Mohamed A.Y. Abdel Malek

Assiut University

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James J. Driscoll

Case Western Reserve University

Ehsan Malek

Case Western Reserve University

Sajjeev Jagannathan

Baylor College of Medicine

Nikhil Vad

Itasca Consultants (United States)

Douaa Sayed

Assiut University

Nabila M. Thabet

Assiut University

Hanan G. Abd El-Azeem

Assiut University

Sahar A. Elgammal

Assiut University

Anil G. Jegga

Cincinnati Children's Hospital Medical Center

Alicia K. Au

University of Pittsburgh

Cooperative Institutions

Assiut University

University of Chile

University of Cincinnati

University of Cincinnati Medical Center

Pontificia Universidad Católica de Chile

Minia University

Medical University of Lublin

Minia University Hospital

Advanced Center for Chronic Diseases

Centre National de la Recherche Scientifique

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Targeting the Proteasome Pathway for the Treatment of Solid Tumors

Resistance to targeted anti-cancer therapeutics (2014)

Nisar Ahmad Elias Anaissie Mohamed A.Y. Abdel Malek James J. Driscoll

Proteostasis

Hematologic malignancy

10.1007/978-3-319-06752-0_9

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Targeting the ubiquitin ligase SKP2 in the myeloma stem-cell like side population.

Journal of Clinical Oncology (2015)

Ehsan Malek Mohamed A.Y. Abdel Malek James J. Driscoll

e13510 Background: While anti-myeloma therapies are effective in eradicating the bulk of tumor cells, intrinsically drug resistant, clonogenic tumor-initiating subpopulations contribute to disease relapse and poor outcomes in multiple myeloma (MM). Side population (SP) cells are an enriched source of therapy-resistant, tumor-initiating cells with stem cell-like features. Here, we investigated the molecular determinants responsible for chemoresistance in the myeloma SP to then identify actionable therapeutic targets. Methods: Side population (SP) cells were isolated from myeloma cell lines and patient samples using Hoechst 33342 dye-based flow cytometry. SP cells represented 1-2% of the tumor population and were used in cell-based assays to determine chemosensitivities relative to the non-SP cells. Results: Gene expression analysis indicated that components of the E3 ubiquitin ligase Skp1-Cul1-FboxSkp2 (SCFSkp2) complex were hyperexpressed in myeloma patients. SP cells were less sensitive to the anti-myeloma effects of the proteasome inhibitors (PIs) bortezomib, carfilzomib and ixazomib relative to non-SP cells. The relative percentage of SP cells was significantly greater in cultures of myeloma cells generated with acquired resistance to each PI. Genetic ablation of Skp2 or Cullin-1 synergistically enhanced the cytotoxic effect of bortezomib. A high-throughput assay was performed using large databases and chemical libraries to identify novel lead compounds that inhibited SCFSkp2-dependent ubiquitination activity. Bortezomib co-treatment with a lead compound identified here enhanced the anti-myeloma effect against SP cells isolated from cell lines and patient bone marrow samples. Conclusions: Taken together, we identify novel molecular determinants of chemoresistance in the myeloma stem cell-like SP. Functional assays demonstrated that SCFSkp2 is hyperexpressed in SP cells and represents an actionable drug target. Pharmacologics to selectively disrupt SCFSkp2 activity hold promise to selectively target chemoresistance with potential therapeutic benefit for myeloma patients.

Side population

Clonogenic assay

10.1200/jco.2015.33.15_suppl.e13510

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Molecular chaperone GRP78 enhances aggresome delivery to autophagosomes to promote drug resistance in multiple myeloma

Oncotarget (2014)

Mohamed A.Y. Abdel Malek Sajjeev Jagannathan Ehsan Malek Douaa Sayed Sahar A. Elgammal

// Mohamed A.Y. Abdel Malek 1,2,3,* , Sajjeev Jagannathan 1,2,* , Ehsan Malek 1,2 , Douaa M. Sayed 4 , Sahar A. Elgammal 3 , Hanan G. Abd El-Azeem 3 , Nabila M. Thabet 3 and James J. Driscoll 1,2,5,6 1 The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 2 Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 3 Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt 4 Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt 5 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 6 University of Cincinnati Cancer Institute, Cincinnati, OH * These authors contributed equally to this work Correspondence: James J. Driscoll, email: // Keywords : GRP78, Aggresome+Autophagosome Pathway, Proteasome, Myeloma, Chemoresistance Received : November 06, 2014 Accepted : December 17, 2014 Published : December 26, 2014 Abstract Despite the clinical benefit of the proteasome inhibitor bortezomib, multiple myeloma (MM) patients invariably relapse through poorly defined mechanisms. Myeloma cells inevitably develop chemoresistance that leads to disease relapse and patient-related deaths. Studies in tumor cell lines and biopsies obtained from patients refractory to therapy have revealed that myeloma cells adapt to stress by inducing expression of glucose-regulated protein 78 (GRP78), an endoplasmic reticulum (ER) chaperone with anti-apoptotic properties. Treatment of myeloma cells with bortezomib increased GRP78 levels and activated GRP78-dependent autophagy. Expression profiling indicated that GRP78-encoding HSPA5 was significantly upregulated in bortezomib-resistant cells. Co-treatment with the anti-diabetic agent metformin suppressed GRP78 and enhanced the anti-proliferative effect of bortezomib. Bortezomib treatment led to GRP78 co-localization with proteotoxic protein aggregates, known as aggresomes. Pharmacologic suppression, genetic ablation or mutational inactivation of GRP78 followed by bortezomib treatment led to the accumulation of aggresomes but impaired autophagy and enhanced anti-myeloma effect of bortezomib. GRP78 was co-immunoprecipitated with the KDEL receptor, an ER quality control regulator that binds proteins bearing the KDEL motif to mediate their retrieval from the Golgi complex back to the ER. Taken together, we demonstrate that inhibition of GRP78 functional activity disrupts autophagy and enhances the anti-myeloma effect of bortezomib.

