Biological evaluation of levofloxacin and its thionated derivatives: antioxidant activity, aldehyde dehydrogenase enzyme inhibition, and cytotoxicity on A549 cell line.

Levofloxacin (LVX) is among the fluoroquinolones antibiotics that has also been studied in vitro and in vivo for its anticancer effects. In this study, we used LVX and novel LVX thionated derivatives; compounds 2 and 3, to evaluate their antioxidant activity, aldehyde dehydrogenase (ALDH) enzymes activity inhibition, and anticancer activity. Combination treatments with doxorubicin (DOX) were investigated as well. The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used to determine the antioxidant activity. The NADH fluorescence spectrophotometric activity assay was used to determine the ALDH inhibitory effects. Resazurin dye method was applied for cell viability assays. Molecular Operating Environment software was used for the molecular docking experiments. Compared to ascorbic acid, DPPH assay showed that compound 3 had the highest antioxidant activity among the tested compounds with approximately 35% scavenging activity. On ALDH enzymes, compound 3 showed a significant ALDH activity inhibition compared to compound 2 at 200 µM. The IC50 values for the tested compounds were approximately 100 µM on A549 cell line, a non-small cell lung cancer (NSCLC) cell line. However, significant enhancement of cytotoxicity and reduction of IC50 values were observed by combining DOX and synergism was achieved with LVX with a combination index value of 0.4. The molecular docking test showed a minimum binding energy with a good affinity for compound 3 towards ALDH enzymes. Thionated LVX derivatives, may be repurposed for NSCLC therapy in combination with DOX, taking into account the antioxidant activity, ALDH activity inhibition, and the molecular docking results of compound 3.

Investigating Carvedilol's Repurposing for the Treatment of Non-Small Cell Lung Cancer via Aldehyde Dehydrogenase Activity Modulation in the Presence of ß-Adrenergic Agonists.

Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). ß-adrenoceptor antagonist drugs (ß-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of ß-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind ß-blockers' anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed ß-blockers' cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC50 of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with ß-agonists, in comparison to the control. This effect might be attributed to ß-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR's multifaceted anticancer properties, implying that combining CAR with ß-agonists could be a useful strategy for lung cancer treatment.

Preparation and Characterization of Capsaicin Encapsulated Polymeric Micelles and Studies of Synergism with Nicotinic Acids as Potential Anticancer Nanomedicines.

Background/Objective/Methods: Capsaicin micelles were prepared by the direct dissolution using the amphiphilic copolymer Pluronic P123 and advanced for substantially novel submicro-nanocytotoxicity. Results: Superior cytotoxicity of capsaicin loaded nanomicelles vs. both the raw capsaicin and reference cisplatin in pancreatic PANC1, breast MCF7, colorectal resistant CACO2, skin A375, lung A549 and prostate PC3 cancer cell lines were delineated. Nicotinic acid (NA) derivative 39 (2-Amino IsoNA) had antiinflammatory potential but consistently lacked antiproliferation in MCF7, PANC1 and CACO2. Besides NA derivatives 8 (5-MethylNA) and 44 (6-AminoNA) exhibited lack of antiinflammation but had comparable antitumorigenesis potency to cisplatin in PANC1 cells. Though capsaicin loaded nanomicelles exerted pronounced antiinflammation (with IC50 value of 510 nM vs. Indomethacin's) in lipopolysacchride-induced inflammation of RAW247.6 macrophages; they lacked DPPH scavenging propensities. Free capsaicin proved more efficacious vs. its loaded nanocarriers to chemosensitize cytotoxicity of combinations with NAs 1(6-Hexyloxy Nicotinic Acid), 5(6-OctyloxyNA), 8(5-MethylNA), 12(6-Thien-2yl-NA), 13(5,6-DichloroNA) and 44(6-AminoNA) in CACO2, PANC1 and prostate PC3. Conclusion: Capsaicin loaded nanomicelles proved more efficacious vs. free capsaicin to chemo-sensitize antiproliferation of cotreatments with NA derivatives, 1, 5, 8, 12, 13 and 44 (in skin A375), 1, 5, 8 and 12 (in breast MCF7), and 1, 5, 12 and 44 (in lung A549).

Newly Substituted Anilino-Fluoroquinolones with Proliferation Inhibition Potential against a Panel of Cancer Cell Lines.

BACKGROUND: From a chemistry point of view, we hypothesized that superlative dual cytotoxicity-radical scavenging bioefficacies of series 4 FQs correlate to their acidic groups and C8-C7 ethylene diamine Chelation Bridge. METHODOLOGY: Newly synthesized 16 lipophilic-acid chelating FQs have been screened for in vitro duality of proliferation inhibition and radical scavenging capacities. RESULTS: Substantially in LPS prompted RAW264.7 macrophages inflammation, IC50 values (µM) in the ascending order of  new FQs' NO scavenging/antiinflammation capacity were 4e<4b<3d<4f<5c0.05). In comparison to classical and robust antineoplastic agent cisplatin and unlike triazoloFQs; nitroFQs (3a, 3b and 3f) and the reduced FQs (4a, 4c, 4d and 4e) exerted antiproliferation IC50 values <50 µM in leukaemia K562. Besides nitroFQ 3, the reduced FQs (4c and 4f) exhibited antineoplastic IC50 values <50 µM in lung A549 carcinoma. NitroFQ 3c and reduced FQs 4b, 4c, and 4f in breast MCF7 and reduced 4c in pancreatic PANC1 had reduction of viability IC50 values <50 µM. NitroFQ 3e, reduced FQs 4b and, 4c and triazoloFQ 5a exerted antiproliferation IC50 values <50 µM in breast T47D cells. Also nitroFQ 3e, reduced FQ 4c and triazoloFQ 5f exhibited antineoplastic IC50 values <50 µM in PC3 prostate cancer cells. Exceptionally triazoloFQ 5a, but neither nitro- nor reduced FQs, had cytotoxicity IC50 value <50 µM in resistant melanoma A375 cells. Unequivocally 4b antineoplastic effectiveness linked with its radical scavenging and antiinflammation effects while 3d and 5c lacked matching antiproliferation potentialities to their exquisite antiinflammation capacities. Explicitly reduced 4e and 4f exerted antiinflammation-selective cytotoxicity duality in vitro. CONCLUSION: Collectively, this work reveals lipophilic-acidic chelator FQs as authentic agents for the repurposing approach in anticancer chemotherapy/prevention.

Rational Development of Novel Activity Probes for the Analysis of Human Cytochromes P450.

The identification and quantification of functional cytochromes P450 (CYPs) in biological samples is proving important for robust analyses of drug efficacy and metabolic disposition. In this study, a novel CYP activity-based probe was rationally designed and synthesised, demonstrating selective binding of CYP isoforms. The dependence of probe binding upon the presence of NADPH permits the selective detection of functionally active CYP. This allows the detection and analysis of these enzymes using biochemical and proteomic methodologies and approaches.