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.
Bornhauser
Beat C
BC
Department of Oncology, Children's Hospital, University of Zurich, Zurich, Switzerland.
Bonapace
Laura
L
Lindholm
Dan
D
Martinez
Rodrigo
R
Cario
Gunnar
G
Schrappe
Martin
M
Niggli
Felix K
FK
Schäfer
Beat W
BW
Bourquin
Jean-Pierre
JP
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage* / Q000494:pharmacology; D015153:Blotting, Western; D020169:Caspases; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D018365:Neoplasm, Residual / Q000175:diagnosis; D010087:Oxides / Q000008:administration & dosage* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011241:Prednisone / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012074:Remission Induction; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D014162:Transfection; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051025:bcl-Associated Death Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D001152:Arsenicals; C494819:BAD protein, human; D005938:Glucocorticoids; D010087:Oxides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051636:X-Linked Inhibitor of Apoptosis Protein; D051025:bcl-Associated Death Protein; D003907:Dexamethasone; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D000077237:Arsenic Trioxide; D011241:Prednisone; D020123:Sirolimus