Hematology

10.18632/oncotarget.3075

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Novel Therapeutic Strategies to Target Protein Quality Control Compartments in Multiple Myeloma

Blood (2014)

Mohamed A.Y. Abdel Malek Sajjeev Jagannathan Ehsan Malek Nikhil Vad Douaa Sayed

Aggresome

Chaperone (clinical)

10.1182/blood.v124.21.3433.3433

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Expression of uPAR [urokinase plasminogen activator receptor], P-glycoprotein 170 and VCAM-1 [vascular cell adhesion molecule] on acute leukaemia cells

Maria Cioch Iwona Hus Dariusz Jawniak Mohamed A.Y. Abdel Malek Joanna Mańko

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Contributors

Elsevier eBooks (2015)

Rajesh K. Aneja Alicia K. Au Monika Cahová Karen Castillo Somi Kim Cho

10.1016/b978-0-12-801033-4.00029-1

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Rare Extraperitoneal Involvement with Fatal Outcome in a Case of Bilateral Luteinized Thecoma of the Ovaries with Sclerosing Peritonitis

Case Reports in Oncological Medicine (2014)

Mohamed A. Medhat Mohamed A.Y. Abdel Malek Saad Zaki Ahmed Helmy James J. Driscoll

We report the case of a woman diagnosed with bilateral luteinized thecoma of the ovaries with sclerosing peritonitis, multiple intraperitoneal cystic lesions, and extraperitoneal lesions of the liver, inferior to the spleen, and high suspicion of bone marrow involvement. The patient developed profound pancytopenia with rapid clinical deterioration and a fatal outcome.

10.1155/2014/904581

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Effective and Elaborative Induction Program for Mitigating Myths and Misconceptions Linked to Hematopoietic Stem Cell Transplantation in a Resource Limited Setting

Indian Journal of Hematology and Blood Transfusion (2023)

Safaa A. A. Khaled Mahmoud M. Elzembely Asmaa Soliman Nahed Shwakat Nashwa Rafaat

Abstract Since the first transplant in 1957 and hematopoietic stem cell transplantation (HSCT) is the curative modality for numerous hematological disorders. Nevertheless, it is not available for all patients. Besides unavailability of matched donors a lot of factors could hinder HSCT in a resource limited setting, as financial and administrative factors. In our daily practice we noticed other factors that hinder HSCT in our center, the common myths and misconceptions about HSCT and donation. This quasi-experimental study assessed, for the first time, common myths and misconceptions about HSCT among 218 medical and nursing students before and after an interventional educational program. The study tool was an investigators' developed self-administered questionnaire. Participants' male to female ratio was 1:2.5, and FAS was middle in 52.7%. Pretest high myths scores were reported in 53.4% and 90% of medical and nursing students that was reduced to 0% and 4% post-test, respectively. Pretest, 26.3% and 7% of medical and nursing students welling to donate HSC, that increased to 66% and 39% post-test, respectively. Rural residency, low and middle FAS associated with higher myths scores. Myths score is an independent effector of willingness to donate HSC among participants. In conclusion medical/nursing students had significant myths and misconceptions about HSCT that was corrected with the educational program. Thus, wide based educational programs about HSCT are mandatory to correct myths and augment HSC donation. www.clinicaltrrial.gov : clinical trial ID NCT05151406.

10.1007/s12288-023-01634-5

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Molecular Cross-Talk between the Autophagy and Apoptotic Networks in Cancer

Elsevier eBooks (2015)

James J. Driscoll Mohamed A.Y. Abdel Malek

10.1016/b978-0-12-801033-4.00002-3

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Citations (2)

Correlation of Non-Coding RNA Expression with Response to Proteasome Inhibitors in Multiple Myeloma

Blood (2014)

Ehsan Malek Tahir Latif Anil G. Jegga Sajjeev Jagannathan Nikhil Vad

Ixazomib

10.1182/blood.v124.21.3415.3415

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