Abstract
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 downregulation 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 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/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.
Original language | English (US) |
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Pages (from-to) | 246-252 |
Number of pages | 7 |
Journal | Cancer Biology and Therapy |
Volume | 6 |
Issue number | 2 |
State | Published - Feb 2007 |
Externally published | Yes |
Keywords
- 2-methoxy antimycin A3
- Animal model
- Apoptosis
- Bcl-x
- BH3 peptide
- Chemotherapy
- Mesothelioma
- Mitochondrial membrane potential
- Small-molecule inhibitor
- Synergy
ASJC Scopus subject areas
- Cancer Research
- Oncology