Low-dose arsenic trioxide sensitizes glucocorticoid-resistant acute lymphoblastic leukemia cells to dexamethasone via an Akt-dependent pathway

• 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.

Nyckelord

Antineoplastic Agents/administration & dosage/*pharmacology

Apoptosis/drug effects

Arsenicals/*administration & dosage/pharmacology

Blotting; Western

Caspases

Cell Line; Tumor/drug effects

Cell Survival/drug effects

Dexamethasone/*pharmacology

Drug Resistance; Neoplasm

Drug Synergism

Glucocorticoids/*pharmacology

Humans

Neoplasm; Residual/diagnosis

Oxides/*administration & dosage/pharmacology

Phosphorylation/drug effects

Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug therapy/metabolism/pathology

Prednisone/pharmacology

Proto-Oncogene Proteins c-akt/*metabolism

RNA; Small Interfering/pharmacology

Reactive Oxygen Species/metabolism

Remission Induction

Signal Transduction

Sirolimus/pharmacology

Transfection

X-Linked Inhibitor of Apoptosis Protein/metabolism

bcl-Associated Death Protein/metabolism

MEDICINE

MEDICIN

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