Selected Statins as Dual Antiproliferative-Antiinflammatory Compounds.

BACKGROUND: We hypothesized that superlative dual cytotoxicity-antiinflammtion bioefficacies of 9 selected lipophilic statins correlate to their chelation effect of 3,5-dihydroxyheptanoic acid. METHODOLOGY: Lipophilic-acid chelating statins have been screened for in vitro duality of proliferation inhibition and NO-radical scavenging capacities. RESULTS: Their spectrum of selectivity indices for safety in PDL fibroblasts -based 72h incubations was reported. Surprisingly despite its lack on macrophages LPS-triggered inflammation over 5-200 µM and unlike the 8 statins; cerivastatin had growth inhibition IC50 values of 40nM (SW620), 110nM (HT29), 2.9 µM (HCT116), 6µM (SW480), and most notably 38µM (<50 µM, in Caco2). Exclusively cerivastatin exerted antitumorigenesis IC50 values <50 µM in all T47D, MCF7 and PANC1 72h cultures. In statins with greater antiinflammation affinity than indomethacin's; lovastatin had cytotoxicity IC50 values <20 µM in SW62050µM in T47D, MCF7 and PANC1; pravastatin had viability reduction IC50 values <50µM in HT2950 µM were for statins in remaining colorectal cancer cell lines, breast cancer and pancreatic cancer cell lines. CONCLUSION: Among the rest, cerivastatin warrants further novel scaffold development to maximize efficacy and optimal molecular action mechanisms of chemotherapy/prevention.

Antiproliferative Activities of Lipophililic Fluoroquinolones- Based Scaffold Against a Panel of Solid and Liquid Cancer Cell Lines.

OBJECTIVES: In this work, 9 lipophilic-acid chelating FQs (fluoroquinolones) comprising chelating groups  have been prepared, characterized and screened for in vitro cytotoxicity, radical scavenging and antiinflammation propensities. METHODS: Using sulforhodamine B colorimetric bioassay vs. cisplatin; FQs-inflicted reductions' of viability against breast T47D and MCF7, Pancreatic PANC-1, colorectal HT29, HCT116, SW620, CACO2, SW480 and Leukaemia K562 cancer cell lines were examined in quadruplicates/dose/cell line. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals' scavenging capacities -as their molecular action mechanism- in comparison to ascorbic acid and indomethacin respectively. Using Griess assay in Lipopolysaccharide (LPS) prompted RAW264.7 macrophages; mitigation of inflammation was investigated. RESULTS: nitroFQ 3b, unlike the rest of FQs in PANC1 and MCF7 cells, exhibited remarkably superior NO-radical scavenging/antiinflammation capacity to indomethacin with respective antiproliferative IC50 values (<50µM) 49 vs. cisplatin's 122 and 6 vs. cisplatin's 28 (p<0.01-0.001; n=4). Reduced FQ 4b of significantly dual DPPH-NO scavenging propensities exerted exceptionally substantial micromolar antiproliferation in colorectal cancer cells with respective antiproliferative IC50 values (<50µM) of HCT116 0.84< HT29 1.6

In vitro Antiproliferative Properties of Lipophililic-Acid Chelating Fluoroquinolones and TriazoloFluoroquinolones with 7-dihaloanilinosubstitution.

