Publications by authors named "Mohammad A Aziz"

8 Publications

  • Page 1 of 1

Emerging Pharmacologic Therapies for Heart Failure With Reduced Ejection Fraction.

CJC Open 2021 May 1;3(5):646-657. Epub 2021 Feb 1.

Cardiovascular Diseases Department, King Faisal Specialist Hospital and Research Centre (Gen. Org.), Jeddah, Saudi Arabia.

The global burden of heart failure has reached epidemic proportions with tremendous health and economic consequences. Sodium glucose cotransporter 2 inhibitors, vericiguat, and omecamtiv mecarbil are novel agents that promise to blunt the high residual risk of heart failure with reduced ejection fraction. We review the vast knowledge base that has rapidly materialized for these agents and is poised to shape the current and future trends and recommendations in heart failure pharmacotherapy.
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http://dx.doi.org/10.1016/j.cjco.2021.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134937PMC
May 2021

Transcriptomics-Based Characterization of the Toxicity of ZnO Nanoparticles Against Chronic Myeloid Leukemia Cells.

Int J Nanomedicine 2020 13;15:7901-7921. Epub 2020 Oct 13.

Brighton and Sussex Medical School, University of Sussex, Brighton, UK.

Introduction: Zinc oxide nanoparticles (ZnO NPs) have recently attracted attention as potential anti-cancer agents. To the best of our knowledge, the toxicity of ZnO NPs against human chronic myeloid leukemia cells (K562 cell line) has not been studied using transcriptomics approach.

Objective: The goals of this study were to evaluate the capability of ZnO NPs to induce apoptosis in human chronic myeloid leukemia cells (K562 cells) and to investigate the putative mechanisms of action.

Methods: We used viability assay and flowcytometry coupled with Annexin V-FITC and propidium iodide to investigate the toxicity of ZnO NPs on K562 cells and normal peripheral blood mononuclear cells. Next we utilized a DNA microarray-based transcriptomics approach to characterize the ZnO NPs-induced changes in the transcriptome of K562 cells.

Results: ZnO NPs exerted a selective toxicity (mainly by apoptosis) on the leukemic cells (≤0.005) and altered their transcriptome; 429 differentially expressed genes (DEGs) with fold change (FC)≥4 and ≤0.008 with corrected ≤0.05 were identified in K562 cells post treatment with ZnO NPs. The over-expressed genes were implicated in "response to zinc", "response to toxic substance" and "negative regulation of growth" (corrected ≤0.05). In contrast, the repressed genes positively regulated "cell proliferation", "cell migration", "cell adhesion", "receptor signaling pathway via JAK-STAT" and "phosphatidylinositol 3-kinase signaling" (corrected ≤0.05). Lowering the FC to ≥1.5 with ≤0.05 and corrected ≤0.1 showed that ZnO NPs over-expressed the anti-oxidant defense system, drove K562 cells to undergo mitochondrial-dependent apoptosis, and targeted NF-κB pathway.

Conclusion: Taken together, our findings support the earlier studies that reported anti-cancer activity of ZnO NPs and revealed possible molecular mechanisms employed by ZnO NPs to induce apoptosis in K562 cells.
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http://dx.doi.org/10.2147/IJN.S261636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568638PMC
November 2020

Molecular classification of colorectal cancer using the gene expression profile of tumor samples.

Exp Biol Med (Maywood) 2019 09 15;244(12):1005-1016. Epub 2019 May 15.

2 King Saud bin Abdulaziz University for Health Sciences, Riyadh 11426, Saudi Arabia.

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http://dx.doi.org/10.1177/1535370219850788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879775PMC
September 2019

Cytotoxic activity of the novel heterocyclic compound G-11 is primarily mediated through intrinsic apoptotic pathway.

Apoptosis 2016 07;21(7):873-86

Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University (NSU), Fort Lauderdale, FL, 33328, USA.

