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 language | English (US) |
|---|---|
| Pages (from-to) | 246-252 |
| Number of pages | 7 |
| Journal | Cancer Biology and Therapy |
| Volume | 6 |
| Issue number | 2 |
| State | Published - Feb 2007 |
| Externally published | Yes |
Fingerprint
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
Cite this
Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma. / Cao, Xiaobo; Rodarte, Charles; Zhang, Lidong; Morgan, Clinton D.; Littlejohn, James E; Smythe, W. Roy.
In: Cancer Biology and Therapy, Vol. 6, No. 2, 02.2007, p. 246-252.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Bcl2/bcl-xL inhibitor engenders apoptosis and increases chemosensitivity in mesothelioma
AU - Cao, Xiaobo
AU - Rodarte, Charles
AU - Zhang, Lidong
AU - Morgan, Clinton D.
AU - Littlejohn, James E
AU - Smythe, W. Roy
PY - 2007/2
Y1 - 2007/2
N2 - 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.
AB - 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.
KW - 2-methoxy antimycin A3
KW - Animal model
KW - Apoptosis
KW - Bcl-x
KW - BH3 peptide
KW - Chemotherapy
KW - Mesothelioma
KW - Mitochondrial membrane potential
KW - Small-molecule inhibitor
KW - Synergy
UR - http://www.scopus.com/inward/record.url?scp=34247336873&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34247336873&partnerID=8YFLogxK
M3 - Article
C2 - 17224645
AN - SCOPUS:34247336873
VL - 6
SP - 246
EP - 252
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
SN - 1538-4047
IS - 2
ER -