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.

Preclinical Studies Evaluating Subacute Toxicity and Therapeutic Efficacy of LQB-118 in Experimental Visceral Leishmaniasis

“…With the aim of developing new drugs, a series of compounds were designed and synthesized using the molecular hybridization of naphthoquinones and pterocarpans (5-7). The pterocarpanquinone LQB-118, the lead compound from this class, has antiprotozoal and anti-leukemic cell line activities, even in cells with an multidrug resistance phenotype (8)(9)(10). We have also demonstrated that LQB-118 is effective in treating experimental cutaneous leishmaniasis via oral delivery (11,12), and the death of Leishmania amazonensis parasites involved oxidative stress with hallmarks of apoptosis (13).…”

Imatinib increases apoptosis index through modulation of survivin subcellular localization in the blast phase of CML cells

“…Briefly, cells were incubated for 24, 48 and 72 h in the presence or absence (control) of various concentrations of imatinib (0.5, 1.0, 2.5, and 5.0 M), ara-C (0.1, 0.5, 1.0, 2.5, 5.0, and 10.0 M), and the drugs in association. The plates were processed as described previously [18]. All of the assays were performed in triplicate.…”

“…The percentage of apoptotic cells was assessed using the Annexin V assay (Genzyme Diagnostics, USA) as described previously [18]. Propidium iodide (PI) was used to avoid necrotic cell detection (Annexin − /PI + ).…”

P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

“…Antibody complexes were visualized by the ECL detection system (GE Healthcare). The expression of caspase-3, XIAP and survivin was normalized with respect to β-actin as previously shown (26).…”