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, Thiago; Magalhães, Fernanda C.; Justo, Graça; Coelho, Marsen Garcia Pinto; Netto, Chaquip D.; Costa, Paulo R.R.; Sabino, K.C.C.

doi:10.1016/j.bmc.2014.04.025

Cited by 15 publications

(13 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Faiões

Frota

Cunha-Júnior

et al. 2018

J Venom Anim Toxins Incl Trop Dis

View full text Add to dashboard Cite

BackgroundDespite the development of new therapies for leishmaniasis, among the 200 countries or territories reporting to the WHO, 87 were identified as endemic for Tegumentary Leishmaniasis and 75 as endemic for Visceral Leishmaniasis. The identification of antileishmanial drug candidates is essential to fill the drug discovery pipeline for leishmaniasis. In the hit molecule LQB-118 selected, the first generation of pterocarpanquinones was effective and safe against experimental visceral and cutaneous leishmaniasis via oral delivery. In this paper, we report the synthesis and antileishmanial activity of the second generation of pterocarpanoquinones.MethodsThe second generation of pterocarpanquinones 2a-f was prepared through a palladium-catalyzed oxyarylation of dihydronaphtalen and chromens with iodolawsone, easily prepared by iodination of lawsone. The spectrum of antileishmanial activity was evaluated in promastigotes and intracellular amastigotes of L. amazonensis, L. braziliensis, and L. infantum. Toxicity was assessed in peritoneal macrophages and selective index calculated by CC50/IC50. Oxidative stress was measured by intracellular ROS levels and mitochondrial membrane potential in treated cells.ResultsIn this work, we answered two pertinent questions about the structure of the first-generation pterocarpanquinones: the configuration and positions of rings B (pyran) and C (furan) and the presence of oxygen in the B ring. When rings B and C are exchanged, we noted an improvement of the activity against promastigotes and amastigotes of L. amazonensis and promastigotes of L. infantum. As to the oxygen in ring B of the new generation, we observed that the oxygenated compound 2b is approximately twice as active against L. braziliensis promastigotes than its deoxy derivative 2a. Another modification that improved the activity was the addition of the methylenedioxy group. A variation in the susceptibility among species was evident in the clinically relevant form of the parasite, the intracellular amastigote. L. amazonensis was the species most susceptible to novel derivatives, whilst L. infantum was resistant to most of them. The pterocarpanoquinones (2b and 2c) that possess the oxygen atom in ring B showed induction of increased ROS production.ConclusionsThe data presented indicate that the pterocarpanoquinones are promising compounds for the development of new leishmanicidal agents.

show abstract

Section: Introductionmentioning

confidence: 99%

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Faiões

Frota

Cunha-Júnior

et al. 2018

J Venom Anim Toxins Incl Trop Dis

View full text Add to dashboard Cite

show abstract

“…These data were in agreement with our findings on the roles of Cyclin D1 and C-myc in PC cell proliferation and cell cycle progression 34 , 35 . However, downregulation of C-myc and Cyclin D1 expression in PC-3 cells was associated with S and G2/M phase arrest rather than G0/G1 phase arrest 36 . This may be explained by the possibility that the induction of cell cycle arrest is not only dependent on the regulation of C-myc and Cyclin D1 but also on other cell cycle regulatory factors.…”

Section: Discussionmentioning

confidence: 83%

FAM46B inhibits cell proliferation and cell cycle progression in prostate cancer through ubiquitination of β-catenin

