Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway
Open Access
- 15 September 2007
- journal article
- Published by American Society of Hematology in Blood
- Vol. 110 (6), 2084-2091
- https://doi.org/10.1182/blood-2006-12-060970
Abstract
Incorporation of apoptosis-inducing agents into current therapeutic regimens is an attractive strategy to improve treatment for drug-resistant leukemia. We tested the potential of arsenic trioxide (ATO) to restore the response to dexamethasone in glucocorticoid (GC)–resistant acute lymphoblastic leukemia (ALL). Low-dose ATO markedly increased in vitro GC sensitivity of ALL cells from T-cell and precursor B-cell ALL patients with poor in vivo response to prednisone. In GC-resistant cell lines, this effect was mediated, at least in part, by inhibition of Akt and affecting downstream Akt targets such as Bad, a proapoptotic Bcl-2 family member, and the X-linked inhibitor of apoptosis protein (XIAP). Combination of ATO and dexamethasone resulted in increased Bad and rapid down-regulation of XIAP, while levels of the antiapoptotic regulator Mcl-1 remained unchanged. Expression of dominant-active Akt, reduction of Bad expression by RNA interference, or overexpression of XIAP abrogated the sensitizing effect of ATO. The inhibitory effect of XIAP overexpression was reduced when the Akt phosphorylation site was mutated (XIAP-S87A). These data suggest that the combination of ATO and glucocorticoids could be advantageous in GC-resistant ALL and reveal additional targets for the evaluation of new antileukemic agents.Keywords
This publication has 40 references indexed in Scilit:
- Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood ALLBlood, 2006
- Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family membersCancer Cell, 2006
- Identification of glucocorticoid-response genes in children with acute lymphoblastic leukemiaBlood, 2006
- Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesisNature Reviews Cancer, 2006
- The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemiaBlood, 2006
- BH3-only proteins Puma and Bim are rate-limiting for γ-radiation– and glucocorticoid-induced apoptosis of lymphoid cells in vivoBlood, 2005
- Identification of genes associated with chemotherapy crossresistance and treatment response in childhood acute lymphoblastic leukemiaCancer Cell, 2005
- mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALLLeukemia, 2005
- The role of BH3-only proteins in the immune systemNature Reviews Immunology, 2005
- Microarray Analysis Uncovers the Induction of the Proapoptotic BH3-only Protein Bim in Multiple Models of Glucocorticoid-induced ApoptosisPublished by Elsevier BV ,2003