Anti-leukemic effects of histone deacetylase (HDAC) inhibition in acute lymphoblastic leukemia (ALL) cells: Shedding light on mitigating effects of NF-κB and autophagy on panobinostat cytotoxicity.

Abstract

Identification of the roles of epigenetic alterations in cancers has suggested that different molecules involved in this process are potentially therapeutic targets. Given the role of histone deacetylases (HDACs) enzymes in leukemogenesis, we designed a study to investigate the anti-leukemic property of panobinostat, a HDAC inhibitor, in acute lymphoblastic leukemia (ALL) cells. Our results showed that panobinostat decreased cell viability of pre-B ALL-derived cells. The favorable anti-leukemic effects of the inhibitor was further confirmed by cell cycle analysis, where we found that panobinostat prolonged the transition of the cells from G1 phase probably through c-Myc-mediated up-regulation of cyclin-dependent kinase inhibitors. Unlike the apoptotic effect of panobinostat on Nalm-6 cells, the expression of anti-apoptotic nuclear factor-kappa B (NF-κB) target genes remained unchanged. Accordingly, we found that the inhibition of NF-κB pathway using bortezomib boosted the effect of panobinostat, indicating that panobinostat-induced apoptosis could be attenuated through the activation of the NF-κB pathway. The results of the present study reflected another aspect of autophagy in leukemic cells, as we showed that although Nalm-6 cells could exploit autophagy to override the anti-survival effect of HDAC inhibition, the presence of an autophagy inhibitor could alter the compensatory circumstance to induce cell death. Beyond panobinostat cytotoxicity as a single agent, synergistic experiments outlined that pharmaceutical targeting of HDACs could amplify the cytotoxicity of vincristine in ALL cells, delineating that panobinostat, either as a single agent or in a combined modality, possesses novel promising potentials for the treatment of ALL.

• Authors: Mahdieh Mehrpouri, Ava Safaroghli-Azar, Atieh Pourbagheri-Sigaroodi, Majid Momeny, Davood Bashash
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 875 Pg. 173050 (May 15 2020) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 32142770 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Histone Deacetylase Inhibitors
• NF-kappa B
• Vincristine
• Bortezomib
• Panobinostat

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Bortezomib (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Epigenesis, Genetic (drug effects)
• G1 Phase (drug effects)
• Gene Expression Regulation, Leukemic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Humans
• NF-kappa B (antagonists & inhibitors, metabolism)
• Panobinostat (pharmacology, therapeutic use)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics, pathology)
• Signal Transduction (drug effects)
• Vincristine (pharmacology, therapeutic use)