Publications by authors named "Amal Kamal Abdel-Aziz"

20 Publications

  • Page 1 of 1

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Dendritic cell vaccine immunotherapy; the beginning of the end of cancer and COVID-19. A hypothesis.

Med Hypotheses 2021 Jan 9;146:110365. Epub 2020 Nov 9.

Biology Department, School of Science and Engineering, American University in Cairo, New Cairo 11835, Egypt. Electronic address:

Immunotherapy is the newest approach to combat cancer. It can be achieved using several strategies, among which is the dendritic cell (DC) vaccine therapy. Several clinical trials are ongoing using DC vaccine therapy either as a sole agent or in combination with other interventions to tackle different types of cancer. Immunotherapy can offer a potential treatment to coronavirus disease 2019 (COVID-19) the worst pandemic facing this generation, a disease with deleterious effects on the health and economic systems worldwide. We hypothesize that DC vaccine therapy may provide a potential treatment strategy to help combat COVID-19. Cancer patients are at the top of the vulnerable population owing to their immune-compromised status. In this review, we discuss DC vaccine therapy in the light of the body's immunity, cancer, and newly emerging infections such as COVID-19 in hopes of better-customized treatment options for patients with multiple comorbidities.
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http://dx.doi.org/10.1016/j.mehy.2020.110365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836805PMC
January 2021

Novel molecular mechanisms underlying the ameliorative effect of N-acetyl-L-cysteine against ϒ-radiation-induced premature ovarian failure in rats.

Ecotoxicol Environ Saf 2020 Dec 29;206:111190. Epub 2020 Aug 29.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Radiotherapy represents a critical component in cancer treatment. However, premature ovarian failure (POF) is a major hurdle of deleterious off-target effects in young females, which, therefore, call for an effective radioprotective agent. The present study aimed to explore the molecular mechanism underlying the protective effects of N-acetyl-L-cysteine (NAC) against γ-radiation-provoked POF. Immature female Sprague-Dawley rats were orally-administered NAC (50 mg/kg) and were exposed to a single whole-body dose of 3.2 Gy ϒ-radiation. NAC administration remarkably reversed abnormal serum estradiol and anti-Müllerian hormone levels by 73% and 40%, respectively while ameliorating the histopathological and ultrastructural alterations-triggered by γ-radiation. Mechanistically, NAC alleviated radiation-induced oxidative damage through significantly increased glutathione peroxidase activity by 102% alongside with decreasing NADPH oxidase subunits (p22 and NOX4) gene expressions by 48% and 38%, respectively compared to the irradiated untreated group. Moreover, NAC administration achieved its therapeutic effect by inhibiting ovarian apoptosis-induced by radiation through downregulating p53 and Bax levels by 33% and 16%, respectively while increasing the Bcl-2 mRNA expression by 135%. Hence, the Bax/Bcl2 ratio and cytochrome c expression were subsequently reduced leading to decreased caspase 3 activity by 43%. Importantly, the anti-apoptotic property of NAC could be attributed to inactivation of MAPK signaling molecules; p38 and JNK, and enhancement of the ovarian vascular endothelial growth factor (VEGF) expression. Taken together, our results suggest that NAC can inhibit radiotherapy-induced POF while preserving ovarian function and structure through upregulating VEGF expression and suppressing NOX4/MAPK/p53 apoptotic signaling.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111190DOI Listing
December 2020

Preclinical models of breast cancer: Two-way shuttles for immune checkpoint inhibitors from and to patient bedside.

Eur J Cancer 2019 11 10;122:22-41. Epub 2019 Oct 10.

Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Biosciences, University of Milan, Milan, Italy. Electronic address:

The Food and Drug Administration has lately approved atezolizumab, anti-programmed death ligand 1 (PD-L1), to be used together with nanoparticle albumin-bound (nab) paclitaxel in treating patients with triple negative breast cancer (BC) expressing PD-L1. Nonetheless, immune checkpoint inhibitors (ICIs) are still challenged by the resistance and immune-related adverse effects evident in a considerable subset of treated patients without conclusive comprehension of the underlying molecular basis, biomarkers and tolerable therapeutic regimens capable of unleashing the anti-tumour immune responses. Stepping back to preclinical models is thus inevitable to address these inquiries. Herein, we comprehensively review diverse preclinical models of BC exploited in investigating ICIs underscoring their pros and cons as well as the learnt and awaited lessons to allow full exploitation of ICIs in BC therapy.
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http://dx.doi.org/10.1016/j.ejca.2019.08.013DOI Listing
November 2019

Tuning mTORC1 activity dictates the response of acute myeloid leukemia to LSD1 inhibition.

Haematologica 2020 08 19;105(8):2105-2117. Epub 2019 Sep 19.

Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy

Lysine specific demethylase-1 (LSD1) has been shown to be critical in acute myeloid leukemia (AML) pathogenesis and this has led to the development of LSD1 inhibitors (LSD1i) which are currently tested in clinical trials. Nonetheless, preclinical studies reported that AML cells frequently exhibit intrinsic resistance to LSD1 inhibition, and the molecular basis for this phenomenon is largely unknown. We explored the potential involvement of mammalian target of rapamycin (mTOR) in mediating the resistance of leukemic cells to LSD1i. Strikingly, unlike sensitive leukemias, mTOR complex 1 (mTORC1) signaling was robustly triggered in resistant leukemias following LSD1 inhibition. Transcriptomic, chromatin immunoprecipitation and functional studies revealed that insulin receptor substrate 1(IRS1)/extracellular-signal regulated kinases (ERK1/2) signaling critically controls LSD1i induced mTORC1 activation. Notably, inhibiting mTOR unlocked the resistance of AML cell lines and primary patient-derived blasts to LSD1i both and In conclusion, mTOR activation might act as a novel pro-survival mechanism of intrinsic as well as acquired resistance to LSD1i, and combination regimens co-targeting LSD1/mTOR could represent a rational approach in AML therapy.
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http://dx.doi.org/10.3324/haematol.2019.224501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395280PMC
August 2020

Comparing apples with oranges: Studying LSD1 inhibitors in cellular assays.

Pharmacol Res 2019 08 8;146:104345. Epub 2019 Jul 8.

Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy; Department of Biosciences, University of Milan, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.phrs.2019.104345DOI Listing
August 2019

Chemotherapy and cognition: comprehensive review on doxorubicin-induced chemobrain.

Cancer Chemother Pharmacol 2019 07 6;84(1):1-14. Epub 2019 Apr 6.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.

Chemobrain refers to a common sequela experienced by a substantial subset of cancer patients exposed to chemotherapeutic treatment, a phenomenon that dramatically deteriorates the survivors' quality of life and prevents them from restoring their pre-cancer life. This review is intended to address the current knowledge regarding the mechanisms underlying the pathophysiology of the chemobrain phenomenon, with special focus on the antineoplastic agent ''doxorubicin'', which has been shown to be implicated in strenuous central neurotoxicity despite being-almost entirely-peripherally confined. Moreover, the assessment of the post-chemotherapy cognitive impairment in both human and animal subjects, and the potential pharmacotherapy and behavioral intervention strategies are reviewed.
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http://dx.doi.org/10.1007/s00280-019-03827-0DOI Listing
July 2019

Serum sclerostin and irisin as predictive markers for atherosclerosis in Egyptian type II diabetic female patients: A case control study.

