RESUMO
We report the development of a potent, selective histone deacetylase 6 (HDAC6) inhibitor. This HDAC6 inhibitor blocks growth of normal and transformed cells but does not induce death of normal cells. The HDAC6 inhibitor alone is as effective as paclitaxel in anticancer activity in tumor-bearing mice.
Assuntos
Antineoplásicos/síntese química , Benzenoacetamidas/química , Benzenoacetamidas/farmacologia , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/genética , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Acetilação/efeitos dos fármacos , Animais , Antineoplásicos/química , Morte Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Desacetilase 6 de Histona , Inibidores de Histona Desacetilases/química , Camundongos , Estrutura Molecular , Paclitaxel , Tubulina (Proteína)/metabolismoRESUMO
Development of isoform-selective histone deacetylase (HDAC) inhibitors is important in elucidating the function of individual HDAC enzymes and their potential as therapeutic agents. Among the eleven zinc-dependent HDACs in humans, HDAC6 is structurally and functionally unique. Here, we show that a hydroxamic acid-based small-molecule N-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB) selectively inhibits HDAC6 catalytic activity in vivo and in vitro. HPOB causes growth inhibition of normal and transformed cells but does not induce cell death. HPOB enhances the effectiveness of DNA-damaging anticancer drugs in transformed cells but not normal cells. HPOB does not block the ubiquitin-binding activity of HDAC6. The HDAC6-selective inhibitor HPOB has therapeutic potential in combination therapy to enhance the potency of anticancer drugs.
Assuntos
Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Acetilação/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Linhagem Celular Transformada/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Doxorrubicina/farmacologia , Etoposídeo/farmacologia , Inibidores de Histona Desacetilases/química , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Camundongos , Trealose/farmacologia , Tubulina (Proteína)/metabolismo , Vorinostat , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Histone deacetylase inhibitors (HDACi) are a new group of anticancer drugs with tumor selective toxicity. Normal cells are relatively resistant to HDACi-induced cell death compared with cancer cells. Previously, we found that vorinostat induces DNA breaks in normal and transformed cells, which normal but not cancer cells can repair. In this study, we found that checkpoint kinase 1 (Chk1), a component of the G2 DNA damage checkpoint, is important in the resistance of normal cells to HDACi in vitro and in vivo. Inhibition of Chk1 activity with Chk1 inhibitor (UCN-01, AZD7762, or CHIR-124) in normal cells increases their sensitivity to HDACi (vorinostat, romidepsin, or entinostat) induced cell death, associated with extensive mitotic disruption. Mitotic abnormalities included loss of sister chromatid cohesion and chromosomal disruption. Inhibition of Chk1 did increase HDACi-induced cell death of transformed cells. Thus, Chk1 is an important factor in the resistance of normal cells, and some transformed cells, to HDACi-induced cell death. Use of Chk1 inhibitors in combination with anticancer agents to treat cancers may be associated with substantial toxicity.