Abstract
EWS-Fli1 plays important roles in oncogenesis of Ewing's family tumors (EFTs). We have reported that EWS-Fli1 inhibits p21waf1/cip1 and p27kip1 expressions, which are degraded by the ubiquitin-proteasome pathway. Bortezomib efficiently up-regulated p21waf1/cip1 and p27kip1 expression, and induced apoptosis accompanied by the expression of cleaved-PARP, DR4 and activated caspase-8 in EFT cells. Since most EFTs deaths result from the tumor being resistant to chemotherapeutic drugs, the effects of novel anti-tumor reagents on drug-resistant tumors were next investigated. The results demonstrated that the drug-resistant EFT clones were cross-resistant to bortezomib probably due to the overexpression of the efflux pumps, P-glycoprotein and MRP1. We further investigated whether the efflux pump inhibitors would modulate the effects of bortezomib. The combination of P-gp-specific or MRP1-specific inhibitors could enhance the anti-tumor effects of bortezomib on the drug-resistant clones. These data suggest that bortezomib might be a substrate of P-gp and MRP1. Although bortezomib would be effective on the primary EFTs, it is necessary to pay attention to the resistance to bortezomib in clinical trials for the advanced cases. The combination of bortezomib and the efflux pump inhibitors might be a promising method as a novel molecular target therapy for advanced EFTs.
| Original language | English |
|---|---|
| Pages (from-to) | 803-811 |
| Number of pages | 9 |
| Journal | International journal of oncology |
| Volume | 31 |
| Issue number | 4 |
| Publication status | Published - Oct 1 2007 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
Cite this
The mechanism of cross-resistance to proteasome inhibitor bortezomib and overcoming resistance in Ewing's family tumor cells. / Nakamura, Tomoyuki; Tanaka, Kazuhiro; Matsunobu, Tomoya; Okada, Takamitsu; Nakatani, Fumihiko; Sakimura, Riku; Hanada, Masuo; Iwamoto, Yukihide.
In: International journal of oncology, Vol. 31, No. 4, 01.10.2007, p. 803-811.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The mechanism of cross-resistance to proteasome inhibitor bortezomib and overcoming resistance in Ewing's family tumor cells
AU - Nakamura, Tomoyuki
AU - Tanaka, Kazuhiro
AU - Matsunobu, Tomoya
AU - Okada, Takamitsu
AU - Nakatani, Fumihiko
AU - Sakimura, Riku
AU - Hanada, Masuo
AU - Iwamoto, Yukihide
PY - 2007/10/1
Y1 - 2007/10/1
N2 - EWS-Fli1 plays important roles in oncogenesis of Ewing's family tumors (EFTs). We have reported that EWS-Fli1 inhibits p21waf1/cip1 and p27kip1 expressions, which are degraded by the ubiquitin-proteasome pathway. Bortezomib efficiently up-regulated p21waf1/cip1 and p27kip1 expression, and induced apoptosis accompanied by the expression of cleaved-PARP, DR4 and activated caspase-8 in EFT cells. Since most EFTs deaths result from the tumor being resistant to chemotherapeutic drugs, the effects of novel anti-tumor reagents on drug-resistant tumors were next investigated. The results demonstrated that the drug-resistant EFT clones were cross-resistant to bortezomib probably due to the overexpression of the efflux pumps, P-glycoprotein and MRP1. We further investigated whether the efflux pump inhibitors would modulate the effects of bortezomib. The combination of P-gp-specific or MRP1-specific inhibitors could enhance the anti-tumor effects of bortezomib on the drug-resistant clones. These data suggest that bortezomib might be a substrate of P-gp and MRP1. Although bortezomib would be effective on the primary EFTs, it is necessary to pay attention to the resistance to bortezomib in clinical trials for the advanced cases. The combination of bortezomib and the efflux pump inhibitors might be a promising method as a novel molecular target therapy for advanced EFTs.
AB - EWS-Fli1 plays important roles in oncogenesis of Ewing's family tumors (EFTs). We have reported that EWS-Fli1 inhibits p21waf1/cip1 and p27kip1 expressions, which are degraded by the ubiquitin-proteasome pathway. Bortezomib efficiently up-regulated p21waf1/cip1 and p27kip1 expression, and induced apoptosis accompanied by the expression of cleaved-PARP, DR4 and activated caspase-8 in EFT cells. Since most EFTs deaths result from the tumor being resistant to chemotherapeutic drugs, the effects of novel anti-tumor reagents on drug-resistant tumors were next investigated. The results demonstrated that the drug-resistant EFT clones were cross-resistant to bortezomib probably due to the overexpression of the efflux pumps, P-glycoprotein and MRP1. We further investigated whether the efflux pump inhibitors would modulate the effects of bortezomib. The combination of P-gp-specific or MRP1-specific inhibitors could enhance the anti-tumor effects of bortezomib on the drug-resistant clones. These data suggest that bortezomib might be a substrate of P-gp and MRP1. Although bortezomib would be effective on the primary EFTs, it is necessary to pay attention to the resistance to bortezomib in clinical trials for the advanced cases. The combination of bortezomib and the efflux pump inhibitors might be a promising method as a novel molecular target therapy for advanced EFTs.
UR - http://www.scopus.com/inward/record.url?scp=35848931009&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=35848931009&partnerID=8YFLogxK
M3 - Article
VL - 31
SP - 803
EP - 811
JO - International Journal of Oncology
JF - International Journal of Oncology
SN - 1019-6439
IS - 4
ER -