Publications by authors named "Ahmad Iskandarani"

11 Publications

  • Page 1 of 1

The metabolic footprint of compromised insulin sensitivity under fasting and hyperinsulinemic-euglycemic clamp conditions in an Arab population.

Sci Rep 2020 10 13;10(1):17164. Epub 2020 Oct 13.

Department of Internal Medicine, Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar.

Metabolic pathways that are corrupted at early stages of insulin resistance (IR) remain elusive. This study investigates changes in body metabolism in clinically healthy and otherwise asymptomatic subjects that may become apparent already under compromised insulin sensitivity (IS) and prior to IR. 47 clinically healthy Arab male subjects with a broad range of IS, determined by hyperinsulinemic-euglycemic clamp (HIEC), were investigated. Untargeted metabolomics and complex lipidomics were conducted on serum samples collected under fasting and HIEC conditions. Linear models were used to identify associations between metabolites concentrations and IS levels. Among 1896 identified metabolites, 551 showed significant differences between fasting and HIEC, reflecting the metabolic switch in energy utilization. At fasting, 336 metabolites, predominantly di- and tri-acylglycerols, showed significant differences between subjects with low and high levels of IS. Changes in amino acid, carbohydrate and fatty acid metabolism in response to insulin were impaired in subjects with low IS. Association of altered mannose and amino acids with IS was also replicated in an independent cohort of T2D patients. We identified metabolic phenotypes that characterize clinically healthy Arab subjects with low levels of IS at their fasting state. Our study is providing further insights into the metabolic pathways that precede IR.
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http://dx.doi.org/10.1038/s41598-020-73723-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555540PMC
October 2020

Greensporone A, a Fungal Secondary Metabolite Suppressed Constitutively Activated AKT via ROS Generation and Induced Apoptosis in Leukemic Cell Lines.

Biomolecules 2019 03 29;9(4). Epub 2019 Mar 29.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.

Greensporone A is a fungal secondary metabolite that has exhibited potential in vitro for anti-proliferative activity in vitro. We studied the anticancer activity of greensporone A in a panel of leukemic cell lines. Greensporone A-mediated inhibition of proliferation is found to be associated with the induction of apoptotic cell death. Greensporone A treatment of leukemic cells causes inactivation of constitutively activated AKT and its downstream targets, including members GSK3 and FOXO1, and causes downregulation of antiapoptotic genes such as Inhibitor of Apoptosis (IAPs) and Bcl-2. Furthermore, Bax, a proapoptotic member of the Bcl-2 family, was found to be upregulated in leukemic cell lines treated with greensporone A. Interestingly, gene silencing of AKT using AKT specific siRNA suppressed the expression of Bcl-2 with enhanced expression of Bax. Greensporone A-mediated increase in Bax/Bcl-2 ratio causes permeabilization of the mitochondrial membrane leading to the accumulation of cytochrome c in the cytoplasm. Greensporone A-induced cytochrome c accumulation causes the activation of caspase cascade and cleavage of its effector, poly(ADP-ribose) polymerase (PARP), leading to apoptosis. Greensporone A-mediated apoptosis in leukemic cells occurs through the generation of reactive oxygen species (ROS) due to depletion of glutathione (GSH) levels. Finally, greensporone A potentiated the anticancer activity of imatinib in leukemic cells. In summary, our study showed that greensporone A suppressed the growth of leukemic cells via induction of apoptotic cell death. The apoptotic cell death occurs by inhibition of AKT signaling and activation of the intrinsic apoptotic/caspase pathways. These results raise the possibility that greensporone A could be developed as a therapeutic agent for the treatment of leukemia and other hematological malignancies.
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http://dx.doi.org/10.3390/biom9040126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523683PMC
March 2019

Anticancer Activity of Camel Milk via Induction of Autophagic Death in Human Colorectal and Breast Cancer Cells

Asian Pac J Cancer Prev 2018 Dec 25;19(12):3501-3509. Epub 2018 Dec 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, State of Qatar. Email:

