Assuntos
Condrossarcoma/patologia , Neoplasias Renais/patologia , Idoso , Carcinoma de Células Renais/patologia , Carcinossarcoma/patologia , Condroma/patologia , Condrossarcoma/complicações , Condrossarcoma/metabolismo , Condrossarcoma/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Neoplasias Renais/complicações , Neoplasias Renais/metabolismo , Neoplasias Renais/secundário , Neoplasias Renais/cirurgia , Neoplasias Pulmonares/secundário , Nefrectomia , Derrame Pleural Maligno/etiologia , Proteínas S100/metabolismo , Neoplasias de Tecidos Moles/patologia , Vimentina/metabolismoRESUMO
Histone deacetylase (HDAC) inhibitors can induce various transformed cells to undergo growth arrest and/or death. Suberoylanilide hydroxamic acid (SAHA) is an HDAC inhibitor which is in phase I/II clinical trials and has shown antitumor activity in hematologic and solid tumors at doses well tolerated by patients. HDAC is the target for SAHA, but the mechanisms of the consequent induced death of transformed cells are not completely understood. In this study, we report that SAHA induced polyploidy in human colon cancer cell line HCT116 and human breast cancer cell lines, MCF-7, MDA-MB-231, and MBA-MD-468, but not in normal human embryonic fibroblast SW-38 and normal mouse embryonic fibroblasts. The polyploid cells lost the capacity for proliferation and committed to senescence. The induction of polyploidy was more marked in HCT116 p21WAF1-/- or HCT116 p53-/- cells than in wild-type HCT116. The development of senescence of SAHA-induced polyploidy cells was similar in all colon cell lines. The present findings indicate that the HDAC inhibitor could exert antitumor effects by inducing polyploidy, and this effect is more marked in transformed cells with nonfunctioning p21WAF1 or p53 genes.
Assuntos
Antineoplásicos/farmacologia , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacologia , Poliploidia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Processos de Crescimento Celular/efeitos dos fármacos , Processos de Crescimento Celular/genética , Neoplasias do Colo/enzimologia , Replicação do DNA/efeitos dos fármacos , Células HCT116 , Humanos , VorinostatRESUMO
Suberoylanilide hydroxamic acid (SAHA) is a potent inhibitor of histone deacetylases (HDACs) that causes growth arrest, differentiation, and/or apoptosis of many tumor types in vitro and in vivo. SAHA is in clinical trials for the treatment of cancer. HDAC inhibitors induce the expression of less than 2% of genes in cultured cells. In this study we show that SAHA induces the expression of vitamin D-up-regulated protein 1/thioredoxin-binding protein-2 (TBP-2) in transformed cells. As the expression of TBP-2 mRNA is increased, the expression of a second gene, thioredoxin, is decreased. In transient transfection assays, HDAC inhibitors induce TBP-2 promoter constructs, and this induction requires an NF-Y binding site. We report here that TBP-2 expression is reduced in human primary breast and colon tumors compared with adjacent tissue. These results support a model in which the expression of a subset of genes (i.e., including TBP-2) is repressed in transformed cells, leading to a block in differentiation, and culture of transformed cells with SAHA causes re-expression of these genes, leading to induction of growth arrest, differentiation, and/or apoptosis.
