9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma

Andrey V. Ugolkov; Gennadiy I. Bondarenko; Oleksii Dubrovskyi; Ana P. Berbegall; Samuel Navarro; Rosa Noguera; Thomas V. O'Halloran; Mary J. Hendrix; Francis J. Giles; Andrew P. Mazar

doi:10.1097/CAD.0000000000000652

9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma

Andrey V. Ugolkov, Gennadiy I. Bondarenko, Oleksii Dubrovskyi, Ana P. Berbegall, Samuel Navarro, Rosa Noguera, Thomas V. O'Halloran, Mary J. Hendrix, Francis J. Giles, Andrew P. Mazar^*

^*Corresponding author for this work

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

27 Scopus citations

Abstract

Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK- 3ß expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.

Original language	English (US)
Pages (from-to)	717-724
Number of pages	8
Journal	Anti-Cancer Drugs
Volume	29
Issue number	8
DOIs	https://doi.org/10.1097/CAD.0000000000000652
State	Published - Sep 1 2018

Funding

This work was supported by generous donations from the Little Heroes Foundation (M.J.H., A.P.M.) and by Cancer Center Support Grant 2 P30 CA060553-19 (A.P. M., A.U.) to the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Keywords

9-ING-41
CPT-11
Chemoresistance
Glycogen synthase kinase-3
Glycogen synthase kinase-3ß
Irinotecan
Neuroblastoma

ASJC Scopus subject areas

Oncology
Pharmacology
Pharmacology (medical)
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1097/CAD.0000000000000652

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@article{198a00bf59164216a1e916ba3d1e796e,

title = "9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma",

abstract = "Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3{\ss} (GSK-3{\ss}) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK- 3{\ss} expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3{\ss} inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.",

keywords = "9-ING-41, CPT-11, Chemoresistance, Glycogen synthase kinase-3, Glycogen synthase kinase-3{\ss}, Irinotecan, Neuroblastoma",

author = "Ugolkov, {Andrey V.} and Bondarenko, {Gennadiy I.} and Oleksii Dubrovskyi and Berbegall, {Ana P.} and Samuel Navarro and Rosa Noguera and O'Halloran, {Thomas V.} and Hendrix, {Mary J.} and Giles, {Francis J.} and Mazar, {Andrew P.}",

note = "Funding Information: This work was supported by generous donations from the Little Heroes Foundation (M.J.H., A.P.M.) and by Cancer Center Support Grant 2 P30 CA060553-19 (A.P. M., A.U.) to the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Publisher Copyright: {\textcopyright} 2018 Wolters Kluwer Health, Inc.",

year = "2018",

month = sep,

day = "1",

doi = "10.1097/CAD.0000000000000652",

language = "English (US)",

volume = "29",

pages = "717--724",

journal = "Anti-Cancer Drugs",

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publisher = "Lippincott Williams and Wilkins",

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T1 - 9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma

AU - Ugolkov, Andrey V.

AU - Bondarenko, Gennadiy I.

AU - Dubrovskyi, Oleksii

AU - Berbegall, Ana P.

AU - Navarro, Samuel

AU - Noguera, Rosa

AU - O'Halloran, Thomas V.

AU - Hendrix, Mary J.

AU - Giles, Francis J.

AU - Mazar, Andrew P.

N1 - Funding Information: This work was supported by generous donations from the Little Heroes Foundation (M.J.H., A.P.M.) and by Cancer Center Support Grant 2 P30 CA060553-19 (A.P. M., A.U.) to the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Publisher Copyright: © 2018 Wolters Kluwer Health, Inc.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK- 3ß expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.

AB - Advanced stage neuroblastoma is a very aggressive pediatric cancer with limited treatment options and a high mortality rate. Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. Using immunohistochemical staining, we observed positive GSK- 3ß expression in 67% of human neuroblastomas (34 of 51 cases). Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. Mouse xenograft studies showed that the combination of clinically relevant doses of CPT-11 and 9-ING-41 led to greater antitumor effect than was observed with either agent alone. These data support the inclusion of patients with advanced neuroblastoma in clinical studies of 9-ING-41, especially in combination with CPT-11.

KW - 9-ING-41

KW - CPT-11

KW - Chemoresistance

KW - Glycogen synthase kinase-3

KW - Glycogen synthase kinase-3ß

KW - Irinotecan

KW - Neuroblastoma

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DO - 10.1097/CAD.0000000000000652

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AN - SCOPUS:85052229794

SN - 0959-4973

VL - 29

SP - 717

EP - 724

JO - Anti-Cancer Drugs

JF - Anti-Cancer Drugs

IS - 8

ER -

9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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