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 journalArticle

2 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)717-724
Number of pages8
JournalAnti-Cancer Drugs
Volume29
Issue number8
DOIs
StatePublished - Sep 1 2018

Fingerprint

Glycogen Synthase Kinase 3
Neuroblastoma
irinotecan
Heterografts
Pediatrics
Apoptosis
Staining and Labeling
Mortality
Therapeutics
Growth
Neoplasms

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

Cite this

Ugolkov, A. V., Bondarenko, G. I., Dubrovskyi, O., Berbegall, A. P., Navarro, S., Noguera, R., ... Mazar, A. P. (2018). 9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma. Anti-Cancer Drugs, 29(8), 717-724. https://doi.org/10.1097/CAD.0000000000000652
Ugolkov, Andrey V. ; Bondarenko, Gennadiy I. ; Dubrovskyi, Oleksii ; Berbegall, Ana P. ; Navarro, Samuel ; Noguera, Rosa ; O'Halloran, Thomas V ; Hendrix, Mary J. ; Giles, Francis J. ; Mazar, Andrew P. / 9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma. In: Anti-Cancer Drugs. 2018 ; Vol. 29, No. 8. pp. 717-724.
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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.}",
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Ugolkov, AV, Bondarenko, GI, Dubrovskyi, O, Berbegall, AP, Navarro, S, Noguera, R, O'Halloran, TV, Hendrix, MJ, Giles, FJ & Mazar, AP 2018, '9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma', Anti-Cancer Drugs, vol. 29, no. 8, pp. 717-724. https://doi.org/10.1097/CAD.0000000000000652

9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma. / Ugolkov, Andrey V.; Bondarenko, Gennadiy I.; Dubrovskyi, Oleksii; Berbegall, Ana P.; Navarro, Samuel; Noguera, Rosa; O'Halloran, Thomas V; Hendrix, Mary J.; Giles, Francis J.; Mazar, Andrew P.

In: Anti-Cancer Drugs, Vol. 29, No. 8, 01.09.2018, p. 717-724.

Research output: Contribution to journalArticle

TY - JOUR

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.

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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U2 - 10.1097/CAD.0000000000000652

DO - 10.1097/CAD.0000000000000652

M3 - Article

VL - 29

SP - 717

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Ugolkov AV, Bondarenko GI, Dubrovskyi O, Berbegall AP, Navarro S, Noguera R et al. 9-ING-41, a small-molecule glycogen synthase kinase-3 inhibitor, is active in neuroblastoma. Anti-Cancer Drugs. 2018 Sep 1;29(8):717-724. https://doi.org/10.1097/CAD.0000000000000652