aminoflavone and Neoplasms

Continuing our studies on the mechanisms underlying the cytotoxicity of potential drugs, we have described several aspects of the in vitro anticancer activity of ruthenium(II) and platinum(II) complexes with bioactive, synthetic aminoflavone ligands. We examined the mechanism of proapoptotic activity of

Topics: Antineoplastic Agents; Apoptosis; Caspase 8; Cisplatin; Coordination Complexes; Drug Resistance, Neoplasm; Flavonoids; Humans; Ligands; Neoplasms; Platinum Compounds; Ruthenium Compounds; Tumor Cells, Cultured

Photodynamic therapy (PDT) has gained much attention in tumor therapy because of its special advantages. PDT heavily depends on the oxygen, yet the tumor microenvironment (TME) is a hypoxic and acid milieu, which weakens the PDT effect. Based on the consideration that the TME deteriorated by the PDT oxygen consumption could activate the hypoxic-sensitive small-molecule drug, we designed and prepared an integrated nanocomposite including zirconium ion metal organic framework (carrier), pyropheophorbide-a (PPa, photosensitizer), and 6-amino flavone (AF, hypoxic-sensitive drug), aiming to exert a cascaded PDT-chemotherapy (CT) antitumor effect and to solve the hypoxic challenge. The prepared nanocomposite showed great stability under the physiological (pH 7.4) condition and could continuously release PPa and AF under slightly acidic pH condition (pH 6.4), suggesting a tumor microenvironment responsive feature. Systematical in vitro and in vivo researches under various conditions (light, dark, hypoxic and normoxic) have showed that the obtained Zr-MOF@PPa/AF@PEG nanoparticles (NPs) had good biocompatibility and could achieve efficient antitumor effects based on PDT- chemotherapy (CT) cascade process. Finally, bright red fluorescence was observed in the tumor cells after internalization implying an application potential in tumor imaging.

Topics: Animals; Biocompatible Materials; Cell Line, Tumor; Cell Survival; Chlorophyll; Drug Liberation; Female; Flavonoids; Humans; Metal-Organic Frameworks; Mice; Mice, Inbred BALB C; Nanocomposites; Neoplasms; Photochemotherapy; Polyethylene Glycols; Singlet Oxygen; Theranostic Nanomedicine; Tumor Microenvironment; Zirconium

Topics: Antineoplastic Agents; Camptothecin; Digoxin; Flavonoids; Humans; Hypoxia-Inducible Factor 1; Mustard Compounds; Neoplasms; Oligonucleotides; Phenylpropionates; Polyethylene Glycols; Topotecan

A reverse-phase liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) method was developed and validated for determination of aminoflavone (AF) in human plasma. Sample preparation involved a liquid-liquid extraction by the addition of 0.25 mL of plasma with 1.0 mL ethyl acetate containing 50 ng/mL of the internal standard zileuton. The analytes were separated on a Waters X-Terra MS C(18) column using a mobile phase consisting of methanol/water containing 0.45% formic acid (70:30, v/v) and isocratic flow at 0.2 mL/min for 6 min. The analytes were monitored by tandem mass spectrometry with electrospray positive ionization. Linear calibration curves were generated over the AF concentration range of 5-2000 ng/mL in human plasma. The lower limit of quantitation (LLOQ) was 5 ng/mL for AF in human plasma. The accuracy and within- and between-day precisions were within the generally accepted criteria for bioanalytical method (<15%). This method was successfully applied to characterize AF plasma concentration-time profile in the cancer patients in a phase I trial.

Topics: Antineoplastic Agents; Chromatography, Liquid; Flavonoids; Humans; Neoplasms; Tandem Mass Spectrometry

Aminoflavone (AF) is entering clinical trials. We recently reported that AF induces DNA-protein cross-links (DPC) and gamma-H2AX in MCF-7 human breast cancer cells. To elucidate the mechanism of action of AF and provide biomarkers indicative of AF activity, we correlated AF activity profile (GI(50)) with gene expression patterns in the NCI-60 cell lines. Sulfotransferases (SULT) showed the highest positive correlation coefficients among approximately 14,000 probe sets analyzed (r = 0.537, P < 0.001). Stable transfection of SULT1A1 into AF-resistant MDA-MB-231 cells sensitized these cells to AF. AF produced DPCs, gamma-H2AX foci, and S-phase arrest in the SULT1A1-transfected but not in the parent MDA-MB-231 cells. Conversely, cells in which SULT1A1 was knocked down by small interfering RNA failed to induce gamma-H2AX. Inhibition of SULTs and cytochrome P450 (CYP) enzymes by natural flavonoids blocked the antiproliferative activity of AF and the formation of AF-DNA adducts. AF also induces SULT1A1 and CYP expression in MCF-7 cells, suggesting the existence of an aryl hydrocarbon receptor-mediated positive feedback for AF activation by CYP and SULT1A1. Metabolism studies showed that AF can be oxidized by CYP at two amino groups to form N-hydroxyl metabolites that are substrates for bioactivation by SULTs. We propose that both N-sulfoxy-groups can be further converted to nitrenium ions that form adducts with DNA and proteins. The results reported here show the importance of SULT1A1 and CYP for AF activation and anticancer activity. They also suggest using SULT1A1 and gamma-H2AX as biomarkers for prediction of AF activity during patient selection and monitoring of clinical trials.

Topics: Adenocarcinoma; Aryl Hydrocarbon Hydroxylases; Arylsulfotransferase; Biotransformation; Breast Neoplasms; Cell Line, Tumor; Cross-Linking Reagents; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Cytochrome P-450 Enzyme System; DNA Adducts; DNA, Neoplasm; Drug Resistance, Neoplasm; Feedback, Physiological; Female; Flavonoids; Gene Expression Regulation, Neoplastic; Histones; Humans; Microsomes, Liver; Neoplasm Proteins; Neoplasms; Prodrugs; Receptors, Aryl Hydrocarbon; Recombinant Fusion Proteins; RNA, Small Interfering