acriflavine and Neoplasms

Acriflavine (ACF) has been known for years as an antibacterial drug. The identification of key oncogenic mechanisms has brought, in recent years, a significant increase in studies on ACF as a multipurpose drug that would improve the prognosis for cancer patients. ACF interferes with the expression of the hypoxia inducible factor, thus acting on metastatic niches of tumors and significantly enhancing the effects of other anticancer therapies. It has been recognized as the most potent HIF-1 inhibitor out of the 336 drugs approved by the FDA. This work presents up-to-date knowledge about the mechanisms of action of ACF and its related prodrug systems in the context of anticancer and SARS-CoV-2 inhibitory properties. It explains the multitask nature of this drug and suggests mechanisms of ACF's action on the coronavirus. Other recent reports on ACF-based systems as potential antibacterial and antiviral drugs are also described.

Topics: Acridines; Acriflavine; Anti-Bacterial Agents; COVID-19 Drug Treatment; Humans; Intercalating Agents; Neoplasms; SARS-CoV-2

There is still a debate for the link between obstructive sleep apnoea (OSA) and cancer. The mechanisms underlying this causality are poorly understood. Several miRNAs are involved in cancer development and progression with expression being influenced by hypoxia. The aims of this work were (i) to compare miRNAs expression in controls versus patients affected by OSA without or with cancer (ONCO-OSA) and (ii) in colorectal cancer cells exposed to intermittent hypoxia (IH), to evaluate miRNAs impact on tumor progression in vitro.. We detected miRNAs by qRT-PCR in patients' sera and in CaCo2 cells exposed to 2-32h of IH with or without acriflavine (ACF), a HIF-1 inhibitor. Viability and transwell invasion test were applied to investigate the proliferation and migration of CaCo2 exposed to IH and treated with miRNA inhibitors or acriflavine. HIF-1α activity was evaluated in CaCo2 cells after IH.. The levels of miR-21, miR-26a and miR-210 increased in OSA and ONCO-OSA patients compared to controls. MiR-23b increased in ONCO-OSA patients, and miR-27b and miR-145 increased in OSA but not ONCO-OSA patients. MiR-21, miR-26a, miR-23b and miR-210 increased in cells after IH. IH stimulated cell proliferation and migration. This effect was reduced after either miRNA inhibition or acriflavine treatment. MiRNA inhibition reduces HIF-1α gene expression. Conversely, acriflavine reduced the expression of these miRNAs.. We identified a signature of miRNAs, induced by the IH environment. They could be implicated in cancer development and progression through a regulatory loop involving HIF-1.

Topics: Acriflavine; Caco-2 Cells; Humans; Hypoxia; MicroRNAs; Neoplasms; Sleep Apnea, Obstructive

We have previously shown that glioblastoma stem cells (GSCs) are enriched in the hypoxic tumor microenvironment, and that monocarboxylate transporter-4 (MCT4) is critical for mediating GSC signaling in hypoxia. Basigin is involved in many physiological functions during early stages of development and in cancer and is required for functional plasma membrane expression of MCT4. We sought to determine if disruption of the MCT-Basigin interaction may be achieved with a small molecule. Using a cell-based drug-screening assay, we identified Acriflavine (ACF), a small molecule that inhibits the binding between Basigin and MCT4. Surface plasmon resonance and cellular thermal-shift-assays confirmed ACF binding to basigin in vitro and in live glioblastoma cells, respectively. ACF significantly inhibited growth and self-renewal potential of several glioblastoma neurosphere lines in vitro, and this activity was further augmented by hypoxia. Finally, treatment of mice bearing GSC-derived xenografts resulted in significant inhibition of tumor progression in early and late-stage disease. ACF treatment inhibited intratumoral expression of VEGF and tumor vascularization. Our work serves as a proof-of-concept as it shows, for the first time, that disruption of MCT binding to their chaperon, Basigin, may be an effective approach to target GSC and to inhibit angiogenesis and tumor progression.

Topics: Acriflavine; Animals; Basigin; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Female; Genes, Reporter; Glioblastoma; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Immunoglobulin Domains; Lactic Acid; Male; Mice; Monocarboxylic Acid Transporters; Muscle Proteins; Neoplasms; Neovascularization, Pathologic; Protein Binding; Protein Interaction Mapping

Acriflavine (ACF), a known antibacterial drug, has recently been recognized as a suitable candidate for cancer chemotherapy. However, the molecular target of ACF is not fully understood, which limits its application in cancer therapy. In this study, we established a structure-specific probe-based pull-down approach to comprehensively profile the potential target of ACF, and we identified DNA dependent protein kinase catalytic subunit (DNA-PKcs) as the direct target of ACF. Since DNA-PKcs facilitates the repair process following DNA double-strand breaks, we further developed a drug combination strategy that combined ACF with the bifunctional alkylating agent melphalan, which exerted a p53-dependent synergistic efficacy against human cancer cells both in vitro and in vivo. With these findings, our study demonstrated that structure-specific probe-based pull-down approaches can be used to identify new functional target of drug, and provided novel opportunities for the development of ACF-based antitumor chemotherapies.

Topics: Acriflavine; Animals; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Comet Assay; DNA Breaks, Double-Stranded; DNA-Activated Protein Kinase; Dose-Response Relationship, Drug; Drug Synergism; HCT116 Cells; HeLa Cells; Humans; Melphalan; Mice, Nude; Molecular Docking Simulation; Neoplasms; Nuclear Proteins; Protein Binding; Protein Kinase Inhibitors; Signal Transduction; Time Factors; Tumor Burden; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays

The performance of Feulgen-acriflavine-SO2 and Hoechst 33258 for cytofluorometric ploidy determination is evaluated and compared. The fast initial fading of acriflavine-SO2 stained nuclei, with substantial reduction in fluorescence intensity within about 10 ms, is shown to be related to changes in DNA-ratios between cell types when measurements are performed using different excitation light intensities. Although low intensity excitation-, without such fading-, was used, the acriflavine-SO2 staining procedure showed large specimen to specimen variability regarding both mean fluorescence intensities and coefficients of variation (CV). The cells in such specimens could be shown to contain the same amount of chromophore using scanning absorbance measurements and the differing fluorescence values therefore probably represent variability in fluorescence yield. Specimens stained with Hoechst 33258 after RNase treatment showed very small deviations in mean fluorescence value between slides, and also much lower CV's than in acriflavine-SO2 stained specimens. The results indicate that with proper internal standards this procedure would allow the detection of deviations in DNA content in the order of 2%.

Topics: Acriflavine; Aminoacridines; Animals; Benzimidazoles; Bisbenzimidazole; Coloring Agents; DNA, Neoplasm; Evaluation Studies as Topic; Flow Cytometry; Hydrolysis; Neoplasms; Neoplasms, Experimental; Rats; Rats, Inbred Strains; Rosaniline Dyes; Time Factors

Topics: Acriflavine; Animals; Anthralin; Aurothioglucose; Carcinogens; Chloroquine; Diazepam; Ethanolamines; Ethionamide; Female; Humans; Hycanthone; Male; Metronidazole; Neoplasms; Neoplasms, Experimental; Oxazepam; Oxymetholone; Oxyphenbutazone; Oxyquinoline; Phenacetin; Phenobarbital; Phenylbutazone; Phenytoin; Pregnancy; Pyrimethamine; Risk

Topics: Acriflavine; Animals; Bromides; Carcinogens; Cell Membrane; Cell Transformation, Neoplastic; Daunorubicin; DNA, Mitochondrial; Ethidium; Humans; Mitochondria; Mitosis; Mutation; Neoplasms; Transcription, Genetic