Abstract
Loss of the PTEN tumor suppressor gene and amplification of the epidermal growth factor receptor (EGFR), which is common in malignant gliomas, result in activation of the mammalian target of rapamycin (mTOR). Rapamycin is a highly specific inhibitor of mTOR and induces a cytostatic effect in various glioma cell lines. DNA-damaging agents such as nitrosourea are widely used in malignant glioma treatment; therefore, we investigated the effect of rapamycin on cell growth and death in combination with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine hydrochloride) in human glioma cells. In U251 malignant glioma (U251MG) cells, we confirmed that rapamycin enhanced ACNU-induced apoptosis. We found that rapamysin inhibited ACNU-induced p21 induction, and knocking down of p21 protein by siRNA enhanced ACNU-induced apoptosis in U251MG cells. Furthermore, adenovirus-mediated over-expression of p21 protein rescued U251MG cells from apoptosis induced by ACNU and rapamycin. Finally, treatment of intracerebral U251MG xenografts with a combination of rapamycin and ACNU in vivo resulted in statistically prolonged median survival (P
| Original language | English |
|---|---|
| Pages (from-to) | 233-244 |
| Number of pages | 12 |
| Journal | Journal of Neuro-Oncology |
| Volume | 84 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Sep 2007 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Clinical Neurology
- Cancer Research
- Oncology
- Neuroscience(all)
Cite this
Specific mTOR inhibitor rapamycin enhances cytotoxicity induced by alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in human U251 malignant glioma cells. / Tanaka, Kazuhiro; Sasayama, Takashi; Mizukawa, Katsu; Kawamura, Atsufumi; Kondoh, Takeshi; Hosoda, Kohkichi; Fujiwara, Toshiyoshi; Kohmura, Eiji.
In: Journal of Neuro-Oncology, Vol. 84, No. 3, 09.2007, p. 233-244.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Specific mTOR inhibitor rapamycin enhances cytotoxicity induced by alkylating agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU) in human U251 malignant glioma cells.
AU - Tanaka, Kazuhiro
AU - Sasayama, Takashi
AU - Mizukawa, Katsu
AU - Kawamura, Atsufumi
AU - Kondoh, Takeshi
AU - Hosoda, Kohkichi
AU - Fujiwara, Toshiyoshi
AU - Kohmura, Eiji
PY - 2007/9
Y1 - 2007/9
N2 - Loss of the PTEN tumor suppressor gene and amplification of the epidermal growth factor receptor (EGFR), which is common in malignant gliomas, result in activation of the mammalian target of rapamycin (mTOR). Rapamycin is a highly specific inhibitor of mTOR and induces a cytostatic effect in various glioma cell lines. DNA-damaging agents such as nitrosourea are widely used in malignant glioma treatment; therefore, we investigated the effect of rapamycin on cell growth and death in combination with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine hydrochloride) in human glioma cells. In U251 malignant glioma (U251MG) cells, we confirmed that rapamycin enhanced ACNU-induced apoptosis. We found that rapamysin inhibited ACNU-induced p21 induction, and knocking down of p21 protein by siRNA enhanced ACNU-induced apoptosis in U251MG cells. Furthermore, adenovirus-mediated over-expression of p21 protein rescued U251MG cells from apoptosis induced by ACNU and rapamycin. Finally, treatment of intracerebral U251MG xenografts with a combination of rapamycin and ACNU in vivo resulted in statistically prolonged median survival (P
AB - Loss of the PTEN tumor suppressor gene and amplification of the epidermal growth factor receptor (EGFR), which is common in malignant gliomas, result in activation of the mammalian target of rapamycin (mTOR). Rapamycin is a highly specific inhibitor of mTOR and induces a cytostatic effect in various glioma cell lines. DNA-damaging agents such as nitrosourea are widely used in malignant glioma treatment; therefore, we investigated the effect of rapamycin on cell growth and death in combination with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU, nimustine hydrochloride) in human glioma cells. In U251 malignant glioma (U251MG) cells, we confirmed that rapamycin enhanced ACNU-induced apoptosis. We found that rapamysin inhibited ACNU-induced p21 induction, and knocking down of p21 protein by siRNA enhanced ACNU-induced apoptosis in U251MG cells. Furthermore, adenovirus-mediated over-expression of p21 protein rescued U251MG cells from apoptosis induced by ACNU and rapamycin. Finally, treatment of intracerebral U251MG xenografts with a combination of rapamycin and ACNU in vivo resulted in statistically prolonged median survival (P
UR - http://www.scopus.com/inward/record.url?scp=35448984024&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35448984024&partnerID=8YFLogxK
U2 - 10.1007/s11060-007-9371-x
DO - 10.1007/s11060-007-9371-x
M3 - Article
VL - 84
SP - 233
EP - 244
JO - Journal of Neuro-Oncology
JF - Journal of Neuro-Oncology
SN - 0167-594X
IS - 3
ER -