reasonably well-preserved mitochondria, whereas necrotic cells showed no distinctive intracellular organelles. Data showed that acriflavine caused both apoptosis and necrosis. Moreover, acriflavine induced oxidative phosphorylation uncoupling. Generally, apoptosis is considered to be mediated either by a change in mitochondrial permeability and cytochrome c release or by plasma membrane death receptor activation. The outer mitochondrial membrane permeability to cytochrome c, with efflux of protons to the cytosol and cytoplasmic acidification, produced a collapse in the electrochemical proton gradient, a decrease in ATP synthesis, and subsequent cytolysis leading to apoptosis and necrosis.

Topics: Acriflavine; Anti-Infective Agents, Local; Apoptosis; Candida; Cytochromes; Dose-Response Relationship, Drug; Microscopy, Electron; Microscopy, Fluorescence; Mitochondria; Necrosis; Oxygen Consumption