Iranian journal of Pediatric Hematology and Oncology

en Synergistic Anti-Cancer Effects of Second-Generation Proteasome Inhibitor Carfilzomib with Doxorubicin and Dexamethasone Via p53-Mediated Apoptosis in Pre-B Acute Lymphoblastic Leukemia Cells قلب Heart پژوهشي Research <div style="border:double windowtext 1.5pt; padding:1.0pt 4.0pt 1.0pt 4.0pt">Background: The ubiquitin-proteasome system (UPS) plays a crucial role in regulating the levels and functions of a large number of proteins in the cell, which are important for cancer cell growth and survival. The proteasome is highly activated in B-cell precursor acute lymphoblastic leukemia (BCP-ALL), which is the most common malignancy in children. The attempt to inhibit proteasome as a therapeutic strategy has been successful for some malignancies. Materials and Methods: In this experimental study, human BCP-ALL cell lines NALM-6 and SUP-B15 were treated with carfilzomib with and without the chemotherapeutic agents. The XTT assay evaluated the viability of the cells. Cell cycle analysis and apoptosis assay were assessed by flow cytometry. RQ-PCR and western blotting evaluated the expression of pro-/anti-apoptotic signals. A drug combination study for synergistic or additive effects of carfilzomib with doxorubicin or dexamethasone was performed. Results: We observed that carfilzomib alone induced G2/M cell cycle arrest and caspase-dependent apoptosis in the human BCP-ALL cells (NALM-6 and SUP-B15). Gene and protein expression analysis indicated the upregulation of pro-apoptotic as well as downregulation of the cell survival and proliferative signals (P-value<0.05). The synergy of carfilzomib with doxorubicin or dexamethasone was revealed in BCP-ALL cells. Conclusion: Our results indicated that proteasome inhibition induces p53-mediated apoptosis in BCP-ALL cells. Since carfilzomib has a synergistic effect with anti-leukemic agents doxorubicin and dexamethasone in BCP-ALL cells, this combined-modality approach might be befitting for patients who do not respond well to conventional chemotherapy.</div> Acute lymphoblastic leukemia, Carfilzomib, Dexamethasone, Doxorubicin, Proteasome 99 118 http://ijpho.ssu.ac.ir/browse.php?a_code=A-10-954-1&slc_lang=en&sid=1 Ali Amini aminia2010@gmail.com 0000-0002-8759-6120 No Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences Mohammad Faranoush faranoushmohammad@gmail.com No Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran Mostafa Paridar mostafaparidar@gmail.com No Ministry of Health and Medical Education, Deputy of Management and Resources Development, Tehran, Iran Ministry of Health and Medical Education, Deputy of Management and Resources Development, Tehran, Iran Ahmad Kazemi Ahmadkazemi743@gmail.com No Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences Mohammad Reza Rezvani mohrezvani50@gmail.com No Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences Majid Safa safa.m@iums.ac.ir 0000-0003-0070-6620 Yes Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences