Objective:The novel compound GCJ-490A has been discovered as a pan-histone deacetylase(HDAC)inhibitor that exerts potent inhibitory activity against HDAC1,HDAC3,and HDAC6.Because of the important roles of HDACs in lun...Objective:The novel compound GCJ-490A has been discovered as a pan-histone deacetylase(HDAC)inhibitor that exerts potent inhibitory activity against HDAC1,HDAC3,and HDAC6.Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue,we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer(NSCLC)in vitro and in vivo in this study.Methods:The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation,apoptosis,and colony formation assays.NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo.Western blot assays,luciferase reporter assays,chromatin immunoprecipitation assays,quantitative real time-PCR,immunohistochemistry,and transcription factor activity assays were used to elucidate possible mechanisms.Results:GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo.Interestingly,inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKαpromoter and enhanced IKKαtranscription,thus decreasing c-Met.Moreover,this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib.Conclusions:These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.展开更多
HDACs and HATs are two kinds of enzymes which catalyse deacetylation and acetylation of histone in eukaryotes, whose dynamic balance has accurate regulation for gene transcription and gene expression of eukaryotes at ...HDACs and HATs are two kinds of enzymes which catalyse deacetylation and acetylation of histone in eukaryotes, whose dynamic balance has accurate regulation for gene transcription and gene expression of eukaryotes at DNA level. Disbalance of them can bring the disorder of proliferation and differentiation in normal cells, and then lead to the initiation of tumor. Their aberrant functions were directly related to the initiation and progression of various tumors, such as promyelocytic leukemia, Hodgkin lymphoma, colonic cancer and gastral cancer. The inhibitors of HDACs are used for treatment of tumor. They can restrain the activity of HDACs and block the inhibition of gene expression caused by the disorder of deacetylation. Its major biological effects lie in inducing differentiation of tumor cells, arresting cell circle at G0/G1, activating cell apoptosis gene, enhancing the sensitivity of chemical therapy and radioactive therapy. So far HDAC has been an important target enzyme in anticancer drug research.展开更多
Immunotherapy has been applied successully to treat B-cell lymphomas in preclinical models or clinical settings.However,immunotherapy resistance is a major challenge for B-cell lymphoma treatment.To overcome this issu...Immunotherapy has been applied successully to treat B-cell lymphomas in preclinical models or clinical settings.However,immunotherapy resistance is a major challenge for B-cell lymphoma treatment.To overcome this issue,combinatorlal therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas.One of such strategies is to combine immunotherapy with histone deacetylase(HDAC)inhi-bitors.HDAC inhibitors can potentially increase tumor immunogenicity,promote antitumor immune respon-ses,or reverse immunosuppressive tumor environments.Thus,the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment.However,not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target.Hence,we suggest that optimal treatment effh-cacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors.Here,we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.展开更多
Over the past years, it has been found that the epigenetic silence of tumor suppressor genes induced by overexpression of histone deacetylases （HDACs） plays an important role in carcinogenesis. Thus, HDAC inhibitors...Over the past years, it has been found that the epigenetic silence of tumor suppressor genes induced by overexpression of histone deacetylases （HDACs） plays an important role in carcinogenesis. Thus, HDAC inhibitors have emerged as the accessory therapeutic agents for multiple human cancers, since they can block the activity of specific HDACs, restore the expression of some tumor suppressor genes and induce cell differentiation, growth arrest and apoptosis. To date, the precise mechanisms by which HDAC inhibitors induce cell death have not yet been fully elucidated and the roles of individual HDAC inhibitors have not been identified. Moreover, the practical uses of HDAC inhibitors in cancer therapy, as well as their synergistic effects with other therapeutic strategies are yet to be evaluated. In this review article, we discuss briefly the recent advances in studies of the developments of anti-cancer HDAC inhibitors and their potential clinical value.展开更多
