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Volume 13, Issue 2 (3-2023)
Iran J Ped Hematol Oncol 2023, 13(2): 99-118 |
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Amini A, Faranoush M, Paridar M, Kazemi A, Rezvani M R, Safa M. 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. Iran J Ped Hematol Oncol 2023; 13 (2) :99-118
URL: http://ijpho.ssu.ac.ir/article-1-720-en.html
URL: http://ijpho.ssu.ac.ir/article-1-720-en.html
Ali Amini 
, Mohammad Faranoush , Mostafa Paridar , Ahmad Kazemi , Mohammad Reza Rezvani , Majid Safa *
, Mohammad Faranoush , Mostafa Paridar , Ahmad Kazemi , Mohammad Reza Rezvani , Majid Safa *
Department of Hematology and Blood Banking Faculty of Allied Medicine Iran University of Medical Sciences
Abstract: (949 Views)
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.
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.
Type of Study: Research |
Subject:
Heart
Received: 2022/04/9 | Accepted: 2023/01/10 | Published: 2023/03/19
Received: 2022/04/9 | Accepted: 2023/01/10 | Published: 2023/03/19
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