PLoS One 2018 7;13(11):e0206761. Epub 2018 Nov 7.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Diabetes mellitus represents a major independent risk factor for developing fatal cardiovascular diseases (CVDs) presumably through accelerating atherosclerosis; the underlying cause of most CVDs. Notably, this relative risk is reported to be higher in women than men. Endeavors directed towards identifying novel reliable predictive biomarkers are immensely thereby urged to improve the long-term outcome in these diabetic female patients. Sclerostin (SOST) is a Wnt signaling antagonist whereas irisin is a muscle-derived factor released after exercising which enhances browning of white adipose tissue. Emerging lines of evidence hint at potential crosstalk between them and CVDs. The present study aimed to assess the serum levels of SOST and irisin in Egyptian type 2 diabetic (T2DM) female patients with and without atherosclerosis and explore the possible relationship between both markers and other studied parameters among the studied cohorts. In this case-control study, 69 female subjects were enrolled; 39 type 2 diabetes patients with atherosclerosis (T2DM+ATHR), 22 type 2 diabetes patients without atherosclerosis (T2DM-ATHR) and 8 healthy controls. Their serum levels of SOST and irisin were assessed using ELISA. Significant increase in SOST levels were found in T2DM+ATHR compared to T2DM-ATHR and control (259.9 ±17.98 vs. 165.8±13.12 and 142.0±13.31 pg/mL respectively, P<0.001). Conversely, irisin levels were significantly lower in T2DM+ATHR (P<0.001) and T2DM-ATHR (P<0.01) compared to the control group (32.91±2.545 and 58.55±13.19 vs. 473.6±112.7 pg/mL). Interestingly, significant correlations between the levels of SOST and both irisin and fasting blood glucose were noticed in T2DM+ATHR group (r = 0.3754 and 0.3381 respectively, P<0.05). In conclusion, to the best of our knowledge, this study is the first to demonstrate the correlation between SOST and irisin levels in atherosclerotic T2DM female patients implying their potential implication in diabetic cardiovascular pathophysiology and supporting their use as reliable diagnostic/prognostic biomarkers for monitoring and preventing CVDs progression of T2DM female patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206761PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221312PMC
April 2019

Mechanistic approach of the inhibitory effect of chrysin on inflammatory and apoptotic events implicated in radiation-induced premature ovarian failure: Emphasis on TGF-β/MAPKs signaling pathway.

Biomed Pharmacother 2019 Jan 3;109:293-303. Epub 2018 Nov 3.

Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Radiotherapy is one of the most relevant treatment modalities for various types of malignancies. However, it causes premature ovarian failure (POF) and subsequent infertility in women of reproductive age; hence urging the development of effective radioprotective agents. Chrysin, a natural flavone, possesses several pharmacological activities owing to its antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, the aim of this study was to investigate the efficacy of chrysin in limiting γ-radiation-mediated POF and to elucidate the underlying molecular mechanisms. Immature female Sprague-Dawley rats were subjected to a single dose of γ-radiation (3.2 Gy) and/or treated with chrysin (50 mg/kg) once daily for two weeks before and three days post-irradiation. Chrysin prevented the radiation-induced ovarian dysfunction by restoring estradiol levels, preserving the normal ovarian histoarchitecture and combating the follicular loss. Eelectron microscopic analysis showed that the disruption of ultrastructure components due to radiation exposure was hampered by chrysin administration. Mechanistically, chrsyin was able to reduce the levels of the inflammatory markers NF-κB, TNF-α, iNOS and COX-2 in radiation-induced ovarian damage. Chrysin also exhibited potent anti-apoptotic effects against radiation-induced cell death by downregulating the expression of cytochrome c and caspase 3. Radiation obviously induced upregulation of TGF-β protein with subsequent phospholyration and hence activation of downstream mitogen-activated protein kinases (MAPKs); p38 and JNK. Notably, administration of chrysin successfully counteracted these effects. These findings revealed that chrysin may be beneficial in ameliorating radiation-induced POF, predominantly via downregulating TGF-β/MAPK signaling pathways leading subsequently to hindering inflammatory and apoptotic signal transduction pathways implicated in POF.
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http://dx.doi.org/10.1016/j.biopha.2018.10.092DOI Listing
January 2019

Comparative study of anti-VEGF Ranibizumab and Interleukin-6 receptor antagonist Tocilizumab in Adjuvant-induced Arthritis.

