DIVERSet JAG Compounds Inhibit Topoisomerase II and Are Effective Against Adult and Pediatric High-Grade Gliomas

Alison Howarth, Claire Simms, Nitesh Kerai, Olivia Allen, Karina Mihajluk, Patricia A. Madureira, Giannis Sokratous, S. Cragg, Sang Y. Lee, Andy D. Morley, Ashkan Keyoumars, Paul A. Cox, Geoffrey J. Pilkington, Richard Hill

Research output: Contribution to journalArticle

Abstract

High-grade gliomas (HGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis in both adult and pediatric patients. Clinical response is compounded by resistance to standard frontline antineoplastic agents, an absence of novel therapeutics, and poor in vitro models to evaluate these. We screened a range of recently identified anticancer compounds in conventional adult, pediatric, and new biopsy-derived HGG models. These in vitro lines showed a range of sensitivity to standard chemotherapeutics, with varying expression levels of the prognostic markers hypoxia-induced factor (HIF) 1α and p53. Our evaluation of lead DIVERSet library compounds identified that JAG-6A, a compound that was significantly more potent than temozolomide or etoposide, was effective against HGG models in two-dimensional and three-dimensional systems; mediated this response by the potent inhibition of topoisomerase Iiα; remained effective under normoxic and hypoxic conditions; and displayed limited toxicity to non-neoplastic astrocytes. These data suggest that JAG-6A could be an alternative topoisomerase IIα inhibitor and used for the treatment of HGG.

Original languageEnglish (US)
Pages (from-to)1375-1385
Number of pages11
JournalTranslational Oncology
Volume12
Issue number10
DOIs
StatePublished - Oct 2019

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Type II DNA Topoisomerase
Glioma
Pediatrics
temozolomide
Topoisomerase II Inhibitors
Etoposide
Brain Neoplasms
Astrocytes
Antineoplastic Agents
Libraries
Biopsy
Therapeutics
Growth
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Howarth, A., Simms, C., Kerai, N., Allen, O., Mihajluk, K., Madureira, P. A., ... Hill, R. (2019). DIVERSet JAG Compounds Inhibit Topoisomerase II and Are Effective Against Adult and Pediatric High-Grade Gliomas. Translational Oncology, 12(10), 1375-1385. https://doi.org/10.1016/j.tranon.2019.07.007
Howarth, Alison ; Simms, Claire ; Kerai, Nitesh ; Allen, Olivia ; Mihajluk, Karina ; Madureira, Patricia A. ; Sokratous, Giannis ; Cragg, S. ; Lee, Sang Y. ; Morley, Andy D. ; Keyoumars, Ashkan ; Cox, Paul A. ; Pilkington, Geoffrey J. ; Hill, Richard. / DIVERSet JAG Compounds Inhibit Topoisomerase II and Are Effective Against Adult and Pediatric High-Grade Gliomas. In: Translational Oncology. 2019 ; Vol. 12, No. 10. pp. 1375-1385.
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abstract = "High-grade gliomas (HGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis in both adult and pediatric patients. Clinical response is compounded by resistance to standard frontline antineoplastic agents, an absence of novel therapeutics, and poor in vitro models to evaluate these. We screened a range of recently identified anticancer compounds in conventional adult, pediatric, and new biopsy-derived HGG models. These in vitro lines showed a range of sensitivity to standard chemotherapeutics, with varying expression levels of the prognostic markers hypoxia-induced factor (HIF) 1α and p53. Our evaluation of lead DIVERSet library compounds identified that JAG-6A, a compound that was significantly more potent than temozolomide or etoposide, was effective against HGG models in two-dimensional and three-dimensional systems; mediated this response by the potent inhibition of topoisomerase Iiα; remained effective under normoxic and hypoxic conditions; and displayed limited toxicity to non-neoplastic astrocytes. These data suggest that JAG-6A could be an alternative topoisomerase IIα inhibitor and used for the treatment of HGG.",
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Howarth, A, Simms, C, Kerai, N, Allen, O, Mihajluk, K, Madureira, PA, Sokratous, G, Cragg, S, Lee, SY, Morley, AD, Keyoumars, A, Cox, PA, Pilkington, GJ & Hill, R 2019, 'DIVERSet JAG Compounds Inhibit Topoisomerase II and Are Effective Against Adult and Pediatric High-Grade Gliomas', Translational Oncology, vol. 12, no. 10, pp. 1375-1385. https://doi.org/10.1016/j.tranon.2019.07.007