Background/ Objective: Camel milk is traditionally known for its human health benefits and believed to be a remedy for various human ailments including cancer. The study was aimed to evaluate the inhibitory effects of commercially available camel milk on cancer cells and its underlying mechanism(s). Materials and Methods: Two cell lines: colorectal cancer HCT 116 and breast cancer MCF-7 were cultured with different doses of camel milk. The effects of camel milk on cell death were determined by MTT assay, viability by trypan blue exclusion assay and migration by in vitro scratch assay. The mechanism was elucidated by western blotting and confocal microscopy was used to confirm autophagy. Results: Camel milk significantly reduced proliferation, viability as well as migration of both the cells. The accumulation of LC3-II protein along with reduction in expression of p62 and Atg 5-12, the autophagy proteins implied induction of autophagy. The (GFP)-LC3 puncta detected by confocal microscopy confirmed the autophagosome formation in response to camel milk treatment. Conclusion: Camel milk exerted antiproliferative effects on human colorectal HCT 116 and breast MCF-7 cancer cells by inducing autophagy.
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http://dx.doi.org/10.31557/APJCP.2018.19.12.3501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428541PMC
December 2018

Greensporone C, a Freshwater Fungal Secondary Metabolite Induces Mitochondrial-Mediated Apoptotic Cell Death in Leukemic Cell Lines.

Front Pharmacol 2018 16;9:720. Epub 2018 Jul 16.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

Therapeutic agents used in the treatment of cancer are known to develop resistance against cancer cells. Hence, there is a continuing need to investigate novel agents for the treatment and management of cancer. Antitumor activity of greensporone C (GC), a new resorcylic acid lactone isolated from an organic extract of a culture of a sp. freshwater fungus, was subjected for screening against a panel of leukemic cell lines (K562, U937, and AR320). In all the three cell lines, cell proliferation was inhibited in dose-dependent fashion. GC further arrested the cells in SubG0 phase in dose-dependent manner. Annexin V/PI dual staining data confirmed apoptotic death of treated K562 and U937 leukemic cells. Treatment with GC suppressed constitutively phosphorylated AKT and downregulated expression of inhibitor of apoptotic proteins XIAP, cIAP-1, and cIAP-2. In summation to this, GC-treated leukemic cells upregulated protein expression of pro-apoptotic proteins, Bax with concomitant decrease in expression of anti-apoptotic proteins including Bcl-2 and Bcl-xL. Upregulation of Bax was associated with cytochrome c release which was confirmed from the collapse of mitochondrial membrane. Released cytochrome c further activated caspase cascade which in turn initiated apoptosis process. Anticancer activity of this isolated fungal compound GC was potentiated via stimulating production of reactive oxygen species (ROS) along with depletion of reduced glutathione (GSH) levels in K562 and U937 leukemic cells. Pretreatment of these cells with -acetyl cysteine prevented GC-induced depletion of reduced GSH level and mitochondrial-caspase-induced apoptosis. Altogether, our data show that GC modulates the apoptotic response of human leukemic cells and raises the possibility of its use as a novel therapeutic strategy for hematological malignancies.
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http://dx.doi.org/10.3389/fphar.2018.00720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054921PMC
July 2018

Accelerated lipid catabolism and autophagy are cancer survival mechanisms under inhibited glutaminolysis.

Cancer Lett 2018 08 17;430:133-147. Epub 2018 May 17.

Department of Physiology and Biophysics, Weill Cornell Medicine - Qatar, Education City, PO 24144, Doha, Qatar. Electronic address:

Suppressing glutaminolysis does not always induce cancer cell death in glutamine dependent tumors because cells may switch to alternative energy sources. To reveal compensatory metabolic pathways, we investigated the metabolome-wide cellular response to inhibited glutaminolysis in cancer cells. Glutaminolysis inhibition with C.968 suppressed cell proliferation but was insufficient to induce cancer cell death. We found that lipid catabolism was activated as a compensation for glutaminolysis inhibition. Accelerated lipid catabolism, together with oxidative stress induced by glutaminolysis inhibition, triggered autophagy. Simultaneously inhibiting glutaminolysis and either beta oxidation with trimetazidine or autophagy with chloroquine both induced cancer cell death. Here we identified metabolic escape mechanisms contributing to cancer cell survival under treatment and we suggest potentially translational strategy for combined cancer therapy, given that chloroquine is an FDA approved drug. Our findings are first to show efficiency of combined inhibition of glutaminolysis and beta oxidation as potential anti-cancer strategy as well as add to the evidence that combined inhibition of glutaminolysis and autophagy may be effective in glutamine-addicted cancers.
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http://dx.doi.org/10.1016/j.canlet.2018.05.017DOI Listing
August 2018

The Replacement of five Consecutive Amino Acids in the Cyt1A Protein of Bacillus thuringiensis Enhances its Cytotoxic Activity against Lung Epithelial Cancer Cells.

Toxins (Basel) 2018 03 16;10(3). Epub 2018 Mar 16.