Genome-edited human induced pluripotent stem cells(iPSCs)hold great promise for therapeutic applications.However,low editing efficiency has hampered the applications of CRISPR-Cas9 technology in creating knockout and ...Genome-edited human induced pluripotent stem cells(iPSCs)hold great promise for therapeutic applications.However,low editing efficiency has hampered the applications of CRISPR-Cas9 technology in creating knockout and homology-directed repair(HDR)-edited iPSC lines,particularly for silent genes.This is partially due to chromatin compaction,inevitably limiting Cas9 access to the target DNA.Among the six HDAC inhibitors we examined,vorinostat,or suberoylanilide hydroxamic acid(SAHA),led to the highest HDR efficiency at both open and closed loci,with acceptable toxicity.HDAC inhibitors equally increased non-homologous end joining(NHEJ)editing efficiencies(~50%)at both open and closed loci,due to the considerable HDAC inhibitor-mediated increase in Cas9 and sgRNA expression.However,we observed more substantial HDR efficiency improvement at closed loci relative to open chromatin(2.8 vs.1.7-fold change).These studies provide a new strategy for HDRediting of silent genes in iPSCs.展开更多
Suberoylanilide hydroxamic acid （SAHA）, as a histone deacetylase （HDAC） inhibitor （HDACi）, was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibito...Suberoylanilide hydroxamic acid （SAHA）, as a histone deacetylase （HDAC） inhibitor （HDACi）, was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors （CNIs） to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus （FK506） in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA- and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon （IFN）-y but increased IL-IO expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4＋ T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORyt in these cells. Moreover, SAHA enhances suppressive function of regulatory T （Treg） cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.展开更多
Epigenetic mechanisms play an important role in the development and persistence of cancer,and histone deacetylase(HDAC)inhibitors are promising anticancer drugs targeting epigenetic modes.Efficient anticancer drugs fo...Epigenetic mechanisms play an important role in the development and persistence of cancer,and histone deacetylase(HDAC)inhibitors are promising anticancer drugs targeting epigenetic modes.Efficient anticancer drugs for the treatment of castration-resistant prostate cancer(CRPC)are sought,and approved HDAC inhibitors have shown promising results on the one hand and severe drawbacks on the other hand.Hence,ways to break the drug resistance mechanisms of existing HDAC inhibitors as well as the design of new promising HDAC inhibitors which can overcome the disadvantages of the classic HDAC inhibitors are of great importance.In this work,HDAC inhibitors with the potential to become a mainstay for the treatment of CRPC in the future as well as suitable combination treatments of HDAC inhibitors with other anticancer drugs leading to considerable synergistic effects in treated CRPCs are discussed.展开更多
Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells.Pharmacological induction of excessively asymmetric mitofissionassociated cell death(...Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells.Pharmacological induction of excessively asymmetric mitofissionassociated cell death(MFAD)by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy.By screening a series of paninhibitors,we identified pracinostat,a pan-histone deacetylase(HDAC)inhibitor,as a novel MFAD inducer,that exhibited a significant anticancer effect on colorectal cancer(CRC)in vivo and in vitro.Pracinostat increased the expression of cyclin-dependent kinase 5(CDK5)and induced its acetylation at residue lysine 33,accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynaminrelated protein 1(Drp1)-mediated mitochondrial peripheral fission.CRC cells with high level of CDK5(CDK5-high)displayed midzone mitochondrial division that was associated with oncogenic phenotype,but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells.Mechanistically,pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor(MFF)to mitochondrial fission 1 protein(FIS1).Thus,our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells,which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.展开更多
