LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]: a novel class of agent with high apoptotic effect in chronic myeloid leukemia cells.
Despite the relevant therapeutic progresses obtained with imatinib, clinical resistance to this drug has emerged and reemerged after cytogenetic remission in a group of patients with chronic myeloid leukemia (CML). Therefore, novel treatment strategies are needed. In this study, we evaluated the anti-CML activity and mechanisms of action of LQB-118, a pterocarpanquinone structurally related to lapachol [2-hydroxy-3-(3-methyl-2-butenyl)-1,4-naphthoquinone]. LQB-118 treatment resulted in an important reduction of cell viability in cell lines derived from CML, both the vincristine-sensitive K562 cell line, and the resistant K562-Lucena (a cell line overexpressing P-glycoprotein). In agreement with these results, the induction of caspase-3 activation by this compound indicated that a significant rate of apoptosis was taking place. In these cell lines, apoptosis induced by LQB-118 was accompanied by a reduction of P-glycoprotein, survivin, and XIAP expression. Moreover, this effect was not restricted to cell lines as LQB-118 produced significant apoptosis rate in cells from CML patients exhibiting multifactorial drug resistance phenotype such as P-glycoprotein, MRP1 and p53 overexpression. The data suggest that LQB-118 has a potent anti-CML activity that can overcome multifactorial drug resistance mechanisms, making this compound a promising new anti-CML agent.
Maia
Raquel C
RC
Laboratório de Hemato-Oncologia Celular e Molecular, Programa de Pesquisa em Hemato-Oncologia Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro, RJ, Brazil. rcmaia@inca.gov.br
Vasconcelos
Flavia C
FC
de Sá Bacelar
Thiago
T
Salustiano
Eduardo J
EJ
da Silva
Luis Felipe R
LF
Pereira
Débora L
DL
Moellman-Coelho
Arthur
A
Netto
Chaquip D
CD
da Silva
Alcides J
AJ
Rumjanek
Vivian M
VM
Costa
Paulo R R
PR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009285:Naphthoquinones / Q000494:pharmacology*; D036343:Pterocarpans / Q000494:pharmacology*; D055815:Young Adult
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C569361:LQB 118; D009285:Naphthoquinones; D036343:Pterocarpans; D053148:Caspase 3