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mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling
Zhang, HY (Zhang, Huiyuan); Dou, J (Dou, Jun); Yu, Y (Yu, Yang); Zhao, YL (Zhao, Yanling); Fan, YH (Fan, Yihui); Cheng, J (Cheng, Jin); Xu, X (Xu, Xin); Liu, W (Liu, Wei); Guan, S (Guan, Shan); Chen, ZH (Chen, Zhenghu); Shi, Y (Shi, Yan); Patel, R (Patel, Roma); Vasudevan, SA (Vasudevan, Sanjeev A.); Zage, PE (Zage, Peter E.); Zhang, H (Zhang, Hong); Nuchtern, JG (Nuchtern, Jed G.); Kim, ES (Kim, Eugene S.); Fu, SB (Fu, Songbin); Yang, JH (Yang, Jianhua)
2015
Source PublicationAPOPTOSIS
ISSN1360-8185
Volume20Issue:1Pages:50-62
Abstract

High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Dox therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.

KeywordNeuroblastoma Mtor Inhibitor Ink128 Chemotherapy Drug Resistance
DOI10.1007/s10495-014-1066-0
Indexed BySCI
WOS IDWOS:000347528900005
Citation statistics
Cited Times:29[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.xjipc.cas.cn/handle/365002/4215
Collection省部共建新疆特有药用资源利用重点实验室
AffiliationHarbin Med Univ, Labratory Med Genet, Harbin 150081, Heilongjiang, Peoples R China;Baylor Coll Med, Dan L Duncan Canc Ctr, Dept Pediat, Texas Childrens Canc Ctr, Houston, TX 77030 USA;Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA;Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Xinjiang Key Lab Plant Resources & Nat Prod Chem, Urumqi 830011, Xinjiang, Peoples R China;Baylor Coll Med, Dan L Duncan Canc Ctr, Michael E DeBakey Dept Surg, Div Pediat Surg, Houston, TX 77030 USA
Recommended Citation
GB/T 7714
Zhang, HY ,Dou, J ,Yu, Y ,et al. mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling[J]. APOPTOSIS,2015,20(1):50-62.
APA Zhang, HY .,Dou, J .,Yu, Y .,Zhao, YL .,Fan, YH .,...&Yang, JH .(2015).mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling.APOPTOSIS,20(1),50-62.
MLA Zhang, HY ,et al."mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling".APOPTOSIS 20.1(2015):50-62.
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