Artemisinin and its derivatives(ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors(HDACi) were known to be able to promote heme synthesis in erythroid c...Artemisinin and its derivatives(ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors(HDACi) were known to be able to promote heme synthesis in erythroid cells. Nevertheless, the effect of HDACi on heme homeostasis in nonerythrocytes remains unknown. We envisioned that the combination of HDACi and artesunate(ARS)might have synergistic antitumor activity through modulating heme synthesis. In vitro studies revealed that combination of ARS and HDACi exerted synergistic tumor inhibition by inducing cell death. Moreover, this combination exhibited more effective antitumor activity than either ARS or HDACi monotherapy in xenograft models without apparent toxicity. Importantly, mechanistic studies revealed that HDACi coordinated with ARS to increase 5-aminolevulinate synthase(ALAS1) expression, and subsequent heme production, leading to enhanced cytotoxicity of ARS. Notably, knocking down ALAS1 significantly blunted the synergistic effect of ARS and HDACi on tumor inhibition, indicating a critical role of ALAS1 upregulation in mediating ARS cytotoxicity. Collectively, our study revealed the mechanism of synergistic antitumor action of ARS and HDACi. This finding indicates that modulation of heme synthesis pathway by the combination based on ARTs and other heme synthesis modulators represents a promising therapeutic approach to solid tumors.展开更多
Diffuse large B-cell lymphoma(DLBCL) is an aggressive type of non-Hodgkin’s lymphoma. A total of 10%-15% of DLBCL cases are associated with myelocytomatosis viral oncogene homolog(MYC) and/or B-cell lymphoma-2(BCL2) ...Diffuse large B-cell lymphoma(DLBCL) is an aggressive type of non-Hodgkin’s lymphoma. A total of 10%-15% of DLBCL cases are associated with myelocytomatosis viral oncogene homolog(MYC) and/or B-cell lymphoma-2(BCL2) translocation or amplification. BCL2 inhibitors have potent anti-tumor effects in DLBCL;however, resistance can be acquired through up-regulation of alternative anti-apoptotic proteins. The histone deacetylase(HDAC) inhibitor chidamide can induce BIM expression, leading to apoptosis of lymphoma cells with good efficacy in refractory recurrent DLBCL. In this study, the synergistic mechanism of chidamide and venetoclax in DLBCL was determined through in vitro and in vivo models. We found that combination therapy significantly reduced the protein levels of MYC, TP53, and BCL2 in activated apoptotic-related pathways in DLBCL cells by increasing BIM levels and inducing cell apoptosis. Moreover, combination therapy regulated expression of multiple transcriptomes in DLBCL cells, involving apoptosis, cell cycle, phosphorylation, and other biological processes, and significantly inhibited tumor growth in DLBCL-bearing xenograft mice. Taken together, these findings verify the in vivo therapeutic potential of chidamide and venetoclax combination therapy in DLBCL, warranting pre-clinical trials for patients with DLBCL.展开更多
Histone deacetylase(HDAC) inhibitors, which represent a structurally diverse group of molecules, have emerged as a novel therapeutic class of molecules with significant anticancer potential. Vorinostat and romidepsin,...Histone deacetylase(HDAC) inhibitors, which represent a structurally diverse group of molecules, have emerged as a novel therapeutic class of molecules with significant anticancer potential. Vorinostat and romidepsin, known as the first generation of HDAC inhibitors, were approved in the United States for the treatment of T-cell lymphomas. Preliminary activity of HDAC inhibitors has also been observed in non-small cell lung cancer(NSCLC) in combination with the existing treatment regimens, of which is the focus of the current review.展开更多
Histone deacetylases（HDACs） are considered to be among the most promising targets for the development of anti-cancer drugs,and HDAC inhibitors（HDACIs） have become a promising class of anti-cancer drugs.To explore ...Histone deacetylases（HDACs） are considered to be among the most promising targets for the development of anti-cancer drugs,and HDAC inhibitors（HDACIs） have become a promising class of anti-cancer drugs.To explore whether thioacetyl group as the zinc binding group（ZBG） and a slight change in the hydrophobicity of the recognition domain of HDACIs could alter their activities,we synthesized a series of cyclo[-L-Am7（SAc）-Aib-L-Phe（n-Cl）D-Pro-] and evaluated their HDAC-inhibitory