Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma.
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.
Cao
Xiaobo
X
Section of Surgery Research, Department of Surgery, Scott & White Memorial Hospital and Clinic, 2401 South 31st Street, Temple, TX 76508, USA.
Rodarte
Charles
C
Zhang
Lidong
L
Morgan
Clinton D
CD
Littlejohn
James
J
Smythe
W Roy
WR
D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D019254:Genes, bcl-2 / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008654:Mesothelioma / Q000188:drug therapy*; D010997:Pleural Neoplasms / Q000188:drug therapy*; D051020:bcl-X Protein / Q000187:drug effects*
C494811:BCL2L1 protein, human; D051020:bcl-X Protein; D000968:Antimycin A