title: 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.
abstract: 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.
authors.affiliation: 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
authors.forename: Raquel C
authors.initials: RC
authors.lastname: Maia
authors.forename: Flavia C
authors.initials: FC
authors.lastname: Vasconcelos
authors.forename: Thiago
authors.initials: T
authors.lastname: de Sá Bacelar
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Salustiano
authors.forename: Luis Felipe R
authors.initials: LF
authors.lastname: da Silva
authors.forename: Débora L
authors.initials: DL
authors.lastname: Pereira
authors.forename: Arthur
authors.initials: A
authors.lastname: Moellman-Coelho
authors.forename: Chaquip D
authors.initials: CD
authors.lastname: Netto
authors.forename: Alcides J
authors.initials: AJ
authors.lastname: da Silva
authors.forename: Vivian M
authors.initials: VM
authors.lastname: Rumjanek
authors.forename: Paulo R R
authors.initials: PR
authors.lastname: Costa
mesh_terms: 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
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C569361:LQB 118; D009285:Naphthoquinones; D036343:Pterocarpans; D053148:Caspase 3