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Research Paper
Bcl2/bcl-xl Inhibitor Engenders Apoptosis and Increases Chemo-sensitivity In Mesothelioma
Xiaobo Cao, Charles Rodarts, Lidong Zhang, Clinton D. Morgan, James Littlejohn and W. Roy Smythe
volume 6 | issue 2
February 2007Pages: 246 - 252
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Meosthelioma is a neoplasm of the pleura that is currently incurable by conventional therapies. Previously, we demonstrated that mesothelioma overexpresses BCL-XL, an anti-apoptotic member of the BCL-2 family. In addition, we have shown that down-regulation of BCL-XL using a BCL-XL 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-xl inhibitor, 2-methoxy antimycin A3, in inducing apoptosis and increasing chemo-sensitivity in vitro and in vivo. Several bcl-xl high-expression tumor cell lines and two normal human cell lines 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 co-administration 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/xl 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.
We now provide open access to journal articles published online for one year or more. This article may be downloaded at the following link:
Download PDFIf the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.