BACKGROUND: Incidence rates and prevalence of cancer are substantially high globally. New safe therapeutic drugs are endorsed to overcome the high toxicity and poor safety profile of clinical anticancer agents. OBJECTIVE: As antineoplastic Vosaroxin is a commercial fluoroquinolone (FQ), we hypothesize that superlative antiproliferation activity of lipophilic FQs/TFQs series correlates to their acidic groups and C8-C7 ethylene diamine Chelation Bridge along with bulky dual halogenations. METHODS: We tested dual lipophilic- acidic chelating FQs with a genuine potential of antiproliferative propensities based on their dual DPPH- and NO- radicals scavenging biocapacities using cell based - and colorimetric assays vs. respective reference agents as their molecular action mechanism. RESULTS: In this work, 9 lipophilic-acid chelating FQs and their cyclized TriazoloFQs (TFQs) designed to bear 7- dihaloanilino substituents with a special focus on dichlorosubstitutions have been prepared, characterized and screened against breast T47D and MCF7, Pancreatic PANC1, colorectal HT29, cervical HELA, lung A375, skin A549, and Leukaemia K562 cancer cell lines using sulforhodamine B colorimetric bioassay. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals' scavenging propensities - as their molecular action mechanism- in comparison to ascorbic acid and indomethacin, respectively. Using Griess assay in lipopolysaccharide (LPS) prompted RAW264.7 macrophages inflammation, IC50 values (µM) in the ascending order of new FQs' NO scavenging/antiinflammation capacity were 4a < 3a < 4c < indomethacin (23.8 < 33.4 < 36 vs. indomethacin's 124, respectively). Exceptionally unlike the rest, reduced FQ, 4b exhibited remarkably superior DPPH radical scavenging capacity to ascorbic acid (IC50 values (µM) 19.9 vs. 123.9, p < 0.001). In comparison to cisplatin; nitroFQs (3a, 3b and 3c), the reduced FQs (4a, 4b, and 4c) and the TFQs (5a, 5b and 5c) exerted substantial micromolar antiproliferation IC50 values < 50 µM in cervical Hela cancer cells but lacked comparable bioactivity in leukaemia K562. In both breast MCF7 and T47D cancer cell lines, FQs/TFQs 4a < 3a < 5b (respective IC50 values (µM) 0.52 < 22.7 < 24 vs. cisplatin's 41.8 and 0.03 < 4.8 < 27 vs. cisplatin's 509), and in both GI system colorectal HT29 and pancreatic PANC1 cancer cells FQs/TFQs 4a < 3a < 5b and 4a< 3a (respective IC50 values (µM) 0.12 < 3.5 < 15.9 vs. cisplatin's 148 and 1.5 < 10.4 vs. cisplatin's 25.5), exerted nanomolar-micromolar affinities of antiproliferation potencies < 50µM. Besides in lung A375 cancer cells FQs/TFQs 4c < 4a < 3a and in skin A549 cancer cells 5c < 3c < 4a < 3a < 4c (respective IC50 values (µM) 0.07 < 3.2 < 10.3 vs. cisplatin's 390 and 0.5 < 2.3 < 3.8 < 8.8 < 17.3 vs. cisplatin's 107) exhibited nanomolar-micromolar antineoplastic capacities < 50 µM. Their spectrum of selectivity indices for safety in fibroblasts PDL-based 72h incubations was reported. Unequivocally 4b reduction of viability effectiveness linked with its DPPH radical scavenging effects (without a matching antiinflammation effect). Explicitly 4a, 3a and 4c exerted exquisite antiinflammation-selective cytotoxicity duality in vitro. CONCLUSION: Such a new potential chelation mechanism can explain the pronounced difference in antineoplastic activity of new FQs/TFQs.

A Novel Class of Functionalized Synthetic Fluoroquinolones with Dual Antiproliferative - Antimicrobial Capacities.

As vosaroxin as a fluoroquinolone (FQ) had anticancer effectiveness; this study aimed to screen new lipophilic FQs for their dual antimicrobial-antiproliferative activities. Using sulforhodamine B assay; 36 lipophilic FQs have been screened for antimicrobial propensities against S. aureus, E. coli, and C. albicans vs. the respective references ciprofloxacin and fluconazole. They were also explored against a battery of cancer cell lines. Normal periodontal ligament fibroblasts (PDL) were tested for safety examination in comparison to the cisplatin. Reduced FQ compound 4g (R-2, 4-DMeOACA) highly scored nanomolar potency with MIC value of 0.004 µM against gram-positive bacteria. The highest activity of the 36 lipophilic FQs was noted on Leukaemia K562, cervical HELA and pancreatic PANC-1 cancer cell lines with respective IC50 value of 0.005 µM for compound R-4-BuACA (4e), 0.40 µM with CHxCA (7a) and 0.11 µM for R-4-HxACA (4f). Tested FQs exhibited cytotoxicity in A549 lung cancer, MCF-7 and T47D breast cancer cell lines. The reduced 4e and 4f compounds have shown nanomolar inhibition against K562 (as of 4e), PANC-1 and MCF-7 (as of 4f) with IC50 values of 0.005, 0.11 and 0.30 µM, respectively. Succinctly FQs' dual gram-positive antibacterial-antineoplastic capacities expand on of drug design scaffolds in lead generation.
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The Evaluation of Potential Cytotoxic Effect of Different Proton Pump Inhibitors on Different Human Cancer Cell Lines.

