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The radiotherapy modulators used in clinic have disadvantages of high toxicity and low selectivity. For the first time, we used the
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Histone deacetylases(HDAC)and its inhibitors have been the hot spots in the field of cancer-treatment.At pres?ent,six HDAC inbibitors(HDACi)have been approved by FDA for the treatment of various hematological neoplasms and solid tu?mors.Besides,a number of new HDACi are undergoing clinical trials in different stages or preclinical experiments,which have shown great inhibitory activities.However,a series of side effects and dose-dependent problems have appeared due to the poor selectivity of inhibitors in HDAC subtypes.So a new HDACi with high-selectity to HDAC subtypes or drug-combination will be of importance to im?prove the therapeutic effect.This review highlights the structure modification in HDACi and multiple drugs combination to summarize the latest evolution of HDACi.
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The antitumor activities of NL-101,aHDACi/DNA damage dual-targeting drug,on human multiple myeloma in vitro and in vivo were studied.Furthermore,the primary mechanisms were revealed.We detected the anti-proliferative activity of NL-101 on 10 human multiple myeloma cell lines,and the combinational effect of NL-101 and bortezomib on RPMI 8226 cell line.The inducing effects of NL-101 on cell cycle arrest and apoptosis were detected by FACS.The effects of NL-101 on acetyled-Histone H3,total Histone H3,acetyled α-Tubulin,total α-Tubulin,phospho-Histone H2A.X and total Histone H2A.X were evaluated by Western blott.We also demonstrated the antitumor activity of NL-101 and the combinational effect of NL-101 and bortezomib on RPMI 8226 xenograft tumor model in vivo.Results showed that NL-101 possessed strong antitumor activities on human multiple myeloma cells in vitro and in vivo.NL-101exhibited significant HDAC inhibitory activity and DNA alkylating activity.NL-101not only inhibited histone deacetylation level,but also increased the DNA damage in multiple myeloma cells.Meanwhile,NL-101 induced cell cycle arrest and apoptosis.Also,the synergistic effect of NL-101 was discovered when combined with bortezomib in vitro and in vivo.These data demonstrated that NL-101 may be a potent agent for the treatment of human multiple myeloma in future.
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O Linfoma de Burkitt (LB) é o subtipo de linfoma de células B mais comum na infância. As recentes descobertasrelacionadas à patogênese do LB evidenciaram a ativação da via de PI3K em cooperação com c-Myc nodesenvolvimento do LB. Neste estudo, observamos que a via de PI3K/Akt é alvo de Inibidores de Histona Deacetilase (HDACi) em células do LB. A combinação do HDACi (NaB) e quimioterapia (VP-16) inibiu aproliferação e levou a parada do ciclo celular em G2/M com concomitante diminuição na fase S. Análises demicroarranjo mostraram regulação diferencial de 500 genes após o tratamento com VP-16, 729 genes com NaB e 1413 genes com a combinação NaB/VP-16, indicando uma possível ação sinérgica dessa combinação. Asanálises transcricionais revelaram alterações nos níveis de RNAm relacionados com processos como: parada no ciclo celular, vias relacionadas com p53, reparo de DNA e fosforilação, incluindo a desregulação de PI3K. Alémdisso, a inibição do crescimento celular foi relacionada com a redução da fosforilação de Akt e diminuição daexpressão de c-Myc em aproximadamente 60% (p≤0.005). Adicionalmente, HDACi levou ao aumento da expressão de miRNAs envolvidos na via de PI3K/Akt e proliferação celular como miR-101, miR-143 e miR-145em linhagem celular de LB. Os níveis dos mesmos miRNAs estavam extremamente reduzidos em 46 amostras tumorais de pacientes com LB. Uma vez determinada a participação da via de PI3K/Akt na resposta ao tratamento com HDACi, investigamos o efeito da combinação de HDACi (SAHA) e inibidor de PI3KLY294002 nas células do LB. Observamos que a combinação é capaz de promover parada das células em G0/G1 com diminuição da proliferação celular...