and antiproliferative activities.The results show that these peptides could inhibit HDAC at 10-9 mol/L level,and could selectively inhibit the proliferation of three human cancer cell lines with IC 50 at 10-6 mol/L level.Docking study was conducted to examine the mechanisms by which these peptides interact with HDAC2.It appeared that a zinc ion in the active site of HDAC was coordinated by the carbonyl oxygen atom of the ZBG in the inhibitor.Both the ZBG domain of all the peptides and the surface recognition domain of cyclo[-L-Am7（SAc）-Aib-L-Phe（o-Cl）-D-Pro-] and that of cyclo[-L-Am7（SAc）-Aib-L-Phe（m-Cl）-D-Pro-] interacted with HDAC2 via hydrogen bonding.Hydrophobic interaction has been considered to provide favorable contributions to stabilizing the complexes,and the introduction of a chlorine atom at the aromatic ring on the L-Phe position of these peptides affected the interaction between each of these inhibitors and the enzyme,resulting in slight change in the structure of the surface recognition domain of the peptides.展开更多
Objective： This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase （HDAC） inhibitor, in com...Objective： This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase （HDAC） inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer （NSCLC）. Methods： Ten patients received oral chidamide 20, 25, or 30 mg twice per week continuously with paclitaxel （175 mg/m2） and carboplatin [area under the curve （AUC） 5 mg/mL/min] administered in a 3-week cycle. Patients with response and stable disease after four cycles maintained chidamide monotherapy until disease progression or unacceptable toxicity. Blood samples were collected for pharmacoldnetic analysis after the first single oral of chidamide and first combination treatment in cycle 1 from all patients. Results： Two dose-limiting toxicities were recorded in the 30 mg cohort, including thrombocytopenia and prolonged neutropenia in the first cycle. Grade 3/4 neutropenia in any cycle was observed in all patients, but was not associated with significant complications. Other grade 3/4 hematologic toxicities included thrombocytopenia and leucopenia. No significant changes were observed in pharmacokinetic parameters for both chidamide and paclitaxel. One patient in the 20 mg cohort had confirmed partial response （PR）. Two out of 5 patients with brain metastases had intracranial complete remission after 4-cycle treatment. Conclusions： Chidamide combined with paclitaxel and carboplatin was generally tolerated without unanticipated toxicities or clinically relevant pharmacokinetic interactions. The recommended dose for chidamide in this combination was established at 20 mg, and a phase II trial is ongoing with this regimen in patients with advanced NSCLC.展开更多
Epigenetic mechanisms,such as DNA methylation and histone modifications(e.g.,acetylation and deacetylation),are strongly implicated in the carcinogenesis of various malignancies.During transcription,the expression and ...Epigenetic mechanisms,such as DNA methylation and histone modifications(e.g.,acetylation and deacetylation),are strongly implicated in the carcinogenesis of various malignancies.During transcription,the expression and functionality of coding gene products are altered following the histone acetylation and deacetylation.These processes are regulated by histone acetyltransferases(HATs)and histone deacetylases(HDACs),respectively.HDAC inhibitors(HDACis)have been developed as promising therapeutic agents,to limit exposure to traditional and toxic chemotherapies and offer more alternatives for some specific malignant diseases with limited options.Mechanistically,these agents affect many intracellular pathways,including cell cycle arrest,apoptosis and differentiation,and their mechanism of action mainly depends on the type of cancer.Currently,five HDACis have been approved for the treatment of several hematological malignancies(e.g.,T-cell lymphoma subtypes and multiple myeloma);while,many of them are tested for further therapeutic indications in solid tumors(e.g.,colorectal,thyroid,breast,lung and pancreatic cancer).Herein,we review the literature and gather all available evidence,from in vitro and in vivo data to clinical trial results,that recognizes the antitumor activity of HDACis on pheochromocytomas and paragangliomas;and supports their clinical implementation in the treatment of these rare neuroendocrine tumors at metastatic setting.展开更多
基金supported by grants from the National Natural Science Foundation of China(Grant Nos.81773763 and 81521005).