OBJECTIVE: To assess the differential cytotoxic activity of PPIs on different human cancer cell lines; namely A549 lung cancer, CACO-2 colorectal cancer, MCF-7 breast cancer, and PANC-1 pancreatic cancer, A375 skin melanoma. METHODS: In this study, the five human cancer cell lines and human non-cancerous fibroblasts were treated with increasing concentration of PPIs Omeprazole (OMP), Esomeprazole (ESOM), and Lansoprazole (LANSO) (50-300µM), over 24h, 48h, and 72h. Cell viability was determined using 3-(4,5- Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay and the IC50 values of PPIs were measured. The most sensitive cell line A375 was used for further investigation. The cytotoxic effects of LANSO on these cells were assessed using Annexin-V Propidium Iodide (AV-PI) flow cytometry. As of action mechanism; anti-inflammatory effects of each PPIs and PPIs-DOXO combination therapy on LPS-stimulated RAW 264.7 mouse macrophages were assessed. RESULTS: Dose and time dependence cytotoxic activity of PPIs on human cancer cell lines was founded. Unlike DOXO; All PPIs had a selective cytotoxic effect in the normal fibroblasts. Unlike the equipotent OMP and ESOM; LANSO was the most potent drug with IC50 values at 72h of 99, 217, 272, 208, 181µM against A375, A549, CACO-2, MCF-7, and PANC-1, respectively. AV-PI flow cytometry revealed dose-dependent apoptotic effects of LANSO alone and substantially enhanced in DOXO-co-treatments. Interestingly unlike ESOM and OMP, LANSO proved more effective than indomethacin in LPS-stimulated RAW 264.7 macrophages. None of the tested compounds, as well as indomethacin, exerted any cytotoxicity against RAW 264.7 macrophages. PPIs-DOXO lacked potential synergistic combination antiinflammation therapies. CONCLUSION: This study provides the evidence that PPIs induce a direct and differential cytotoxic activity against human cancer cell line by the induction of the apoptosis. Moreover, PPIs increase cancer cell lines sensitivity to doxorubicin via apoptosis augmentation. Nevertheless, PPIs-DOXO lacked potential synergistic combination therapies in either antiproliferation or anti-inflammation.

Dual Glycation-Inflammation Modulation, DPP-IV and Pancraetic Lipase Inhibitory Potentials and Antiproliferative Activity of Novel Fluoroquinolones.

Paramount efforts by pharmaceutical industry to identify new targets for obesity-diabetes (Diabesity) pharmacological intervention have led to a number of agents developed and directed at DPP IV [dipeptidyl peptidase IV] enzyme inhibition thereby enhancing endogenous insulinotropic incretins. Besides antioxidative-antiinflammtory molecules that inhibit accumulation of advanced glycation end products (AGEs) can be good candidates for ameliorating diabetic complications. Fluoroquinolones (FQs) have been identified recently as potent inhibitors of pancreatic lipase (PL). The suggested association between obesity and colorectal cancer initiated the evaluation of antiproliferative activity of the new FQs and TFQs against a panel of obesity related colorectal cells (HT29, HCT116, SW620 CACO2 and SW480). The aim of the current study is to examine the potential of newly synthesized FQs and triazolofluoroquinolones (TFQs) derivatives as dual inhibitors for glycation and inflammation, DPP IV inhibitors, PL inhibitors for dual management of obesity and diabetes, as well as antiprolifertaive efficacy against colorectal cancer cell lines. Sulforodamine B (SRB) colorimetric assay revealed that some derivatives exhibited unselective cytotoxity against HT29, HCT116, SW620 CACO2 and SW480. The superior antiglycation activity of the reduced derivatives 4a and 4b over that of aminoguanidine with respective IC50 (µM) values of 3.05±0.33 and 8.51±3.21; none of the tested synthetic compounds could perform equally effectively to Diprotin A, a dose dependent inhibitor of DPP IV. Compounds 4a, 5a, 3b, 4b and 5b demonstrated anti-inflammatory IC50 values exceeding that of indomethacin. Compounds 3a and 4a showed IC50 lower than 10 µM as PL inhibitors. In conclusion, FQ and TFQ derivatives may unveil new antiobesity and anticancer agents in the future. Our research qualifies FQs and TFQs as promising candidates for the development of related α-dicarbonyl scavengers as therapeutic agents to protect cells against carbonyl stress.

Correlates of resistin and retinol-binding protein 4 in metabolic syndrome patients with and without prediabetes.

