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Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma.

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.
AuthorsXiaobo Cao, Charles Rodarte, Lidong Zhang, Clinton D Morgan, James Littlejohn, W Roy Smythe
JournalCancer biology & therapy (Cancer Biol Ther) Vol. 6 Issue 2 Pg. 246-52 (Feb 2007) ISSN: 1538-4047 [Print] United States
PMID17224645 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • BCL2L1 protein, human
  • bcl-X Protein
  • Antimycin A
Topics
  • Antimycin A (analogs & derivatives, pharmacology, therapeutic use)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology, therapeutic use)
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Genes, bcl-2 (drug effects)
  • Humans
  • In Vitro Techniques
  • Mesothelioma (drug therapy)
  • Pleural Neoplasms (drug therapy)
  • bcl-X Protein (drug effects)

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