文摘Objective:The novel compound GCJ-490A has been discovered as a pan-histone deacetylase(HDAC)inhibitor that exerts potent inhibitory activity against HDAC1,HDAC3,and HDAC6.Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue,we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer(NSCLC)in vitro and in vivo in this study.Methods:The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation,apoptosis,and colony formation assays.NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo.Western blot assays,luciferase reporter assays,chromatin immunoprecipitation assays,quantitative real time-PCR,immunohistochemistry,and transcription factor activity assays were used to elucidate possible mechanisms.Results:GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo.Interestingly,inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKαpromoter and enhanced IKKαtranscription,thus decreasing c-Met.Moreover,this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib.Conclusions:These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.
文摘HDACs and HATs are two kinds of enzymes which catalyse deacetylation and acetylation of histone in eukaryotes, whose dynamic balance has accurate regulation for gene transcription and gene expression of eukaryotes at DNA level. Disbalance of them can bring the disorder of proliferation and differentiation in normal cells, and then lead to the initiation of tumor. Their aberrant functions were directly related to the initiation and progression of various tumors, such as promyelocytic leukemia, Hodgkin lymphoma, colonic cancer and gastral cancer. The inhibitors of HDACs are used for treatment of tumor. They can restrain the activity of HDACs and block the inhibition of gene expression caused by the disorder of deacetylation. Its major biological effects lie in inducing differentiation of tumor cells, arresting cell circle at G0/G1, activating cell apoptosis gene, enhancing the sensitivity of chemical therapy and radioactive therapy. So far HDAC has been an important target enzyme in anticancer drug research.
文摘Immunotherapy has been applied successully to treat B-cell lymphomas in preclinical models or clinical settings.However,immunotherapy resistance is a major challenge for B-cell lymphoma treatment.To overcome this issue,combinatorlal therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas.One of such strategies is to combine immunotherapy with histone deacetylase(HDAC)inhi-bitors.HDAC inhibitors can potentially increase tumor immunogenicity,promote antitumor immune respon-ses,or reverse immunosuppressive tumor environments.Thus,the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment.However,not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target.Hence,we suggest that optimal treatment effh-cacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors.Here,we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.
文摘Over the past years, it has been found that the epigenetic silence of tumor suppressor genes induced by overexpression of histone deacetylases （HDACs） plays an important role in carcinogenesis. Thus, HDAC inhibitors have emerged as the accessory therapeutic agents for multiple human cancers, since they can block the activity of specific HDACs, restore the expression of some tumor suppressor genes and induce cell differentiation, growth arrest and apoptosis. To date, the precise mechanisms by which HDAC inhibitors induce cell death have not yet been fully elucidated and the roles of individual HDAC inhibitors have not been identified. Moreover, the practical uses of HDAC inhibitors in cancer therapy, as well as their synergistic effects with other therapeutic strategies are yet to be evaluated. In this review article, we discuss briefly the recent advances in studies of the developments of anti-cancer HDAC inhibitors and their potential clinical value.
基金supported by the National Natural Science Foundation of China(81870149,82070115,81770198,81700184,81570164,81861148029,81700183,81421002,81890990,81730006)National Key Research and Development Program of China(2019YFA0110803,2019YFA0110204,2016YFA0100600,2017YFA0103400)+4 种基金CAMS Innovation Fund for Medical Sciences(CIFMS)(2017-I2M-B&R-04,2019-I2M-1-006,2017-I2M-1-015,2016-I2M-1-017,2017-I2M-2-001)Ministry of Science and Technology of China(2015CB964902,2015CB964400)Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2018PT31004)CAMS Key Laboratory of Gene Therapy for Blood Diseases(2017PT31047,2018PT31038)American Heart Association(18IPA34170301)。
文摘Genome-edited human induced pluripotent stem cells(iPSCs)hold great promise for therapeutic applications.However,low editing efficiency has hampered the applications of CRISPR-Cas9 technology in creating knockout and homology-directed repair(HDR)-edited iPSC lines,particularly for silent genes.This is partially due to chromatin compaction,inevitably limiting Cas9 access to the target DNA.Among the six HDAC inhibitors we examined,vorinostat,or suberoylanilide hydroxamic acid(SAHA),led to the highest HDR efficiency at both open and closed loci,with acceptable toxicity.HDAC inhibitors equally increased non-homologous end joining(NHEJ)editing efficiencies(~50%)at both open and closed loci,due to the considerable HDAC inhibitor-mediated increase in Cas9 and sgRNA expression.However,we observed more substantial HDR efficiency improvement at closed loci relative to open chromatin(2.8 vs.1.7-fold change).These studies provide a new strategy for HDRediting of silent genes in iPSCs.