Background Resistin and retinol-binding protein 4 (RBP4) can work in an intricate in metabolic syndrome (MetS) and prediabetes (PreDM) molecular crosstalk. Materials and methods Resistin and RBP4 were evaluated using colorimetric enzyme-linked immunosorbent assays (ELISAs) in 29 normoglycemic MetS, 30 newly diagnosed drug naïve MetS-preDM patients and 29 lean and normoglycemic controls. Results In this cross-sectional design; the gradual increase in resistin levels (ng/mL), though not ascribed any statistically marked variation, was appreciable in both normoglycemic and preDM MetS groups vs. controls. RBP4 mean circulating levels (ng/mL) in both MetS groups (non-diabetic and preDM) invariably lacked discrepancy vs. controls. Except for fasting plasma glucose (FPG) and A1C; no further intergroup discrepancy could be identified between MetS arms. Adiposity indices: body mass index (BMI), body adiposity index (BAI) and lipid accumulation product (LAP) (but not conicity index) were substantially higher in both MetS (non- and preDM) groups vs. those of controls. Likewise, the atherogenicity index of plasma [but not non-high-density lipoprotein-cholesterol (nonHDL-C)/HDL-C ratio, or triglyceride (TG)/HDL-C ratio] or any of the hematological indices [red cell distribution width (RDW-CV %), monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR) and platelet (PLT) to lymphocyte ratios (PLR)] had any marked variations as compared to controls. Low-density lipoprotein-cholesterol (LDL-C)/HDL-C ratio,visceral adiposity index, and waist circumference (WC)/hip circumference (HC) ratio were noticeably greater in MetS-preDM vs. normoglycemic MetS recruits. Neither biomarker could relate to each other, or any of the atherogenecity indices in 59 MetS participants (non- and preDM). Unlike RBP4; resistin associated proportionally with each of HC, BAI, MLR and NLR. Conclusions Both biomarkers can be putative indicator/surrogate prognostic tools for the prediction/prevention and pharmacotherapy of MetS anomalies.

Correlates of zinc finger BED domain-containing protein 3 and ghrelin in metabolic syndrome patients with and without prediabetes.

Background Ghrelin and zinc finger BED domain-containing protein 3 (ZBED3) are distinctively cross linked with prediabetes (preDM) and metabolic syndrome (MetS). Materials and methods In a cross-sectional design with 29 normoglycemic MetS and 30 newly diagnosed drug naïve preDM/MetS patients vs. 29 lean and normoglycemic controls; ghrelin and ZBED3 were evaluated using colorimetric enzymatic assays. Results While ZBED3 mean circulating levels (ng/mL) in both MetS groups (normoglycemic and preDM) invariably lacked discrepancy vs. controls; Appreciably ghrelin levels (ng/mL) in preDM/MetS (but not normoglycemic MetS) participants were markedly higher vs. controls. Except for fasting plasma glucose (FPG) and glycosylated-hemoglobin (HbA1C); no further intergroup discrepancy could be identified between the MetS arms. Remarkably adiposity indices (body mass index (BMI), body adiposity index (BAI), and lipid accumulation product (LAP), but not conicity index (CI) or visceral adiposity index (VAI)); atherogenicity index of plasma (but not non-high-density lipoprotein-cholesterol (non-HDL-C/HDL-C) ratio, or total cholesterol (TC)/HDL-C ratio) or any of hematological indices (red cell distribution width (RDW-CV%), monocyte to lymphocyte ratio (MLR), neutrophil to lymphocyte ratio (NLR) and platelet (PLT) to lymphocyte ratio (PLR)) were substantially higher in both MetS (non- and preDM) groups vs. those of controls. Exceptionally low-density lipoprotein -cholesterol (LDL-C)/HDL-C ratio, and waist circumference (WC)/hip circumference (HC) ratio were much more pronounced in MetS-preDM vs. normoglycemic MetS recruits. In the MetS pool (both normoglycemic and preDM, n = 58), neither biomarker could relate to each other, or any of clinical parameters, adiposity or atherogenecity indices. Exceptionally ghrelin correlated significantly and inversely with age. ZBED3 correlated significantly and directly with RDW-CV% in the same pool of MetS recruits (n = 59). Conclusions Both biomarkers can not be ruled out as putative predictive/surrogate prognostic tools for metabolic anomalies prevention and pharmacotherapy.