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

Meosthelioma 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 downregulation 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.