基金ACKNOWLEDGEMENTS This work was supported by grants from the National Key Basic Research Program of China （2009CB522402） and the National Natural Science Foundation of China （31170856, U0832009 and 30772046）.
文摘Suberoylanilide hydroxamic acid （SAHA）, as a histone deacetylase （HDAC） inhibitor （HDACi）, was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors （CNIs） to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus （FK506） in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA- and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon （IFN）-y but increased IL-IO expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4＋ T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORyt in these cells. Moreover, SAHA enhances suppressive function of regulatory T （Treg） cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.
文摘Epigenetic mechanisms play an important role in the development and persistence of cancer,and histone deacetylase(HDAC)inhibitors are promising anticancer drugs targeting epigenetic modes.Efficient anticancer drugs for the treatment of castration-resistant prostate cancer(CRPC)are sought,and approved HDAC inhibitors have shown promising results on the one hand and severe drawbacks on the other hand.Hence,ways to break the drug resistance mechanisms of existing HDAC inhibitors as well as the design of new promising HDAC inhibitors which can overcome the disadvantages of the classic HDAC inhibitors are of great importance.In this work,HDAC inhibitors with the potential to become a mainstay for the treatment of CRPC in the future as well as suitable combination treatments of HDAC inhibitors with other anticancer drugs leading to considerable synergistic effects in treated CRPCs are discussed.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82103208,and 82002948)the Guangdong Basic and Applied Basic Research Foundation(Grant Nos.:2022A1515220212,and 2023A1515030115)+1 种基金National Key R&D Program of China(Grant No.:2020YFE0202200)Jinan University National College Students'Innovation and Entrepreneurship Training Program(Program No.:202110559085).
文摘Divisions at the periphery and midzone of mitochondria are two fission signatures that determine the fate of mitochondria and cells.Pharmacological induction of excessively asymmetric mitofissionassociated cell death(MFAD)by switching the scission position from the mitochondrial midzone to the periphery represents a promising strategy for anticancer therapy.By screening a series of paninhibitors,we identified pracinostat,a pan-histone deacetylase(HDAC)inhibitor,as a novel MFAD inducer,that exhibited a significant anticancer effect on colorectal cancer(CRC)in vivo and in vitro.Pracinostat increased the expression of cyclin-dependent kinase 5(CDK5)and induced its acetylation at residue lysine 33,accelerating the formation of complex CDK5/CDK5 regulatory subunit 1 and dynaminrelated protein 1(Drp1)-mediated mitochondrial peripheral fission.CRC cells with high level of CDK5(CDK5-high)displayed midzone mitochondrial division that was associated with oncogenic phenotype,but treatment with pracinostat led to a lethal increase in the already-elevated level of CDK5 in the CRC cells.Mechanistically,pracinostat switched the scission position from the mitochondrial midzone to the periphery by improving the binding of Drp1 from mitochondrial fission factor(MFF)to mitochondrial fission 1 protein(FIS1).Thus,our results revealed the anticancer mechanism of HDACi pracinostat in CRC via activating CDK5-Drp1 signaling to cause selective MFAD of those CDK5-high tumor cells,which implicates a new paradigm to develop potential therapeutic strategies for CRC treatment.
