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.