Toxicol Appl Pharmacol 2018 10 17;356:65-75. Epub 2018 Jul 17.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address:

Although the precise etiology of Rheumatoid arthritis (RA) remains obscure, heightened immune response is thought to play a vital role in provoking joint inflammation and bone erosion. This study aims at comparatively evaluating the effects of two monoclonal antibodies Ranibizumab (RANI) as anti-VEGF antibody and Tocilizumab (TCZ) as interleukin-6 receptor (IL-6R) antagonist, against adjuvant induced arthritis in rats. CFA-induced arthritic rats were treated for three consecutive weeks with Methotrexate (MTX), TCZ and RANI monotherapy. Clinical assessment of RA, bone erosion, inflammatory, angiogenic and apoptotic markers were determined to assess the anti-arthritic effect. Liver enzymes and histopathological examination of liver and spleen were assessed to evaluate the toxicity profile of the tested therapeutic agents. MTX, TCZ and RANI monotherapy significantly enhanced the anti-arthritic parameters in comparison with the Complete Freund's Adjuvant (CFA)-induced arthritic rats through significant reduction of ankle and paw swelling. Also, they significantly reduced inflammatory, angiogenic and apoptotic markers. Importantly, Ranibizumab showed better effect than the standard anti-rheumatic drugs Methotrexate (MTX) or Tocilizumab (TCZ) in bone protection and cartilage health; hence proves to be a promising new therapeutic agent for RA.
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http://dx.doi.org/10.1016/j.taap.2018.07.014DOI Listing
October 2018

Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors.

Eur J Med Chem 2018 Jul 6;155:316-336. Epub 2018 Jun 6.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt. Electronic address:

In light of the emergence of resistance against the currently available EGFR inhibitors, our study focuses on tackling this problem through the development of dual EGFR/HER2 inhibitors with improved enzymatic affinities. Guided by the binding mode of the marketed dual EGFR/HER2 inhibitor, Lapatinib, we proposed the design of dual EGFR/HER2 inhibitors based on the 6-phenylthieno[2,3-d]pyrimidine as a core scaffold and hinge binder. After two cycles of screening aiming to identify the optimum aniline headgroup and solubilizing group, we eventually identified 27b as a dual EGFR/HER2 inhibitor with IC values of 91.7 nM and 1.2 μM, respectively. Notably, 27b dramatically reduced the viability of various patient-derived cancer cells preferentially overexpressing EGFR/HER2 (A431, MDA-MBA-361 and SKBr3 with IC values of 1.45, 3.5 and 4.83 μM, respectively). Additionally, 27b efficiently thwarted the proliferation of lapatinib-resistant human non-small lung carcinoma (NCI-H1975) cells, harboring T790 M mutation, with IC of 4.2 μM. Consistently, 27b significantly blocked EGF-induced EGFR activation and inactivated its downstream AKT/mTOR/S6 signalling pathway triggering apoptotic cell death in NCI-H1975 cells. The present study presents a promising candidate for further design and development of novel EGFR/HER2 inhibitors capable of overcoming EGFR TKIs resistance.
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http://dx.doi.org/10.1016/j.ejmech.2018.06.011DOI Listing
July 2018

Corrigendum: From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib.

Front Pharmacol 2018 12;9:101. Epub 2018 Feb 12.

Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.

[This corrects the article on p. 718 in vol. 8, PMID: 29066973.].
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http://dx.doi.org/10.3389/fphar.2018.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5816586PMC
February 2018

From Resistance to Sensitivity: Insights and Implications of Biphasic Modulation of Autophagy by Sunitinib.

Front Pharmacol 2017 10;8:718. Epub 2017 Oct 10.

Max F. Perutz Laboratories, Department of Microbiology and Immunobiology, University of Vienna, Vienna, Austria.

