Publications by authors named "Rifat Akram Hamoudi"

4 Publications

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Mol Pharmacol 2021 May 14. Epub 2021 May 14.

Centre de Recherche des Cordeliers, INSERM UMRS1138, France

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multi-target inhibitor sorafenib is a first-line treatment for patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the anti-diabetic drug metformin have a survival disadvantage compared to patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg/d) could influence the antitumoral effects of sorafenib (15 mg/kg/d) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, concomitant sequential dosing regimens. We observed that the administration of metformin six hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. When drugs are administrated sequentially, metformin alters the anti-tumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMPK pathway as well as major transcriptomic changes are associated with the loss of the anti-tumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were co-treated with metformin and sorafenib.
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May 2021

Azithromycin Differentially Alters TCR-Activated Helper T Cell Subset Phenotype and Effector Function.

Front Immunol 2020 30;11:556579. Epub 2020 Sep 30.

Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates.

In addition to their antibiotic activities, azithromycin (AZM) exhibits anti-inflammatory effects in various respiratory diseases. One of the potent anti-inflammatory mechanisms is through inhibition of CD4+ helper T (Th) cell effector function. However, their impact on specific Th subset is obscure. Herein, we demonstrate the cellular basis of phenotypic and functional alterations associated with Th subsets following AZM treatment . Using well-characterized Th subset specific chemokine receptors, we report significant suppression of T cell receptor (TCR)-stimulated hyperactivated CCR4+CXCR3+ (Th0) expansion compared to CCR4-CXCR3+ (Th1-like) and CCR4+CXCR3- (Th2-like) cells. Interestingly, this effect was associated with diminished cell proliferation. Furthermore, AZM significantly inhibited the inflammatory cytokines IFN-γ and IL-4 production, CCR4 and CXCR3 receptor expression, and viability of Th0, Th1-like, and Th2-like subsets. Our findings suggest that AZM differentially affects TCR-activated Th subsets phenotype and function, and CCR4 and CXCR3 downregulation and suppressed Th0 subset expansion could potentially influence their trafficking and differentiation into cytokine-producing effector cells.
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June 2021

Gasdermin D Hypermethylation Inhibits Pyroptosis And LPS-Induced IL-1β Release From NK92 Cells.

Immunotargets Ther 2019 14;8:29-41. Epub 2019 Oct 14.

College of Medicine, and the Immuno-Oncology Group, Sharjah Institute for Medical Research, University of Sharjah, Sharjah 27272, United Arab Emirates.

Introduction: Although natural killer (NK) are major cells used to treat cancer patients, recent clinical trials showed that NK92 cells can be also used for the same purpose due to their high anti-tumor activity. Here, we examined whether these cells might be inflammatory due to the release of interleukin-1β (IL-1β), and whether the anti-inflammatory molecules dimethyl fumarate (DMF), or monomethyl fumarate (MMF) impair this activity.

Methods: NK92 cells were examined for the synthesis and release of IL-1β utilizing RT-PCR and ELISA assay, respectively. The expression of hydroxy-carboxylic acid receptors (HCA) HCA and HCA was detected by immunoblotting, flow cytometry, immunofluorescence and RT-PCR assays. The activation of caspase-1 and Gasdermin D (GSDMD) was evaluated by immunoblot assay. Pyroptosis was demonstrated by immunofluorescence imaging. Expression of DNA methyltransferases (DNMTs) mRNA was determined by whole transcriptome and immunoblot analyses.

Results: LPS-induced the release of IL-1β from NK92 cells, whereas DMF or MMF inhibited this induction. The effect of these drugs was due to inhibiting the conversion of procaspase-1 into active caspase-1. NK92 cells highly expressed GSDMD, a pyroptotic-mediated molecule. However, LPS induced the distribution of GSDMD into the cell membranes, corroborated with the presence of pyroptotic bodies, an activity that was inhibited by DMF or MMF. These molecule also inhibited the generation of GSDMD through DNMT-mediated hypermethylation of the promoter region of gene. These results were supported by increased expression of DNMTs mRNA as determined by whole transcriptome analysis.

Discussion: Our results are the first to show that NK92 cells utilize GSDMD pathway to release IL-1β. Further, DMF and MMF which were previously shown to enhance NK cell cytotoxicity, also inhibit the inflammatory effects of these cells, making them most suitable for treating cancer patients.  .
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October 2019

Correlation of securin and Ki67 in invasive breast carcinoma.

Histol Histopathol 2019 Jun 3;34(6):697-709. Epub 2018 Dec 3.

Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Alexandria University, Alexandria, Egypt.

Aims: To identify the role of securin (PTTG) as a prognostic marker in invasive breast carcinoma and its possible relation to ki67 and to evaluate the use of ImmunoRatio® as a tool for calculating ki67 and securin labelling indices.

Methods: Securin and ki67 immunohistochemical staining were performed on tissue microarray sections representative of 118 patients diagnosed with invasive breast carcinoma from 2005 to 2011. Assessment of immunohistochemical staining was carried out using both visual counting and ImmunoRatio®. The 118 cases were categorized into 2 groups according to their clinical outcome; the first group (G1) (n=77) comprised patients who were disease-free while the second group (G2) (n=41) included patients who developed either recurrence and/or metastasis at the end of 24 months follow-up duration.

Results: Both securin and ki67 labelling indices (LIs) obtained by visual counting were significantly higher in G2, while only securin LIs acquired by ImmunoRatio® were significantly higher in G2. Securin assessment by visual counting was the most accurate (AUC=0.775) in identifying patients who will likely suffer from recurrence and/or distant metastasis. Pearson correlation showed r=0.638, p<0.001 for Ki67 and r=0.671, p<0.001 for securin. Linear regression analysis showed a significant correlation between ki67 and securin, B=1.75, p<0.001.

Conclusion: The present results suggest that securin may add to the prognostic value of ki67 in highlighting intra-tumoural heterogeneity in invasive breast carcinoma patients with poor clinical outcome. In addition, the study showed that since securin has a visual counting cutoff with more than 1%, making it easier to use as a breast cancer biomarker in conjunction with ki67 to predict the outcome of the cases more accurately than using only ki67. However, a multivariate analysis on a larger cohort of patients is mandatory to test its potential prognostic value.
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June 2019