Biological & Environmental Sciences Department, College of Arts and Sciences, Qatar University, P.O. Box 2713 Doha, Qatar.

Cyt1A protein is a cytolytic protein encoded by the gene of subsp. (Bti) as part of the parasporal crystal proteins produced during the sporulation. Cyt1A protein is unique compared to the other endotoxins present in these parasporal crystals. Unlike δ-endotoxins, Cyt1A protein does not require receptors to bind to the target cell and activate the toxicity. It has the ability to affect a broad range of cell types and organisms, due to this characteristic. Cyt1A has been recognized to not only target the insect cells directly, but also recruit other endotoxins by acting as receptors. Due to these mode of actions, Cyt1A has been studied for its cytolytic activity against human cancer cell lines, although not extensively. In this study, we report a novel Cyt1A protein produced by a Bti strain QBT229 isolated from Qatar. When tested for its cytotoxicity against lung cancer cells, this local strain showed considerably higher activity compared to that of the reference Bti and other strains tested. The possible reasons for such enhanced activity were explored at the gene and protein levels. It was evidenced that five consecutive amino acid replacements in the β8 sheet of the Cyt1A protein enhanced the cytotoxicity against the lung epithelial cancer cells. Such novel Cyt1A protein with high cytotoxicity against lung cancer cells has been characterized and reported through this study.
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http://dx.doi.org/10.3390/toxins10030125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869413PMC
March 2018

Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells.

PLoS One 2017 13;12(7):e0180895. Epub 2017 Jul 13.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, State of Qatar.

The X-linked inhibitor of apoptosis (XIAP) is a viable molecular target for anticancer drugs that overcome apoptosis-resistance of malignant cells. XIAP is an inhibitor of apoptosis, mediating through its association with BIR3 domain of caspase 9. Embelin, a quinone derivative isolated from the Embelia ribes plant, has been shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities via inhibiting XIAP activity. In this study, we found that embelin causes a dose-dependent suppression of proliferation in leukemic cell lines K562 and U937. Embelin mediated inhibition of proliferation correlates with induction of apoptosis. Furthermore, embelin treatment causes loss of mitochondrial membrane potential and release of cytochrome c, resulting in subsequent activation of caspase-3 followed by polyadenosin-5'-diphosphate-ribose polymerase (PARP) cleavage. In addition, embelin treatment of leukemic cells results in a decrease of constitutive phosphorylations/activation level of AKT and downregulation of XIAP. Gene silencing of XIAP and AKT expression showed a link between XIAP expression and activated AKT in leukemic cells. Interestingly, targeting of XIAP and PI3-kinase/AKT signaling augmented inhibition of proliferation and induction of apoptosis in leukemic cells. Altogether these findings raise the possibility that embelin alone or in combination with inhibitors of PI3-kinase/AKT pathway may have therapeutic usage in leukemia and possibly other malignancies with up-regulated XIAP pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180895PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509148PMC
September 2017

Bortezomib-mediated downregulation of S-phase kinase protein-2 (SKP2) causes apoptotic cell death in chronic myelogenous leukemia cells.

J Transl Med 2016 Mar 9;14:69. Epub 2016 Mar 9.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, State of Qatar.

Background: Proteasome inhibitors are attractive cancer therapeutic agents because they can regulate apoptosis-related proteins. Bortezomib also known as Velcade(®), a proteasome inhibitor that has been approved by the food and drug administration for treatment of patients with multiple myeloma, and many clinical trials are ongoing to examine to the efficacy of bortezomib for the treatment of other malignancies. Bortezomib has been shown to induce apoptosis and inhibit cell growth of many cancer cells. In current study, we determine whether bortezomib induces cell death/apoptosis in CML.

Methods: Cell viability was measured using MTT assays. Apoptosis was measured by annexin V/PI dual staining and DNA fragmentation assays. Immunoblotting was performed to examine the expression of proteins. Colony assays were performed using methylcellulose.

Results: Treatment of CML cells with bortezomib results in downregulation of S-phase kinase protein 2 (SKP2) and concomitant stabilization of the expression of p27Kip1. Furthermore, knockdown of SKP2 with small interference RNA specific for SKP2 caused accumulation of p27Kip1. CML cells exposed to bortezomib leads to conformational changes in Bax protein, resulting in loss of mitochondrial membrane potential and leakage of cytochrome c to the cytosol. In the cytosol, cytochrome c causes sequential activation of caspase-9, caspase-3, PARP cleavage and apoptosis. Pretreatment of CML cells with a universal inhibitor of caspases, z-VAD-fmk, prevents bortezomib-mediated apoptosis. Our data also demonstrated that bortezomib treatment of CML downregulates the expression of inhibitor of apoptosis proteins. Finally, inhibition of proteasome pathways by bortezomib suppresses colony formation ability of CML cells.