Sunitinib, a multityrosine kinase inhibitor, is currently the standard first-line therapy in metastatic renal cell carcinoma (mRCC) and is also used in treating patients with pancreatic neuroendocrine and imatinib-resistant gastrointestinal stromal tumors (GIST). Nevertheless, most patients eventually relapse secondary to intrinsic or acquired sunitinib resistance. Autophagy has been reported to contribute to both chemo-sensitivity and -resistance. However, over the last few years, controversial regulatory effects of sunitinib on autophagy have been reported. Since gaining insights into the underlying molecular insights and clinical implications is indispensible for achieving optimum therapeutic response, this minireview article sheds light on the role of a network of prosurvival signaling pathways recently identified as key mediators of sunitinib resistance with established and emerging functions as autophagy regulators. Furthermore, we underscore putative prognostic biomarkers of sunitinib responsiveness that could guide clinicians toward patient stratification and more individualized therapy. Importantly, innovative therapeutic strategies/approaches to overcome sunitinib resistance both evaluated in preclinical studies and perspective clinical trials are discussed which could ultimately be translated to better clinical outcome.
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http://dx.doi.org/10.3389/fphar.2017.00718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641351PMC
October 2017

Astaxanthin Ameliorates Doxorubicin-Induced Cognitive Impairment (Chemobrain) in Experimental Rat Model: Impact on Oxidative, Inflammatory, and Apoptotic Machineries.

Mol Neurobiol 2018 Jul 16;55(7):5727-5740. Epub 2017 Oct 16.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt.

Chemobrain refers to a common sequelae experienced by 15-80% of cancer patients exposed to chemotherapeutics. The antineoplastic agent doxorubicin (DOX) has been implicated in a strenuous neurotoxicity manifested as decline in cognitive functions, most probably via cytokine-induced oxidative and nitrosative damage to brain tissues. Astaxanthin (AST), a naturally occurring carotenoid, is reputable for its outstanding antioxidant, anti-inflammatory, and antiapoptotic activities. Therefore, the aim of the current study was to investigate the potential neuroprotective and memory-enhancing effects of AST against DOX-induced behavioral and neurobiological abnormalities. Briefly, AST treatment (25 mg/kg) significantly protected against DOX-induced memory impairment. Furthermore, AST restored hippocampal histopathological architecture, halted DOX-induced oxidative and inflammatory insults, mitigated the increase in acetylcholinesterase activity, and consistently downregulated the overactive apoptotic machineries. In conclusion, these findings suggest that AST offers neuroprotection against DOX-induced cognitive impairment which could be explained at least partly by its antioxidant, anti-inflammatory, and antiapoptotic effects.
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http://dx.doi.org/10.1007/s12035-017-0797-7DOI Listing
July 2018

Dual modulation of MCL-1 and mTOR determines the response to sunitinib.

J Clin Invest 2017 01 28;127(1):153-168. Epub 2016 Nov 28.

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3β activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.
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http://dx.doi.org/10.1172/JCI84386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199697PMC
January 2017

The tyrosine kinase inhibitor, sunitinib malate, induces cognitive impairment in vivo via dysregulating VEGFR signaling, apoptotic and autophagic machineries.

Exp Neurol 2016 09 7;283(Pt A):129-41. Epub 2016 Jun 7.

Zoology Department, Faculty of Science, Ain Shams University, Cairo, Egypt.

Chemobrain refers to a cluster of cognitive deficits which affects almost 4-75% of chemotherapy-treated cancer patients. Sunitinib, an FDA-approved multityrosine kinase inhibitor, is currently used in treating different types of tumors. Despite being regarded as targeted therapy which blunts sustained angiogenesis in cancer milieu through inhibiting vascular endothelial growth factor receptor 2 (VEGFR2) signaling, the latter has a cardinal role in cognition. Recent clinical reports warned that sunitinib adversely affected memory processing in cancer patients. Nevertheless, the underlying mechanisms have not been investigated yet. Hence, we explored the impact of a clinically relevant dose of sunitinib on memory processing in vivo and questioned the implication of VEGFR2 signaling, autophagy and apoptosis. Strikingly, sunitinib preferentially impaired spatial cognition as evidenced in Morris water maze, T-maze and passive avoidance task. Consistently, sunitinib degenerated cortical and hippocampal neurons as assessed by histopathological examination and toluidine blue staining. Ultrastructural examination also depicted chromatin condensation, mitochondrial damage and accumulated autophagosomes. Digging deeper, central VEGF/VEGFR2/mTOR signaling was robustly suppressed. Besides, sunitinib boosted cortical and hippocampal p53 and executioner caspase-3 and decreased nuclear factor kappa B and Bcl-2 levels promoting apoptotic cell death. It also profoundly impeded neuronal autophagic flux as shown by decreased beclin-1 and Atg5 and increased p62/SQTSM1 levels. To our knowledge, this is the first study to provide molecular insights into sunitinib-induced chemofog where impeded VEGFR2 signaling and autophagic and hyperactivated apoptotic machineries act in neurodegenerative concert. Importantly, our findings shed light on potential therapeutic strategies to be exploited in the management of sunitinib-induced chemobrain.
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http://dx.doi.org/10.1016/j.expneurol.2016.06.004DOI Listing
September 2016

