Epigenetic drug combination overcomes osteoblast-induced chemoprotection in pediatric acute lymphoid leukemia.
Although there has been much progress in the treatment of acute lymphoblastic leukemia (ALL), decreased sensitivity to chemotherapy remains a significant issue. Recent studies have shown how interactions with the bone marrow microenvironment can protect ALL cells from chemotherapy and allow for the persistence of the disease. Epigenetic drugs have been used for the treatment of ALL, but there are no reports on whether these drugs can overcome bone marrow-induced chemoprotection. Our study investigates the ability of the DNA methyltransferase inhibitor azacitidine and the histone deacetylase inhibitor panobinostat to overcome chemoprotective effects mediated by osteoblasts. We show that the combination of azacitidine and panobinostat has a synergistic killing effect and that this combination is more effective than cytarabine in inducing ALL cell death in co-culture with osteoblasts. We also show that this combination can be used to sensitize ALL cells to chemotherapeutics in the presence of osteoblasts. Finally, we demonstrate that these effects can be replicated ex vivo in a number of mouse passaged xenograft lines from both B-ALL and T-ALL patients with varying cytogenetics. Thus, our data provides evidence that azacitidine and panobinostat can successfully overcome osteoblast-induced chemoprotection in vitro and ex vivo in both B-ALL and T-ALL cells.
Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, United States; Department of Biological Sciences, University of Delaware, Wilmington, DE 19716, United States.
Anthony
A
Quagliano
Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, United States. Electronic address: anil.g@nemours.org.
Anilkumar
A
Gopalakrishnapillai
Nemours Center for Childhood Cancer Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19803, United States; Department of Biological Sciences, University of Delaware, Wilmington, DE 19716, United States. Electronic address: barwe@medsci.udel.edu.
Sonali P
SP
Barwe
D000818:Animals; D001374:Azacitidine / Q000494:pharmacology / Q000627:therapeutic use; D018920:Coculture Techniques; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D044127:Epigenesis, Genetic / Q000187:drug effects*; D064593:Heterografts; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D010006:Osteoblasts / Q000473:pathology; D000077767:Panobinostat; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D014407:Tumor Cells, Cultured
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D000077767:Panobinostat; D015254:DNA Modification Methylases; D001374:Azacitidine
Acute lymphoid leukemia; Azacitidine; Chemoprotection; Epigenetic; Osteoblasts; Panobinostat