DIVERSet JAG Compounds Inhibit Topoisomerase II and Are Effective Against Adult and Pediatric High-Grade Gliomas. / Howarth, Alison; Simms, Claire; Kerai, Nitesh; Allen, Olivia; Mihajluk, Karina; Madureira, Patricia A.; Sokratous, Giannis; Cragg, S.; Lee, Sang Y.; Morley, Andy D.; Keyoumars, Ashkan; Cox, Paul A.; Pilkington, Geoffrey J.; Hill, Richard.

In: Translational Oncology, Vol. 12, No. 10, 10.2019, p. 1375-1385.

Research output: Contribution to journalArticle

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T1 - DIVERSet JAG Compounds Inhibit Topoisomerase II and Are Effective Against Adult and Pediatric High-Grade Gliomas

AU - Howarth, Alison

AU - Simms, Claire

AU - Kerai, Nitesh

AU - Allen, Olivia

AU - Mihajluk, Karina

AU - Madureira, Patricia A.

AU - Sokratous, Giannis

AU - Cragg, S.

AU - Lee, Sang Y.

AU - Morley, Andy D.

AU - Keyoumars, Ashkan

AU - Cox, Paul A.

AU - Pilkington, Geoffrey J.

AU - Hill, Richard

PY - 2019/10

Y1 - 2019/10

N2 - High-grade gliomas (HGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis in both adult and pediatric patients. Clinical response is compounded by resistance to standard frontline antineoplastic agents, an absence of novel therapeutics, and poor in vitro models to evaluate these. We screened a range of recently identified anticancer compounds in conventional adult, pediatric, and new biopsy-derived HGG models. These in vitro lines showed a range of sensitivity to standard chemotherapeutics, with varying expression levels of the prognostic markers hypoxia-induced factor (HIF) 1α and p53. Our evaluation of lead DIVERSet library compounds identified that JAG-6A, a compound that was significantly more potent than temozolomide or etoposide, was effective against HGG models in two-dimensional and three-dimensional systems; mediated this response by the potent inhibition of topoisomerase Iiα; remained effective under normoxic and hypoxic conditions; and displayed limited toxicity to non-neoplastic astrocytes. These data suggest that JAG-6A could be an alternative topoisomerase IIα inhibitor and used for the treatment of HGG.

AB - High-grade gliomas (HGGs) are aggressive primary brain tumors with local invasive growth and poor clinical prognosis in both adult and pediatric patients. Clinical response is compounded by resistance to standard frontline antineoplastic agents, an absence of novel therapeutics, and poor in vitro models to evaluate these. We screened a range of recently identified anticancer compounds in conventional adult, pediatric, and new biopsy-derived HGG models. These in vitro lines showed a range of sensitivity to standard chemotherapeutics, with varying expression levels of the prognostic markers hypoxia-induced factor (HIF) 1α and p53. Our evaluation of lead DIVERSet library compounds identified that JAG-6A, a compound that was significantly more potent than temozolomide or etoposide, was effective against HGG models in two-dimensional and three-dimensional systems; mediated this response by the potent inhibition of topoisomerase Iiα; remained effective under normoxic and hypoxic conditions; and displayed limited toxicity to non-neoplastic astrocytes. These data suggest that JAG-6A could be an alternative topoisomerase IIα inhibitor and used for the treatment of HGG.

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