Discovery of Potent VEGFR-2 Inhibitors based on Furopyrimidine and Thienopyrimidne Scaffolds as Cancer Targeting Agents.

Sci Rep 2016 Apr 15;6:24460. Epub 2016 Apr 15.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abassia, Cairo 11566, Egypt.

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In this study, a series of novel furo[2,3-d]pyrimidine and thieno[2,3-d]pyrimidine based-derivatives were designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The synthesized compounds were evaluated for their ability to in vitro inhibit VEGFR-2 kinase enzyme. Seven compounds (15b, 16c, 16e, 21a, 21b, 21c and 21e) demonstrated highly potent dose-related VEGFR-2 inhibition with IC50 values in nanomolar range, of which the thieno[2,3-d]pyrimidine based-derivatives (21b, 21c and 21e) exhibited IC50 values of 33.4, 47.0 and 21 nM respectively. Moreover, furo[2,3-d]pyrimidine-based derivative (15b) showed the strongest inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 99.5% inhibition at 10 μM concentration. Consistent with our in vitro findings, compounds (21b and 21e) orally administered at 5 and 10 mg/kg/day for 8 consecutive days demonstrated potent anticancer activity in Erhlich ascites carcinoma (EAC) solid tumor murine model. Such compounds blunted angiogenesis in EAC as evidenced by reduced percent microvessel via decreasing VEGFR-2 phosphorylation with subsequent induction of apoptotic machinery. Furthermore, Miles vascular permeability assay confirmed their antiangiogenic effects in vivo. Intriguingly, such compounds showed no obvious toxicity.
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http://dx.doi.org/10.1038/srep24460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832243PMC
April 2016

Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner.

Nat Commun 2014 Dec 4;5:5637. Epub 2014 Dec 4.

1] Department of Experimental Oncology, European Institute of Oncology, IEO, 20139 Milan, Italy [2] Department of Biosciences, University of Milan, 20100 Milan, Italy [3] Drug Development Program, European Institute of Oncology, IEO, 20139 Milan, Italy.

Mcl-1 is a unique Bcl-2 family member that plays crucial roles in apoptosis. Apoptosis-unrelated functions of Mcl-1 are however emerging, further justifying its tight regulation. Here we unravel a novel mechanism of Mcl-1 regulation mediated by the haplo-insufficient tumour suppressor Beclin 1. Beclin 1 negatively modulates Mcl-1 stability in a reciprocal manner whereby depletion of one leads to the stabilization of the other. This co-regulation is independent of autophagy and of their physical interaction. Both Beclin 1 and Mcl-1 are deubiquitinated and thus stabilized by binding to a common deubiquitinase, USP9X. Beclin 1 and Mcl-1 negatively modulate the proteasomal degradation of each other through competitive displacement of USP9X. The analysis of patient-derived melanoma cells and tissue samples shows that the levels of Beclin 1 decrease, while Mcl-1 levels subsequently increase during melanoma progression in a significant inter-dependent manner. The identified inverse co-regulation of Beclin 1 and Mcl-1 represents a mechanism of functional counteraction in cancer.
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http://dx.doi.org/10.1038/ncomms6637DOI Listing
December 2014

Modulation of imatinib cytotoxicity by selenite in HCT116 colorectal cancer cells.

