The pterocarpanquinone LQB-118 induces apoptosis in acute myeloid leukemia cells of distinct molecular subtypes and targets FoxO3a and FoxM1 transcription factors

Abstract

Acute myeloid leukemia (AML) patients' outcome is usually poor, mainly because of drug resistance phenotype. The identification of new drugs able to overcome mechanisms of chemoresistance is essential. The pterocarpanquinone LQB-118 compound has been shown to have a potent cytotoxic activity in myeloid leukemia cell lines and patient cells. Our aim was to investigate if LQB-118 is able to target FoxO3a and FoxM1 signaling pathways while sensitizing AML cell lines. LQB-118 induced apoptosis in both AML cell lines HL60 (M3 FAB subtype) and U937 (M4/M5 FAB subtype). Cell death occurred independently of alterations in cell cycle distribution. In vivo administration revealed that LQB-118 was not cytotoxic to normal bone marrow-derived cells isolated from mice. LQB-118 induced FoxO3a nuclear translocation and upregulation of its direct transcriptional target Bim, in HL60 cells. However, LQB-118 induced FoxO3a nuclear exclusion, followed by Bim downregulation, in U937 cells. Concomitantly, LQB-118 exposure reduced FoxM1 and Survivin expression in U937 cells, but this effect was more subtle in HL60 cells. Taken together, our data suggest that LQB-118 has a selective and potent antitumor activity against AML cells with distinct molecular subtypes, and it involves differential modulation of the signaling pathways associated with FoxO3a and FoxM1 transcription factors.

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).…”

The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance

“…In addition to the more conventional chemotherapeutic drugs, the FOXO3 and FOXM1 transcription factors have emerged as the master regulators in novel molecular targeting anticancer agent resistance too. The pterocarpanquinone compound LQB-118 can induce apoptosis in drug-resistant myeloid leukaemic cells through specifically targeting FOXO3 and FOXM1[30]. Activation of FOXO3 has also been shown to reverse mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 inhibitor AZD6244 chemoresistance in human cancer [31].…”

Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics

“…Multi-substituted naphthoquinones, including shikonin [35,36,37,38,39] and its derivative SH-7 [40], and other dihydroxy or dimethoxy 1,4-naphthoquinones [41,42], compared with mono- or di-substituted naphthoquinones, demonstrated superior in vitro activity against AML cells with IC 50 s ranging 0.1–4 μM. Heterocyclic monomeric naphthoquinones included furanonaphthoquinones FNQ3 [43] and FN6-one [44], β-lapachone [45,46,47,48,49] and nor-β-lapachone [45,46,50,51], dunnione [47], and pterocarpanquinone LQB-118 [28,52]. FNQ3 was significantly more effective than low dose cytarabine in reducing cell viability ( p < 0.001) and combining the two drugs led to an even greater reduction in cell viability in NB4 and U937 cells ( p < 0.01) [43].…”