基金supported by grants from the National Natural Science Foundation of China(grants 31501182,81573299 and81730094)the “111 Project” from the Ministry of Education of China to Hongbin Sun+1 种基金the State Administration of Foreign Experts Affairs of China,China(No.111-2-07)Fundamental Research Funds for the Central Universities,China(2632017ZD05)
文摘Artemisinin and its derivatives(ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors(HDACi) were known to be able to promote heme synthesis in erythroid cells. Nevertheless, the effect of HDACi on heme homeostasis in nonerythrocytes remains unknown. We envisioned that the combination of HDACi and artesunate(ARS)might have synergistic antitumor activity through modulating heme synthesis. In vitro studies revealed that combination of ARS and HDACi exerted synergistic tumor inhibition by inducing cell death. Moreover, this combination exhibited more effective antitumor activity than either ARS or HDACi monotherapy in xenograft models without apparent toxicity. Importantly, mechanistic studies revealed that HDACi coordinated with ARS to increase 5-aminolevulinate synthase(ALAS1) expression, and subsequent heme production, leading to enhanced cytotoxicity of ARS. Notably, knocking down ALAS1 significantly blunted the synergistic effect of ARS and HDACi on tumor inhibition, indicating a critical role of ALAS1 upregulation in mediating ARS cytotoxicity. Collectively, our study revealed the mechanism of synergistic antitumor action of ARS and HDACi. This finding indicates that modulation of heme synthesis pathway by the combination based on ARTs and other heme synthesis modulators represents a promising therapeutic approach to solid tumors.
基金supported by the National Natural Science Foundation of China(Nos.81460030 and 81770221)。
文摘Diffuse large B-cell lymphoma(DLBCL) is an aggressive type of non-Hodgkin’s lymphoma. A total of 10%-15% of DLBCL cases are associated with myelocytomatosis viral oncogene homolog(MYC) and/or B-cell lymphoma-2(BCL2) translocation or amplification. BCL2 inhibitors have potent anti-tumor effects in DLBCL;however, resistance can be acquired through up-regulation of alternative anti-apoptotic proteins. The histone deacetylase(HDAC) inhibitor chidamide can induce BIM expression, leading to apoptosis of lymphoma cells with good efficacy in refractory recurrent DLBCL. In this study, the synergistic mechanism of chidamide and venetoclax in DLBCL was determined through in vitro and in vivo models. We found that combination therapy significantly reduced the protein levels of MYC, TP53, and BCL2 in activated apoptotic-related pathways in DLBCL cells by increasing BIM levels and inducing cell apoptosis. Moreover, combination therapy regulated expression of multiple transcriptomes in DLBCL cells, involving apoptosis, cell cycle, phosphorylation, and other biological processes, and significantly inhibited tumor growth in DLBCL-bearing xenograft mice. Taken together, these findings verify the in vivo therapeutic potential of chidamide and venetoclax combination therapy in DLBCL, warranting pre-clinical trials for patients with DLBCL.
基金Supported by a grant of New Key Drug Formulation Grand in the 12th Five-Year Plan of the National Science and Technology Project of China(No.2012zx09303-012)
文摘Histone deacetylase(HDAC) inhibitors, which represent a structurally diverse group of molecules, have emerged as a novel therapeutic class of molecules with significant anticancer potential. Vorinostat and romidepsin, known as the first generation of HDAC inhibitors, were approved in the United States for the treatment of T-cell lymphomas. Preliminary activity of HDAC inhibitors has also been observed in non-small cell lung cancer(NSCLC) in combination with the existing treatment regimens, of which is the focus of the current review.
