1.The pterocarpanquinone LQB-118 induces apoptosis in acute myeloid leukemia cells of distinct molecular subtypes and targets FoxO3a and FoxM1 transcription factors.
Nestal de Moraes G1, Castro CP1, Salustiano EJ2, Dumas ML3, Costas F1, Lam EW4, Costa PR2, Maia RC1. Int J Oncol. 2014 Nov;45(5):1949-58. doi: 10.3892/ijo.2014.2615. Epub 2014 Aug 21.
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.
2.The therapeutical potential of a novel pterocarpanquinone LQB-118 to target inhibitor of apoptosis proteins in acute myeloid leukemia cells.
de Souza Reis FR1, de Faria FC, Castro CP, de Souza PS, da Cunha Vasconcelos F, Bello RD, da Silva AJ, Costa PR, Maia RC. Anticancer Agents Med Chem. 2013 Feb;13(2):341-51.
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.
3.The pterocarpanquinone LQB-118 inhibits tumor cell proliferation by downregulation of c-Myc and cyclins D1 and B1 mRNA and upregulation of p21 cell cycle inhibitor expression.
Martino T1, Magalhães FC1, Justo GA1, Coelho MG1, Netto CD2, Costa PR2, Sabino KC3. Bioorg Med Chem. 2014 Jun 15;22(12):3115-22. doi: 10.1016/j.bmc.2014.04.025. Epub 2014 Apr 20.
The incidence of cancer grows annually worldwide and in Brazil it is the second cause of death. The search for anti-cancer drugs has then become urgent. It depends on the studies of natural and chemical synthesis products. The antitumor action of LQB-118, a pterocarpanquinone structurally related to lapachol, has been demonstrated to induce mechanisms linked to leukemia cell apoptosis. This work investigated some mechanisms of the in vitro antitumor action of LQB-118 on prostate cancer cells. LQB-118 reduced the expression of the c-Myc transcription factor, downregulated the cyclin D1 and cyclin B1 mRNA levels and upregulated the p21 cell cycle inhibitor. These effects resulted in cell cycle arrest in the S and G2/M phases and inhibition of tumor cell proliferation. LQB-118 also induced programmed cell death of the prostate cancer cells, as evidenced by internucleosomal DNA fragmentation and annexin-V positive cells. Except the cell cycle arrest in the S phase and enhanced c-Myc expression, all the mechanisms observed here for the in vitro antitumor action of LQB-118 were also found for Paclitaxel, a traditional antineoplastic drug.
4.Effectiveness of the local or oral delivery of the novel naphthopterocarpanquinone LQB-118 against cutaneous leishmaniasis.
da Cunha-Júnior EF1, Pacienza-Lima W, Ribeiro GA, Netto CD, do Canto-Cavalheiro MM, da Silva AJ, Costa PR, Rossi-Bergmann B, Torres-Santos EC. J Antimicrob Chemother. 2011 Jul;66(7):1555-9. doi: 10.1093/jac/dkr158. Epub 2011 Apr 29.
OBJECTIVES: This paper describes the antileishmanial properties of LQB-118, a new compound designed by molecular hybridization, orally active in Leishmania amazonensis-infected BALB/c mice.