The Therapeutical Potential of a Novel Pterocarpanquinone LQB-118 to Target Inhibitor of Apoptosis Proteins in Acute Myeloid Leukemia Cells

Abstract

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.

The pterocarpanquinone LQB 118 induces apoptosis in tumor cells through the intrinsic pathway and the endoplasmic reticulum stress pathway

“…In this work, we analyzed the effect of a new pterocarpanquinone (LQB 118) [1,2,8] against two different leukemic cells lines, both susceptible to it, but presenting different levels of sensitivity to the compound: the CML cell line K562 and the ALL cell line Jurkat. This pterocarpanquinone has been shown to be effective against other leukemia cell lines such as HL-60, Daudi, and the MDR K562-Lucena-1 [1,2], but showed low toxicity against normal cells, being toxic only at concentrations greater than 10 mmol/l in PBMC cells from healthy donors [2].…”

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

“…The hit molecule selected LQB-118 ( 1 ) (Fig. 1 ) showed antineoplasic activity against cultured breast cancer, leukemia, lung cancer cell lines and prostate cancer cell [ 5 – 10 ], some of which present a Multidrug Resistance phenotype [ 11 ]. This hit showed low toxicity for PBMC human blood cells and cell line macrophages, evidencing a high selectivity index [ 3 ].…”

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

“…Table 1 shows the naphthoquinone derivatives that have been reported to have anti-AML activity. Mono- or di-substituted monomeric naphthoquinones, including menadione [19], juglone [20], lawson [21], glycinyl-1,4-naphthoquinone [22], plumbagin [23,24,25,26,27], lapachol (and nor-lapachol) [21,28,29], atovaquone [30,31], ramentaceone [32], cordiaquinone J [33], and TW-92 [34] showed anti-AML activity in different AML cell lines and primary cells from AML patients with wide IC 50 s ranging from 0.6 to 100 micromolar (μM), Table 1. Atovaquone was found to have an additive effect when combined with standard induction chemotherapy (cytarabine and daunorubicin) in AML cell lines [31].…”

“…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].…”