Conclusions: Altogether, these findings suggest that bortezomib suppresses the cell proliferation via induction of apoptosis in CML cells by downregulation of SKP2 with concomitant accumulation of p27Kip1, suggesting that proteasomal pathway may form novel therapeutic targets for better management of CML.
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http://dx.doi.org/10.1186/s12967-016-0823-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784454PMC
March 2016

ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model.

Int J Cancer 2015 Aug 21;137(3):698-709. Epub 2015 Jan 21.

Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon.

The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy.
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http://dx.doi.org/10.1002/ijc.29407DOI Listing
August 2015

EAPB0503, a novel imidazoquinoxaline derivative, inhibits growth and induces apoptosis in chronic myeloid leukemia cells.

Anticancer Drugs 2014 Jul;25(6):624-32

Departments of aAnatomy, Cell Biology and Physiological Sciences bInternal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon cPharmacochemistry and Biomolecules Labs, Faculty of Pharmacy, Montpellier 1 University, Montpellier dHematology Lab and Blood Diseases Department, Bordeaux University Hospital, Victor Segalen University, Bordeaux, France.

Imatinib, the first-generation tyrosine kinase inhibitor, revolutionized the therapeutic management of chronic myeloid leukemia (CML) and is highly effective in inducing remissions and prolonging the survival of CML patients. However, one-third of patients develop intolerance or resistance to treatment, and CML stem cells remain insensitive to this therapy, leading almost inevitably to relapse upon treatment discontinuation. Imidazoquinoxalines are imiquimod derivatives that induce growth inhibition and induction of caspase-dependent apoptosis in melanoma and T-cell lymphoma cells. We investigated the effects of EAPB0203 and EAPB0503, two novel imidazoquinoxaline derivatives, on human CML cell lines and showed that they induced a dose-dependent and time-dependent cell growth inhibition. EAPB0503 proved more potent and induced a specific cell cycle arrest in mitosis in CML cells and direct activation of apoptosis as evidenced by increased pre-G0 population, breakdown of mitochondrial membrane potential, PARP cleavage, and DNA breakage. Interestingly, EAPB0503 decreased BCR-ABL oncoprotein levels. The combination of EAPB0503 with imatinib synergized to inhibit the proliferation of CML cells, and most importantly, EABP0503 inhibited the proliferation of imatinib-resistant CML cells, offering promising therapeutic modalities that would circumvent resistance to tyrosine kinase inhibitors and improve the prognosis of CML.
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http://dx.doi.org/10.1097/CAD.0000000000000084DOI Listing
July 2014

Effective targeting of chronic myeloid leukemia initiating activity with the combination of arsenic trioxide and interferon alpha.

Int J Cancer 2014 Feb 10;134(4):988-96. Epub 2013 Sep 10.

Department of Anatomy, Cell Biology and Physiology, American University of Beirut, Beirut, Lebanon.

Imatinib is the standard of care in chronic meloid leukemia (CML) therapy. However, imatinib is not curative since most patients who discontinue therapy relapse indicating that leukemia initiating cells (LIC) are resistant. Interferon alpha (IFN) induces hematologic and cytogenetic remissions and interestingly, improved outcome was reported with the combination of interferon and imatinib. Arsenic trioxide was suggested to decrease CML LIC. We investigated the effects of arsenic and IFN on human CML cell lines or primary cells and the bone marrow retroviral transduction/transplantation murine CML model. In vitro, the combination of arsenic and IFN inhibited proliferation and activated apoptosis. Importantly, arsenic and IFN synergistically reduced the clonogenic activity of primary bone marrow cells derived from CML patients. Finally, in vivo, combined interferon and arsenic treatment, but not single agents, prolonged the survival of primary CML mice. Importantly, the combination severely impaired engraftment into untreated secondary recipients, with some recipients never developing the disease, demonstrating a dramatic decrease in CML LIC activity. Arsenic/IFN effect on CML LIC activity was significantly superior to that of imatinib. These results support further exploration of this combination, alone or with imatinib aiming at achieving CML eradication rather than long-term disease control.
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http://dx.doi.org/10.1002/ijc.28427DOI Listing
February 2014