Basic Clin Pharmacol Toxicol 2015 Jan 25;116(1):37-46. Epub 2014 Jul 25.

Pharmacology & Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.

Imatinib is a principal therapeutic agent for targeting colorectal tumours. However, mono-targeting by imatinib does not always achieve complete cancer eradication. Selenite, a well-known chemopreventive agent, is commonly used in cancer patients. In this study, we aimed to explore whether selenite can modulate imatinib cytotoxicity in colorectal cancer cells. HCT116 cells were treated with different concentrations of imatinib and/or selenite for 24, 48 and 72 hr. Imatinib-selenite interaction was analysed using isobologram equation. As indicators of apoptosis, DNA fragmentation, caspase-3 activity, Bcl-2 expression were explored. Autophagic machinery was also checked by visualizing acidic vesicular organelles and measuring Beclin-1 expression. Furthermore, reactive oxygen and nitrogen species were also examined. This study demonstrated that selenite synergistically augmented imatinib cytotoxicity in HCT116 cells as demonstrated by combination and dose reduction indices. Supranutritional dose of selenite when combined with imatinib induced apoptotic machinery by decreasing Bcl-2 expression, increasing caspase-3 activity and subsequently fragmenting DNA and blunted cytoprotective autophagy by decreasing Beclin-1 expression and autophagosomes formation. Moreover, their combination induced cell cycle S-phase block, increased total thiol content and reduced nitric oxide levels. In conclusion, selenite synergizes imatinib cytotoxicity through multi-barrelled molecular targeting, providing a novel therapeutic approach for colorectal cancer.
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http://dx.doi.org/10.1111/bcpt.12281DOI Listing
January 2015

Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries.

Chem Biol Interact 2014 Jun 18;217:28-40. Epub 2014 Apr 18.

Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address:

Tyrosine kinases play a pivotal role in oncogenesis. Although tyrosine kinase inhibitors as sunitinib malate are used in cancer therapy, emerging studies report compromised cytotoxicity when used as monotherapy and thus combinations with other anti-cancer agents is recommended. Chloroquine is a clinically available anti-malarial agent which has been shown to exhibit anti-cancer activity. In the current study, we questioned whether chloroquine can modulate sunitinib cytotoxicity. We found that chloroquine synergistically augmented sunitinib cytotoxicity on human breast (MCF-7 and T-47D), cervical (Hela), colorectal (Caco-2 and HCT116), hepatocellular (HepG2), laryngeal (HEp-2) and prostate (PC3) cancer cell lines as indicated by combination and concentration reduction indices. These results were also consistent with that of Ehrlich ascites carcinoma (EAC) Swiss albino mice models as confirmed by tumor volume, weight, histopathological examination and PCNA expression. Sunitinib induced autophagy via upregulating beclin-1 expression which was blocked by chloroquine as evidenced by accumulated SQTSM1/p62 level. Furthermore, chloroquine augmented sunitinib-induced apoptosis by decreasing survivin level and increasing caspase 3 activity. Chloroquine also enhanced the antiangiogenic capacity of sunitinib as indicated by decreased CD34 expression and peritoneal/skin angiogenesis. Sunitinib when combined with chloroquine also increased reactive nitrogen species production via increasing inducible nitric oxide synthase expression and nitric oxide level whilst reduced reactive oxygen species production by increasing GSH level, activities of glutathione peroxidase and catalase and reducing lipid peroxides compared to sunitinib-only treated group. Taken together, these findings suggest that chloroquine enhanced sunitinib cytotoxicity in a synergistic manner via inducing apoptosis while switching off autophagic and angiogenic machineries. Nevertheless, further studies are required to elucidate the efficacy and safety profile of such combination.
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http://dx.doi.org/10.1016/j.cbi.2014.04.007DOI Listing
June 2014