Cancer, Biology and Therapy. 2007 Feb 26;6(2) [Epub ahead of print] [Link]
Cao X, Rodarte C, Zhang L, Morgan CD, Littlejohn J, Smythe WR.
Section of Surgery Research, Department of Surgery, Scott & White Memorial Hospital and Clinic, Scott, Sherwood and Brindley Foundation, The Texas A&M University System, Health Science Center, College of Medicine, Temple, Texas, USA.
Meosthelioma [sic] 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.