RESUMO
BACKGROUND: Histone deacetylase inhibitors (HDACi) are used to treat patients with cutaneous T-cell lymphoma (CTCL), but they show limited efficacy. Hence, combination therapies should be explored to enhance the effectiveness of HDACis. OBJECTIVE: This study was conducted to identify novel therapeutic targets that can be combined with HDACis for treating CTCL. METHODS: We performed a global kinome profiling assay of three CTCL cell lines (HH, MJ, and Hut78) with three HDACis (romidepsin, vorinostat, and belinostat) using the PamChip® microarray. The three cell lines were co-treated with romidepsin and an inhibitor against the tyrosine kinase pathway. RESULTS: Principal component analysis revealed that kinome expression patterns were mainly related to the cell origin and were not affected by the drugs. Few kinases were commonly activated by the HDACis. Most identified kinases were Src-associated molecules, such as annexin A2, embryonal Fyn-associated substrate, and progesterone receptor. Phosphorylated Src was not observed in any untreated cell lines, whereas Src phosphorylation was detected in two of the three cell lines after HDACi treatment. Ponatinib, a Src inhibitor, significantly enhanced romidepsin-induced apoptosis not only in HH, MJ, and Hut78 cells, but also in Myla and SeAx CTCL cell lines. CONCLUSION: The Src pathway is a possible target for combination therapy involving HDACis for CTCL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Depsipeptídeos/farmacologia , Depsipeptídeos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Linfoma Cutâneo de Células T/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Neoplasias Cutâneas/patologia , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Vorinostat/farmacologia , Vorinostat/uso terapêutico , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismoAssuntos
Linfócitos do Interstício Tumoral/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Reguladores/imunologia , Idoso , Biópsia , Contagem de Linfócito CD4 , Fatores de Transcrição Forkhead/metabolismo , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/radioterapia , Masculino , Receptor de Morte Celular Programada 1/metabolismo , Remissão Espontânea , Pele/imunologia , Pele/patologia , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/radioterapia , Linfócitos T Reguladores/metabolismoAssuntos
Anticorpos Antivirais/sangue , Portador Sadio/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Síndrome de Sézary/diagnóstico , Idoso de 80 Anos ou mais , Anticorpos Antivirais/imunologia , Biópsia , Portador Sadio/sangue , Portador Sadio/virologia , Diagnóstico Diferencial , Humanos , Leucemia-Linfoma de Células T do Adulto/diagnóstico , Masculino , Síndrome de Sézary/imunologia , Síndrome de Sézary/patologia , Síndrome de Sézary/virologia , Pele/imunologia , Pele/patologiaRESUMO
BACKGROUND: The anticancer effects of histone deacetylase inhibitors (HDACi) vary between patients, and their molecular mechanisms remain poorly understood. Previously, we have identified heat shock 70â¯kDa protein 1A (HSPA1A, also known as HSP72) as the most overexpressed protein in valproic acid (VPA)-resistant cell lines. KNK437, an inhibitor of heat shock proteins, enhanced the cytotoxic effects of not only VPA but also vorinostat, another HDACi. However, the mechanisms underlying the role of HSP72 in resistance against HDACi remain largely unknown. OBJECTIVE: The purpose of this study was to identify the mechanisms underlying the role of HSP72 in HDACi resistance. METHODS: We established an HSP72-overexpressing Jurkat cell line and used it to assess the functional role of HSP72 following treatment with the HDACi vorinostat and VPA. RESULTS: HDACi-induced apoptosis, assessed using annexin V assays, sub-G1 fraction analysis, and PARP cleavage, was significantly lower in HSP72-overexpressing cells than in control cells. The HDACi-induced upregulation in caspase-3, -8, and -9 activity, as well as the HDACi-induced reduction in mitochondrial membrane potential, were also suppressed following HSP72 overexpression. The basal expression levels of Bcl-2, phosphorylated Bad, and XIAP increased in HSP72-overexpressing cells, whereas HDACi-induced Bid truncation and the suppression of Bad expression. Furthermore, vorinostat-induced histone hyperacetylation was also diminished in HSP72-overexpressing cells. CONCLUSION: These findings clearly demonstrate that HSP72 inhibits HDACi-induced apoptosis.