Natural and chemically synthesized heterocyclic compounds have been explored for their potential use as anticancer agents. We had synthesized non-natural heterocyclic analogs and evaluated their anti-tumor activity by measuring effect on cell proliferation and induction of apoptosis in different cell lines. Previously, we identified a pyrazole-containing compound (G-11) showing cytotoxic effect towards leukemia and lymphoma cell lines. In this study, we further investigated the mechanistic aspects of anticancer properties of G-11 in HL-60 cell line. We demonstrated that cytotoxic effect of G-11 is mediated by caspase-dependent apoptosis. However, the involvement of mitochondrial dysfunction induced by G-11 was independent of caspases. G-11 triggered generation of ROS, caused disruption of mitochondrial transmembrane potential, increased release of cytochrome c to the cytosol, and altered the expression of Bcl-2 and Bax proteins. These results suggest significant involvement of intrinsic apoptotic pathway. This study comprehensively details the possible mechanisms of action of a novel heterocyclic compound which could find its potential use as an anticancer agent.
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http://dx.doi.org/10.1007/s10495-016-1248-zDOI Listing
July 2016

Novel anticancer compound [trifluoromethyl-substituted pyrazole N-nucleoside] inhibits FLT3 activity to induce differentiation in acute myeloid leukemia cells.

Cancer Lett 2016 Jun 23;375(2):199-208. Epub 2016 Feb 23.

Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University (NSU), Fort Lauderdale, FL 33328, United States.

Anticancer properties of chemically synthesized compounds have continuously been optimized for better efficacy and selectivity. Derivatives of heterocyclic compounds are well known to have selective antiproliferative effect against many types of cancer. In this study, we investigated the ability of an indigenously synthesized anticancer molecule, G-11 [1-(2",3",4",6"-Tetra-O-acetyl-β-D-glucopyranosyl)-4-(3'-trifluoromethylphenylhydrazono)-3-trifluoromethyl-1,4-dihydropyrazol-5-one], to cause selective cytotoxicity and induce differentiation in the acute myeloid leukemia HL-60 cells. G-11 was able to exert cytotoxic effect on hematological (Jurkat, U937, K562, HL-60, CCRF-SB) and solid tumor (MCF-7, HepG2, HeLa, Caco-2) cell lines, with IC50 values significantly lower than noncancerous cells (HEK-293, BJ and Vero) and normal peripheral blood mononuclear cells. G-11 induced differentiation of HL-60 cells to granulocytes and monocytes/macrophages by inhibiting the activation of FLT3 (CD135 tyrosine kinase). ITD-FLT3 mutation found in many acute myeloid leukemia patients could also be targeted by G-11 as exhibited by its inhibitory effect on MOLM-13 and MV4-11 cell lines. Molecular docking studies suggest the involvement of Leu616, Asp698, Cys694 and Cys828 residues in binding of G-11 to FLT3. The ability of G-11 to cause selective cytotoxicity and induce differentiation in cancer cells could be clinically relevant for therapeutic gains.
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http://dx.doi.org/10.1016/j.canlet.2016.02.028DOI Listing
June 2016

The pyridone-annelated isoindigo (5'-Cl) induces apoptosis, dysregulation of mitochondria and formation of ROS in leukemic HL-60 cells.

Cell Physiol Biochem 2015 27;35(5):1958-74. Epub 2015 Mar 27.

Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), National Guard Health Affairs, Riyadh, Kingdom of Saudi Arabia.

Background/aims: In our quest to develop an isoindigo with improved efficacy and bioavailability, we recently synthesized a series of novel substituted pyridone-annelated isoindigo and evaluated their antiproliferative effects. We identified the compound [(E)-1-(5'-Chloro-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f] quinoline-8-carboxylic acid], abbreviated as 5'-Cl, which shows selective antiproliferative activities against various cancer cell lines mediated through apoptosis. Here we have investigated the molecular mechanisms underlying the apoptotic activity of 5'-Cl in the human promyelocytic leukemia HL-60 cells.

Methods: We employed different methods to determine the apoptotic pathways triggered by 5'-Cl in HL-60 cells, using flow cytometry, nuclear staining, caspases activation, mitochondria functioning, generation of reactive oxygen species (ROS) and Western blotting techniques.

