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

Xiaobo Cao, Charles Rodarte, Lidong Zhang, Clinton D. Morgan, James E Littlejohn, W. Roy Smythe

Research output: Contribution to journalArticle

33 Scopus citations

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 languageEnglish (US)
Pages (from-to)246-252
Number of pages7
JournalCancer Biology and Therapy
Volume6
Issue number2
StatePublished - Feb 2007
Externally publishedYes

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

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  • Cite this

    Cao, X., Rodarte, C., Zhang, L., Morgan, C. D., Littlejohn, J. E., & Smythe, W. R. (2007). Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma. Cancer Biology and Therapy, 6(2), 246-252.