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1.
Int J Mol Sci ; 24(6)2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36982651

RESUMO

In contrast to class I/IIb/pan histone deacetylase inhibitors (HDACi), the role of class IIa HDACi as anti-cancer chemosensitizing agents is less well understood. Here, we studied the effects of HDAC4 in particular and the class IIa HDACi CHDI0039 on proliferation and chemosensitivity in Cal27 and cisplatin-resistant Cal27CisR head and neck squamous cell cancer (HNSCC). HDAC4 and HDAC5 overexpression clones were generated. HDAC4 overexpression (Cal27_HDAC4) increased proliferation significantly compared to vector control cells (Cal27_VC). Chicken chorioallantoic membrane (CAM) studies confirmed the in vitro results: Cal27_HDAC4 tumors were slightly larger than tumors from Cal27_VC, and treatment with CHDI0039 resulted in a significant decrease in tumor size and weight of Cal27_HDAC4 but not Cal27_VC. Unlike class I/pan-HDACi, treatment with CHDI0039 had only a marginal impact on cisplatin cytotoxicity irrespective of HDAC4 and HDAC5 expression. In contrast, the combination of CHDI0039 with bortezomib was synergistic (Chou-Talalay) in MTT and caspase 3/7 activation experiments. RNAseq indicated that treatment with CHDI0039 alters the expression of genes whose up- or downregulation is associated with increased survival in HNSCC patients according to Kaplan-Meier data. We conclude that the combination of class IIa HDACi with proteasome inhibitors constitutes an effective treatment option for HNSCC, particularly for platinum-resistant cancers.


Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Humanos , Inibidores de Histona Desacetilases/farmacologia , Bortezomib/farmacologia , Cisplatino , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética
2.
Eur J Med Chem ; 211: 113095, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33360560

RESUMO

Targeting epigenetic dysregulation has emerged as a valuable therapeutic strategy in cancer treatment. Especially epigenetic combination therapy of histone deacetylase inhibitors (HDACi) with established anti-cancer drugs has provided promising results in preclinical and clinical studies. The structural optimization of alkoxyamide-based class I/IIb inhibitors afforded improved analogs with potent efficacy in cisplatin-resistant head and neck carcinoma cells and bortezomib-resistant leukemia cells. The most promising HDACi showed a superior synergistic cytotoxic activity as compared to vorinostat and class I HDACi in combination with cisplatin, leading to a full reversal of the chemoresistant phenotype in head and neck cancer cell lines, as well in combination with the proteasome inhibitors (bortezomib and carfilzomib) in a panel of leukemic cell lines. Furthermore, the most valuable alkoxyamide-based HDACi exhibited strong ex vivo anticancer efficacy against primary patient samples obtained from different therapy-resistant leukemic entities.


Assuntos
Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Epigenômica/métodos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Leucemia/tratamento farmacológico , Antineoplásicos/farmacologia , Sinergismo Farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Inibidores de Histona Desacetilases/farmacologia , Humanos , Leucemia/patologia
3.
Bioorg Med Chem ; 28(1): 115108, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31787463

RESUMO

Although histone deacetylase inhibitors (HDACi) have shown promising antitumor effects in specific types of blood cancer, their effects on solid tumors are limited. Previously, we developed LMK235 (5), a class I and class IIb preferential HDACi with chemosensitizing effects on breast cancer, ovarian cancer and HNSCC. Based on its promising effects on solid tumor cells, we modified the cap group of 5 to improve its anticancer activity. The tri- and dimethoxy-phenyl substituted compounds 13a and 13d turned out to be the most potent HDAC inhibitors of this study. The isoform profiling revealed a dual HDAC2/HDAC6 inhibition profile, which was confirmed by the acetylation of α-tubulin and histone H3 in Cal27 and Cal27CisR. In combination with cisplatin, both compounds enhanced the cisplatin-induced cytotoxicity via caspase-3/7 activation. The effect was more pronounced in the cisplatin resistant subline Cal27CisR. The pretreatment with 13d resulted in a complete resensitisation of Cal27CisR with IC50 values in the range of the parental cell line. Therefore, 13d may serve as an epigenetic tool to analyze and modulate the cisplatin resistance of solid tumors.


