Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma.
Cancer Biol Ther
; 6(2): 246-52, 2007 Feb.
Article
em En
| MEDLINE
| ID: mdl-17224645
ABSTRACT
Mesothelioma is a neoplasm of the pleura that is currently incurable by conventional therapies. Previously, we demonstrated that mesothelioma overexpresses BCL-X(L), an anti-apoptotic member of the BCL-2 family. In addition, we have shown that down regulation of BCL-X(L) using a BCL-X(L) antisense oligonucleotide engenders mesothelioma apoptotic cell death in vitro and in vivo. The purpose of this study is to evaluate the efficacy of bcl2/bcl-x(L) inhibitor, 2-methoxy antimycin A3, in inducing apoptosis and increasing chemo-sensitivity in vitro and in vivo. Several bcl-x(L) high-expression tumor cell lines and one normal human cell line were exposed to 2-methoxy antimycin A3. 2-methoxy antimycin A3 demonstrated significant growth inhibition only in these tumor cell lines, with little effect on normal human cells. Treatment with 2-methoxy antimycin A3 alone resulted in a dramatic increase in the induction of apoptosis in the cancer cells. Apoptosis occurs through decreasing mitochondrial membrane potential and caspase activation. Notably, treatment with 2-methoxy antimycin A3 does not alter BCL-2 family protein expression. Synergistic inhibition of tumor growth by the coadministration of cisplatin and 2-methoxy antimycin A3 was observed in both in vitro and in vivo experiments. Together, these findings indicate that exposure of cancer cells to small molecule Bcl-2/x(L) inhibitors such as 2-methoxy antimycin A3 alone, or in the combination with other chemotherapeutics, may represent a novel therapeutic strategy in treatment of cancer, especially mesothelioma.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Pleurais
/
Protocolos de Quimioterapia Combinada Antineoplásica
/
Genes bcl-2
/
Proteína bcl-X
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Mesotelioma
/
Antimicina A
Limite:
Humans
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article