The pentacyclic 1,4-naphthoquinones 1a-d were cytotoxic (IC(50) approximately 2-7 microM) to human leukemic cell lines K562 (oxidative stress-resistant), Lucena-1 (MDR phenotype) and Daudi. Fresh leukemic cells obtained from patients, some with the MDR phenotype, were also sensitive to these compounds. The pentacyclic 1,4-naphthoquinones 1a and 1c induced apoptotic cell death in cells from leukemic patients as determined by flow cytometry. Conversely, the cell lines were highly insensitive to lapachol (2) and alpha-lapachone (3). Mitomycin-C inhibited cell proliferation at concentrations as low as 0.5 microM. The low toxicity against lymphocytes activated by phytohemagglutinin shows that these compounds are selective for the cancer cells studied. Previous data suggest that these compounds (1a-d) can be bioactivated in situ by reduction followed by rearrangement leading to enones, which are powerful alkylating agents. In contrast, lapachol (2) and beta-lapachone (3), which cannot be bioactivated by reduction, showed little activity against the same cell lines.

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.

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.

No abstract

No abstract