Assuntos
Amidas/farmacologia , Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Amidas/síntese química , Amidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
4.
Bioorg Med Chem ; 27(22): 115087, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31561937

RESUMO

Epigenetic control plays an important role in gene regulation through chemical modifications of DNA and post-translational modifications of histones. An essential post-translational modification is the histone acetylation/deacetylation-process which is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The mammalian zinc dependent HDAC family is subdivided into three classes: class I (HDACs 1-3, 8), class II (IIa: HDACs 4, 5, 7, 9; IIb: HDACs 6, 10) and class IV (HDAC 11). In this review, recent studies on the biological role and regulation of class IIa HDACs as well as their contribution in neurodegenerative diseases, immune disorders and cancer will be presented. Furthermore, the development, synthesis, and future perspectives of selective class IIa inhibitors will be highlighted.


Assuntos
Epigenômica/métodos , Histona Desacetilases/metabolismo , Humanos
5.
Bioorg Med Chem ; 27(19): 115036, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31431326

RESUMO

A series of α,ß-unsaturated hydroxamic acid derivatives as novel HDAC inhibitors (HDACi) with structural modifications of the connecting unit and the CAP group was synthesized. The in vitro evaluation against the human cancer cell lines A2780 and Cal27 identified 6e and 7j as the most potent compounds regarding HDAC inhibitory activity and inhibition of proliferation. Isoform profiling against HDAC2, 4, 6 and 8 revealed a preference for HDAC2 and 6 for both compounds in contrast to the pan HDACi panobinostat. 6e and 7j enhanced significantly cisplatin-induced cytotoxicity in a combination treatment mediated by increased apoptosis induction and caspase-3/7 activation. The interaction between 6e or 7j and cisplatin was highly synergistic and more pronounced for the cisplatin resistant subline Cal27CisR. IC50 values of cisplatin were even lower in Cal27CisR pretreated with 6e or 7j than for the parental cell line Cal27. Based on our findings, the novel dual class I/HDAC6 inhibitors could serve as an option to overcome cisplatin resistance with fewer side effects in comparison to panobinostat.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Inibidores de Histona Desacetilases/síntese química , Humanos , Ácidos Hidroxâmicos/síntese química , Panobinostat/farmacologia , Vorinostat/farmacologia
6.
Int J Mol Sci ; 20(12)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234549

RESUMO

High grade serous ovarian cancer (HGSOC) is the most common and aggressive ovarian cancer subtype with the worst clinical outcome due to intrinsic or acquired drug resistance. Standard treatment involves platinum compounds. Cancer development and chemoresistance is often associated with an increase in histone deacetylase (HDAC) activity. The purpose of this study was to examine the potential of HDAC inhibitors (HDACi) to increase platinum potency in HGSOC. Four HGSOC cell lines with different cisplatin sensitivity were treated with combinations of cisplatin and entinostat (class I HDACi), panobinostat (pan-HDACi), or nexturastat A (class IIb HDACi), respectively. Inhibition of class I HDACs by entinostat turned out superior in increasing cisplatin potency than pan-HDAC inhibition in cell viability assays (MTT), apoptosis induction (subG1), and caspase 3/7 activation. Entinostat was synergistic with cisplatin in all cell lines in MTT and caspase activation assays. MTT assays gave combination indices (CI values) < 0.9 indicating synergism. The effect of HDAC inhibitors could be attributed to the upregulation of pro-apoptotic genes (CDNK1A, APAF1, PUMA, BAK1) and downregulation of survivin. In conclusion, the combination of entinostat and cisplatin is synergistic in HGSOC and could be an effective strategy for the treatment of aggressive ovarian cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , Cistadenocarcinoma Seroso/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular , Cistadenocarcinoma Seroso/enzimologia , Cistadenocarcinoma Seroso/fisiopatologia , Sinergismo Farmacológico , Feminino , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/fisiopatologia , Panobinostat/farmacologia , Panobinostat/uso terapêutico , Compostos de Fenilureia/farmacologia , Compostos de Fenilureia/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico
7.
J Mol Cell Biol ; 10(1): 33-47, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28992066

