The therapeutical potential of a novel pterocarpanquinone LQB-118 to target inhibitor of apoptosis proteins in acute myeloid leukemia cells.
Acute myeloid leukemia (AML) is a challenging neoplasm that despite therapeutic advances requires efforts to overcome the multidrug resistance (MDR) phenotype, the major cause of relapse. The pterocarpanquinone LQB-118 is a new compound that induces apoptosis in leukemia cells. The objective of this work was to analyze the role of LQB-118 in inhibiting the inhibitor of apoptosis proteins (IAPs), XIAP and survivin, as well as in modulating the subcellular localization of NFκB, in comparison with idarubicin. LQB- 118 was more effective in inducing apoptosis than idarubicin in both AML Kasumi-1 cell line and cells from patients despite their MDR phenotype. LQB-118-induced apoptosis was accompanied by a marked inhibition of IAPs, and cytoplasmatic NFκB subcellular localization. On the other hand, idarubicin increased the IAPs expression and translocated NFκB to the nucleus. The inhibition profile of survivin induced by LQB-118 was comparable to the survivin inhibition profile when we investigated the efficiency of survivin-small interfering RNA (siRNA) treatment. LQB-118 as well as survivin-siRNA contributed similarly to the increase in apoptosis rate of Kasumi-1 cells. The data indicated that there is a functional interaction between the survivin, XIAP and NFκB, which appears to be involved in idarubicin resistance of Kasumi-1 cells. The efficacy of LQB-118 to induce cell death through inhibiting survivin suggests that this IAP may be involved in the chemoresistance phenotype in AML cells. Our findings suggest that LQB-118 might be a promising therapeutic approach for AML patients through survivin downregulation.
Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer INCA, Rio de Janeiro, RJ, Brazil.
Flaviana R
FR
de Souza Reis
Fernanda C Casal
FC
de Faria
Carolina P
CP
Castro
Paloma S
PS
de Souza
Flavia
F
da Cunha Vasconcelos
Reinaldo D
RD
Bello
Alcides J
AJ
da Silva
Paulo R R
PR
Costa
Raquel C
RC
Maia
D000293:Adolescent; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D002648:Child; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007223:Infant; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009285:Naphthoquinones / Q000494:pharmacology*; D036343:Pterocarpans / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D051034:Inhibitor of Apoptosis Proteins; C569361:LQB 118; D009285:Naphthoquinones; D036343:Pterocarpans