Burkitt lymphoma (BL) is a B-cell lymphoma more common in children. The recent discovery in BL pathogenesis highlighted the activation of PI3K pathway in cooperation with Myc in BL development . In this study we demonstrated that PI3K/Akt pathway is a target to HDACi in BL cells. The combination of HDACi (NaB) and chemotherapy (VP16), inhibitedthe proliferation and enhanced the blockage of the cell cycle progression at G2/M with a concurrent decrease in the S phase. Microarray profile showed a synergistic action of NaB/VP-16 combination through the differential regulation of 1413 genes compared to 500 genes regulated by VP-16 and 729 by NaB. Transcriptional analyses showed changes in mRNA levels of pathways related to p53, DNA repair, phosphorylation, PI3K deregulation.Besides, the inhibiton of the cell growth was related to reduced Akt phosphorylation, and decrease of c-Myc protein expression by about 60% (p ≤ 0.005). Moreover, HDACi enhancedthe expression of miRNAs related to PI3K/Akt pathway and proliferation as miR-101, miR-143, and miR-145 in BL cell line. The same miRs were found to be extremely downregulated in 46 paediatric BL samples. Since PI3K/Akt pathway is involved in HDACi treatmentresponse, we investigated the effect of HDACi SAHA and PI3Ki LY294002 combination in BL cells. The combination leads to cell cycle arrest in G0/G1 fase, cell proliferation inhibition. The SAHA/LY294002 treatment also inhibits the cell migration. The combinedtreatment decreased the number of polarized cells, observed by α-tubulin and f-actin staining. However it was not related to Cdc42 expression. In addition, SAHA treatment leads to tubulinacethylation, which is HDAC6 target. Rho family as Rho A, B, C; Rac 1, 2 e 3 e Rnd 1, 2 e 3 expression increased. Nevertheless, only RhoB protein levels were correlated to qPCR data...
Subject(s)
Humans , Male , Female , Child , Burkitt Lymphoma , Cell Movement , Cell Proliferation , MicroRNAsABSTRACT
Histone deacetylase inhibitors (HDACI) can improve the acetylation status of histone N-terminal, which will exert the effect on treatment. The N-terminal of histone modifications belongs to the category of epigenetics. Epigenetics mainly refers to the study of the heritable variation without change in DNA sequence. HDACI had been paid much attention as a new non-cytotoxic an-ti-cancer targeted drug. Thus, the application of this drug in clinical research is widespread. After the U.S. Food and Drug Administra-tion approved two HDACIs for the treatment of cutaneous T-cell lymphoma, the clinical applications of HDACI in other subtypes of T-cell lymphoma have obtained increasing attention. Studies on the mechanism of HDACI provide the theoretical basis for the applica-tion of HDACIs in other subtypes of T-cell lymphoma. In this article, we reviewed the mechanism and clinical trials of HDACIs on the treatment of T-cell lymphoma.
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Objective Epithelial mesenchymal transition (EMT) has a role in the proliferation and metastasis of various types of cells.This study investigates the hepatic oval cell's mechanism of EMT induced by histone deacetylase inhibition and the resulting cell motility increase from EMT.Methods Hepatic oval cell stem cell markers and marker changes were detected by flow cytometry,and after histone deacetylase inhibition induced EMT,the morphological changes were recorded.Western blot and quantitative real-time polymerase chain reaction detected the expression of E-cadherin,vimentin and Snail.Furthermore,confocal microscopy analysis recognized the nuclear translocation of Snail.Results Flow cytometry revealed no changes in the stem cell properties of hepatic oval cells in the cell culture process.Oval cell EMT,induced by HDACi,was observed through morphological changes,a reduction of the epithelial cell marker E cadherin,and an increase of the mesenchymal cell marker Vimentin.HDACi can promote the expression and nuclear translocation of Snail,which is the key hepatic oval cell transcription factor for both EMT and enhanced motility.Therefore,Snail RNA interference can suppress HDACi induced EMT in hepatic oval cells.Conclusions In conclusion,histone deacetylase inhibition induces hepatic oval cell epithelial-mesenchymal transition by Snail.