基金Supported by the National Major Scientific and Technological Special Project of China(No.2011ZX09501-001)
文摘Histone deacetylases（HDACs） are considered to be among the most promising targets for the development of anti-cancer drugs,and HDAC inhibitors（HDACIs） have become a promising class of anti-cancer drugs.To explore whether thioacetyl group as the zinc binding group（ZBG） and a slight change in the hydrophobicity of the recognition domain of HDACIs could alter their activities,we synthesized a series of cyclo[-L-Am7（SAc）-Aib-L-Phe（n-Cl）D-Pro-] and evaluated their HDAC-inhibitory and antiproliferative activities.The results show that these peptides could inhibit HDAC at 10-9 mol/L level,and could selectively inhibit the proliferation of three human cancer cell lines with IC 50 at 10-6 mol/L level.Docking study was conducted to examine the mechanisms by which these peptides interact with HDAC2.It appeared that a zinc ion in the active site of HDAC was coordinated by the carbonyl oxygen atom of the ZBG in the inhibitor.Both the ZBG domain of all the peptides and the surface recognition domain of cyclo[-L-Am7（SAc）-Aib-L-Phe（o-Cl）-D-Pro-] and that of cyclo[-L-Am7（SAc）-Aib-L-Phe（m-Cl）-D-Pro-] interacted with HDAC2 via hydrogen bonding.Hydrophobic interaction has been considered to provide favorable contributions to stabilizing the complexes,and the introduction of a chlorine atom at the aromatic ring on the L-Phe position of these peptides affected the interaction between each of these inhibitors and the enzyme,resulting in slight change in the structure of the surface recognition domain of the peptides.
基金supported in part by grants from Chinese National Major Project for New Drug Innovation(2012ZX09303012-001)
文摘Objective： This phase I study was to evaluate safety, maximum tolerated dose, pharmacokinetics and preliminary antitumor activity of chidamide, a novel subtype-selective histone deacetylase （HDAC） inhibitor, in combination with paclitaxel and carboplatin in patients with advanced non-small cell lung cancer （NSCLC）. Methods： Ten patients received oral chidamide 20, 25, or 30 mg twice per week continuously with paclitaxel （175 mg/m2） and carboplatin [area under the curve （AUC） 5 mg/mL/min] administered in a 3-week cycle. Patients with response and stable disease after four cycles maintained chidamide monotherapy until disease progression or unacceptable toxicity. Blood samples were collected for pharmacoldnetic analysis after the first single oral of chidamide and first combination treatment in cycle 1 from all patients. Results： Two dose-limiting toxicities were recorded in the 30 mg cohort, including thrombocytopenia and prolonged neutropenia in the first cycle. Grade 3/4 neutropenia in any cycle was observed in all patients, but was not associated with significant complications. Other grade 3/4 hematologic toxicities included thrombocytopenia and leucopenia. No significant changes were observed in pharmacokinetic parameters for both chidamide and paclitaxel. One patient in the 20 mg cohort had confirmed partial response （PR）. Two out of 5 patients with brain metastases had intracranial complete remission after 4-cycle treatment. Conclusions： Chidamide combined with paclitaxel and carboplatin was generally tolerated without unanticipated toxicities or clinically relevant pharmacokinetic interactions. The recommended dose for chidamide in this combination was established at 20 mg, and a phase II trial is ongoing with this regimen in patients with advanced NSCLC.
文摘Epigenetic mechanisms,such as DNA methylation and histone modifications(e.g.,acetylation and deacetylation),are strongly implicated in the carcinogenesis of various malignancies.During transcription,the expression and functionality of coding gene products are altered following the histone acetylation and deacetylation.These processes are regulated by histone acetyltransferases(HATs)and histone deacetylases(HDACs),respectively.HDAC inhibitors(HDACis)have been developed as promising therapeutic agents,to limit exposure to traditional and toxic chemotherapies and offer more alternatives for some specific malignant diseases with limited options.Mechanistically,these agents affect many intracellular pathways,including cell cycle arrest,apoptosis and differentiation,and their mechanism of action mainly depends on the type of cancer.Currently,five HDACis have been approved for the treatment of several hematological malignancies(e.g.,T-cell lymphoma subtypes and multiple myeloma);while,many of them are tested for further therapeutic indications in solid tumors(e.g.,colorectal,thyroid,breast,lung and pancreatic cancer).Herein,we review the literature and gather all available evidence,from in vitro and in vivo data to clinical trial results,that recognizes the antitumor activity of HDACis on pheochromocytomas and paragangliomas;and supports their clinical implementation in the treatment of these rare neuroendocrine tumors at metastatic setting.
