Autoregulated expression of p53 from an adenoviral vector confers superior tumor inhibition in a model of prostate carcinoma gene therapy

Autor(es)

Tamura, Rodrigo Esaki ; da Silva Soares, Rafael Bento ; Costanzi-Strauss, Eugenia ; Strauss, Bryan E.

• Tipo de documento: Artigo Científico
• Fonte: CANCER BIOLOGY & THERAPY; v. 17, n. 12, p. 1221-1230, 2016.
• Citações Web of Science: 5

Resumo

Alternative treatments for cancer using gene therapy approaches have shown promising results and some have even reached the marketplace. Even so, additional improvements are needed, such as employing a strategically chosen promoter to drive expression of the transgene in the target cell. Previously, we described viral vectors where high-level transgene expression was achieved using a p53-responsive promoter. Here we present an adenoviral vector (AdPGp53) where p53 is employed to regulate its own expression and which outperforms a traditional vector when tested in a model of gene therapy for prostate cancer. The functionality of AdPGp53 and AdCMVp53 were compared in human prostate carcinoma cell lines. AdPGp53 conferred greatly enhanced levels of p53 protein and induction of the p53 target gene, p21, as well as superior cell killing by a mechanism consistent with apoptosis. DU145 cells were susceptible to induction of death with AdPGp53, yet PC3 cells were quite resistant. Though AdCMVp53 was shown to be reliable, extremely high-level expression of p53 offered by AdPGp53 was necessary for tumor suppressor activity in PC3 and DU145. In situ gene therapy experiments revealed tumor inhibition and increased overall survival in response to AdPGp53, but not AdCMVp53. Upon histologic examination, only AdPGp53 treatment was correlated with the detection of both p53 and TUNEL-positive cells. This study points to the importance of improved vector performance for gene therapy of prostate cancer. (AU)

• Processo FAPESP: 11/21256-8 - Combinação de agentes quimioterápicos e vetores adenovirais expressando p53 na terapia contra o câncer de próstata
• Beneficiário: Rodrigo Esaki Tamura
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 07/50210-0 - Combinacoes estrategicas entre os promotores virais e transgenes destinadas a terapia genica do cancer.
• Beneficiário: Bryan Eric Strauss
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/25167-5 - Transferência gênica de p19Arf e interferon-beta: delineando a importância de sua combinação em modelos murinos de terapia gênica do câncer
• Beneficiário: Bryan Eric Strauss
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 05/03543-9 - Construção e caracterização do vetor pAdPGp14IRESp53: um vetor de adenovírus bicistrônico que combina ação e regulação gênica
• Beneficiário: Rafael Bento da Silva Soares
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto