MTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling

Huiyuan Zhang; Jun Dou; Yang Yu; Yanling Zhao; Yihui Fan; Jin Cheng; Xin Xu; Wei Liu; Shan Guan; Zhenghu Chen; Yan Shi; Roma Patel; Sanjeev A. Vasudevan; Peter Zage; Hong Zhang; Jed G. Nuchtern; Eugene S. Kim; Songbin Fu; Jianhua Yang

doi:10.1007/s10495-014-1066-0

MTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling

Huiyuan Zhang, Jun Dou, Yang Yu, Yanling Zhao, Yihui Fan, Jin Cheng, Xin Xu, Wei Liu, Shan Guan, Zhenghu Chen, Yan Shi, Roma Patel, Sanjeev A. Vasudevan, Peter Zage, Hong Zhang, Jed G. Nuchtern, Eugene S. Kim, Songbin Fu, Jianhua Yang

Research output: Contribution to journal › Article › peer-review

50 Scopus citations

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.

Original language	English (US)
Pages (from-to)	50-62
Number of pages	13
Journal	Apoptosis
Volume	20
Issue number	1
DOIs	https://doi.org/10.1007/s10495-014-1066-0
State	Published - Jan 2015

Keywords

Chemotherapy
Drug resistance
INK128
Neuroblastoma
mTOR inhibitor

ASJC Scopus subject areas

Pharmacology
Pharmaceutical Science
Clinical Biochemistry
Cell Biology
Biochemistry, medical
Cancer Research

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Zhang, H., Dou, J., Yu, Y., Zhao, Y., Fan, Y., Cheng, J., Xu, X., Liu, W., Guan, S., Chen, Z., Shi, Y., Patel, R., Vasudevan, S. A., Zage, P., Zhang, H., Nuchtern, J. G., Kim, E. S., Fu, S., & Yang, J. (2015). MTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling. Apoptosis, 20(1), 50-62. https://doi.org/10.1007/s10495-014-1066-0

@article{863f7560a1a7423bba41ec5401f48558,

title = "MTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling",

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.",

keywords = "Chemotherapy, Drug resistance, INK128, Neuroblastoma, mTOR inhibitor",

author = "Huiyuan Zhang and Jun Dou and Yang Yu and Yanling Zhao and Yihui Fan and Jin Cheng and Xin Xu and Wei Liu and Shan Guan and Zhenghu Chen and Yan Shi and Roma Patel and Vasudevan, {Sanjeev A.} and Peter Zage and Hong Zhang and Nuchtern, {Jed G.} and Kim, {Eugene S.} and Songbin Fu and Jianhua Yang",

note = "Funding Information: We appreciate Dr. Andrew Davidoff (St. Judes{\textquoteright}s Children{\textquoteright}s Research Hospital, Memphis, TN, USA) and Dr. Robert Seeger (Children{\textquoteright}s Hospital of Los Angeles, Los Angeles, CA, USA) for providing the neuroblastoma cell lines described in this paper. This work was supported by the NIH/NINDS grants 1R01NS072420 (J.Y.) and 1R21NS085467 (J.Y.). Jin Cheng is a recipient of China Scholarship Council training grant. Publisher Copyright: {\textcopyright} 2014 Springer Science+Business Media New York.",

year = "2015",

month = jan,

doi = "10.1007/s10495-014-1066-0",

language = "English (US)",

volume = "20",

pages = "50--62",

journal = "Apoptosis",

issn = "1360-8185",

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T1 - MTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling

AU - Zhang, Huiyuan

AU - Dou, Jun

AU - Yu, Yang

AU - Zhao, Yanling

AU - Fan, Yihui

AU - Cheng, Jin

AU - Xu, Xin

AU - Liu, Wei

AU - Guan, Shan

AU - Chen, Zhenghu

AU - Shi, Yan

AU - Patel, Roma

AU - Vasudevan, Sanjeev A.

AU - Zage, Peter

AU - Zhang, Hong

AU - Nuchtern, Jed G.

AU - Kim, Eugene S.

AU - Fu, Songbin

AU - Yang, Jianhua

N1 - Funding Information: We appreciate Dr. Andrew Davidoff (St. Judes’s Children’s Research Hospital, Memphis, TN, USA) and Dr. Robert Seeger (Children’s Hospital of Los Angeles, Los Angeles, CA, USA) for providing the neuroblastoma cell lines described in this paper. This work was supported by the NIH/NINDS grants 1R01NS072420 (J.Y.) and 1R21NS085467 (J.Y.). Jin Cheng is a recipient of China Scholarship Council training grant. Publisher Copyright: © 2014 Springer Science+Business Media New York.

PY - 2015/1

Y1 - 2015/1

N2 - 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.

AB - 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.

KW - Chemotherapy

KW - Drug resistance

KW - INK128

KW - Neuroblastoma

KW - mTOR inhibitor

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AN - SCOPUS:84922104229

SN - 1360-8185

VL - 20

SP - 50

EP - 62

JO - Apoptosis

JF - Apoptosis

IS - 1

ER -

MTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling

Abstract

Keywords

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