Tao

Liu

et al. 2018

Exp Mol Med

View full text Add to dashboard Cite

FAM46B is a member of the family with sequence similarity 46. Little is known about the expression and functional role(s) of FAM46B in prostate cancer (PC). In this study, the expression of FAM46B expression in The Cancer Genome Atlas, GSE55945, and an independent hospital database was measured by bioinformatics and real-time PCR analysis. After PC cells were transfected with siRNA or a recombinant vector in the absence or presence of a β-catenin signaling inhibitor (XAV-939), the expression levels of FAM46B, C-myc, Cyclin D1, and β-catenin were measured by western blot and real-time PCR. Cell cycle progression and cell proliferation were measured by flow cytometry and the CCK-8 assay. The effects of FAM46B on tumor growth and protein expression in nude mice with PC tumor xenografts were also measured. Our results showed that FAM46B was downregulated but that β-catenin was upregulated in patients with PC. FAM46B silencing promoted cell proliferation and cell cycle progression in PC, which were abrogated by XAV-939. Moreover, FAM46B overexpression inhibited PC cell cycle progression and cell proliferation in vitro and tumor growth in vivo. FAM46B silencing promoted β-catenin protein expression through the inhibition of β-catenin ubiquitination. Our data clearly show that FAM46B inhibits cell proliferation and cell cycle progression in PC through ubiquitination of β-catenin.

show abstract

“…The in situ evidencef or the formation of QM after electrochemicalr eduction of LQB-118 ( Figure 9) is an additional proof of the understandingo fthe molecular mechanism of biological action. [14][15][16][17][18][19][20][21][22][23][24][25] As imilar bioreductive alkylation was proposed previously by Moorea nd Czeniak for mitomycinC, [35] which contains al atent quinone functionality after reduction with NQO1 [NAD(P)H quinone dehydrogenase 1] (two-electron reduction). The reductive activation of mitomycins providess electivity in the targeting of solid tumors because it is favored in the oxygen-deprived environment of tumor cells and inhibited by the oxygen-rich environment of healthy tissues.…”

Section: Spectroelectrochemical Experimentsmentioning

confidence: 99%

“…[18] Furthermore, it inhibits proliferation and inducesa poptosis in leukemic cells through the activation of caspase-3. [19] LQB-118 inducest he programmed cell death of prostate cancerc ells [20] and hasa ntineoplastic activity against lung cancer cells. [21] This pterocarpanquinone significantly reduces ascites or solid Ehrlich andB 16F10 melanoma growth in vivo and ameliorates side effects, such as cachexia.…”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species Release, Alkylating Ability, and DNA Interactions of a Pterocarpanquinone: A Test Case for Electrochemistry

et al. 2016

Self Cite

View full text Add to dashboard Cite

The electrochemistry of a redox‐based bioactive pterocarpanquinone, designated as LQB‐118, and its precursor chromenquinone (CQ) was investigated in protic and aprotic media with a focus on the reduction mechanism in both media, the reactivity with oxygen, and the interaction with biological targets, such as DNA. UV/Vis spectroelectrochemistry clarified the proposed mechanism. The appearance of bands at λ=331, 400, and 600 nm suggests the generation of transient quinonemethides (QM). Electrochemical experiments revealed homogeneous electron transfer to oxygen. LQB‐118 itself interacts with calf‐thymus DNA and ssDNA in solution. It, and its electrogenerated intermediates, have been shown to decrease the diagnostic oxidation peaks of guanosine and adenosine residues. These results, together with electrochemical evidence for the formation of QMs and the reductive addition of thiols, partly explain the reported cytotoxic and parasiticidal effects of this quinone. Overall, the electrochemical methods do well to predict the molecular mechanism of the biological activity of the present class of compounds. As an additional competitive advantage, electrochemistry allows reductive cleavage in situ, the characterization of the generated intermediate, the calculation of the number of transferred electrons, and positively mimics in vitro and in vivo experiments.

show abstract

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

Cited by 15 publications

References 33 publications

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

Second-generation pterocarpanquinones: synthesis and antileishmanial activity

FAM46B inhibits cell proliferation and cell cycle progression in prostate cancer through ubiquitination of β-catenin

Reactive Oxygen Species Release, Alkylating Ability, and DNA Interactions of a Pterocarpanquinone: A Test Case for Electrochemistry

Contact Info

Product

Resources

About