Results: Low concentrations (1-8 µM) of 5'-Cl inhibited the growth of HL-60 cells in a dose and time-dependent manner. Cytotoxicity of this compound is found to be mediated by a caspase-dependent apoptosis. Also, there were indications of caspase independent apoptosis as z-VAD-FMK failed to fully rescue the cells from 5'-Cl-induced apoptosis. In addition, the compound triggered generation of Reactive Oxygen Species (ROS), caused depolarization of the mitochondrial inner membrane, decreased the level of cellular ATP, modulated the expression and phosphorylation of Bcl-2 leading to loss of its association with Bax and increased the release of cytochrome c to the cytosol of treated cells. The effects of 5'-Cl on mitochondria and apoptosis were substantially blocked in the presence of a combination between z-VAD-FMK and either of the ROS scavenger N-acetyl-L-cysteine (NAC) or pyrrolidine dithiocarbamate (PDTC).

Conclusion: We demonstrated that the growth inhibitory effects of 5'-Cl in HL-60 cells involve multiple pathways of apoptosis and dysregulation of mitochondrial functions.
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http://dx.doi.org/10.1159/000374004DOI Listing
December 2015

Identification of STAT3-independent regulatory effects for protein inhibitor of activated STAT3 by binding to novel transcription factors.

Cancer Biol Ther 2011 Jul 15;12(2):139-51. Epub 2011 Jul 15.

Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, OH USA.

Protein Inhibitor of Activated Signal Transducer and Activators of Transcription 3 (PIAS3) is a molecule that regulates STAT3 and has antiproliferative properties. Glioblastoma and squamous cell lung cancer lack PIAS3 expression. To test the hypothesis that PIAS3 transcriptional effects are STAT3-independent, we developed models for STAT3 knockdown and PIAS3 over-expression. PIAS3 expression results in a distinct transcriptional profile that does not occur with STAT3 knockdown. We identify novel transcription factor binding partners for PIAS3 including ETS, EGR1, NR1I2, and GATA1. PIAS3 binds to these factors and regulates their transcriptional effects resulting in alterations in canonical pathways including Wnt/β-catenin signaling and functions such as cell death and proliferation. A model is proposed by which PIAS3 effects EGR1 regulated pathways.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154286PMC
http://dx.doi.org/10.4161/cbt.12.2.15732DOI Listing
July 2011

Probabilistic modeling of DNA mismatch repair effects on cell cycle dynamics and iododeoxyuridine-DNA incorporation.

Cancer Res 2007 Nov;67(22):10993-1000

Department of Electrical Engineering and Computer Science, Case Western Reserve University, and University Hospitals Case Medical Center, Cleveland, Ohio 44106-6068, USA.

Previous studies in our laboratory have described increased and preferential radiosensitization of mismatch repair-deficient (MMR(-)) HCT116 colon cancer cells with 5-iododeoxyuridine (IUdR). Indeed, our studies showed that MMR is involved in the repair (removal) of IUdR-DNA, principally the G:IU mispair. Consequently, we have shown that MMR(-) cells incorporate 25% to 42% more IUdR than MMR(+) cells, and that IUdR and ionizing radiation (IR) interact to produce up to 3-fold greater cytotoxicity in MMR(-) cells. The present study uses the integration of probabilistic mathematical models and experimental data on MMR(-) versus MMR(+) cells to describe the effects of IUdR incorporation upon the cell cycle for the purpose of increasing IUdR-mediated radiosensitivity in MMR(-) cells. Two computational models have been developed. The first is a stochastic model of the progression of cell cycle states, which is applied to experimental data for two synchronized isogenic MMR(+) and MMR(-) colon cancer cell lines treated with and without IUdR. The second model defines the relation between the percentage of cells in the different cell cycle states and the corresponding IUdR-DNA incorporation at a particular time point. These models can be combined to predict IUdR-DNA incorporation at any time in the cell cycle. These mathematical models will be modified and used to maximize therapeutic gain in MMR(-) tumors versus MMR(+) normal tissues by predicting the optimal dose of IUdR and optimal timing for IR treatment to increase the synergistic action using xenograft models and, later, in clinical trials.
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http://dx.doi.org/10.1158/0008-5472.CAN-07-0966DOI Listing
November 2007
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