RESUMO

Transcription factor TFIIA is controlled by complex regulatory networks including proteolysis by the protease Taspase 1, though the full impact of cleavage remains elusive. Here, we demonstrate that in contrast to the general assumption, de novo produced TFIIA is rapidly confined to the cytoplasm via an evolutionary conserved nuclear export signal (NES, amino acids 21VINDVRDIFL30), interacting with the nuclear export receptor Exportin-1/chromosomal region maintenance 1 (Crm1). Chemical export inhibition or genetic inactivation of the NES not only promotes TFIIA's nuclear localization but also affects its transcriptional activity. Notably, Taspase 1 processing promotes TFIIA's nuclear accumulation by NES masking, and modulates its transcriptional activity. Moreover, TFIIA complex formation with the TATA box binding protein (TBP) is cooperatively enhanced by inhibition of proteolysis and nuclear export, leading to an increase of the cell cycle inhibitor p16INK, which is counteracted by prevention of TBP binding. We here identified a novel mechanism how proteolysis and nuclear transport cooperatively fine-tune transcriptional programs.


Assuntos
Núcleo Celular/metabolismo , Endopeptidases/metabolismo , Carioferinas/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Transcrição TFIIA/metabolismo , Transporte Ativo do Núcleo Celular , Linhagem Celular , Células HeLa , Humanos , Modelos Moleculares , Sinais de Exportação Nuclear , Conformação Proteica , Fator de Transcrição TFIIA/análise , Fator de Transcrição TFIIA/genética , Ativação Transcricional , Proteína Exportina 1
8.
Biol Chem ; 396(4): 367-76, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25720119

RESUMO

Proteases are key regulators of life. Human Threonine Aspartase1 processes substrates, such as the mixed-lineage leukemia (MLL) protein, containing two cleavage sites, CS1 and CS2. Likewise, MLL's Drosophila ortholog trithorax is cleaved by Drosophila Threonine Aspartase1 (dTasp), suggesting a mechanistic coevolution. However, a detailed analysis of dTasp's function was missing so far. Here, active and inactive dTasp mutants allowed to compare substrate recognition and cleavage site selectivity of human and Drosophila enzymes. In contrast to the human protease, our cell-based assay revealed a preferential processing of CS2-like (QLD↓Gx[xD/Dx]) targets for dTasp, whereas cleavage of CS1-like targets (QVD↓Gx[xD/Dx]) was significantly impaired. Systematic mutagenesis of the CS2 sequence defined the motif x[FILMW]D↓Gx[xD/Dx] as the consensus cleavage sequence for dTasp. Substrate species selectivity of the enzymes was uncovered by demonstrating that dTasp cleaves Drosophila TFIIA, but not the human ortholog, suggesting evolutionary divergence of TFIIA downstream networks. Also, Drosophila USF2 was neither predicted nor cleaved by dTasp. Moreover, we found that dTasp cleavage site selectivity is independent of heterocomplex formation, as dTasp exists predominantly as an αß-monomer. Collectively, we provide novel insights into evolutionary similarities and divergence concerning Threonine Aspartase1 function in different species, which may aid to dissect and better target human Threonine Aspartase1 in malignancies.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/enzimologia , Endopeptidases/metabolismo , Sequência de Aminoácidos , Animais , Drosophila/química , Drosophila/metabolismo , Proteínas de Drosophila/química , Endopeptidases/química , Células HeLa , Humanos , Dados de Sequência Molecular , Multimerização Proteica , Especificidade da Espécie , Especificidade por Substrato , Fator de Transcrição TFIIA/metabolismo , Fatores Estimuladores Upstream/metabolismo
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