Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells

Sameer Agnihotri, Sheila Mansouri, Kelly Burrell, Mira Li, Yasin Mamatjan, Jeff Liu, Romina Nejad, Sushil Kumar, Shahrzad Jalali, Sanjay K. Singh, Alenoush Vartanian, Eric Xueyu Chen, Shirin Karimi, Olivia Singh, Severa Bunda, Seyed Alireza Mansouri, Kenneth D. Aldape, Gelareh Zadeh

Research output: Contribution to journalArticle

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Abstract

Purpose: Hexokinase II (HK2) protein expression is elevated in glioblastoma (GBM), and we have shown that HK2 could serve as an effective therapeutic target for GBM. Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient-derived glioma stem cells (GSCs), and mouse models of GBM. Experimental Design: We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2-associated gene signature. We next determined the EC 50 of the compounds by treating glioma cell lines and GSCs. Selected compounds showing significant impact in vitro were used to treat mice and examine their effect on survival and tumor characteristics. The effect of compounds on the metabolic activity in glioma cells was also assessed in vitro. Results: This screen identified the azole class of antifungals as inhibitors of tumor metabolism. Among the compounds tested, ketoconazole and posaconazole displayed the greatest inhibitory effect on GBM both in vitro and in vivo. Treatment of mice bearing GBM with ketoconazole and posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. In addition, treatment with azoles resulted in increased proportion of apoptotic cells. Conclusions: Overall, we provide evidence that azoles exert their effect by targeting genes and pathways regulated by HK2. These findings shed light on the action of azoles in GBM. Combined with existing literature and preclinical results, these data support the value of repurposing azoles in GBM clinical trials.

Original languageEnglish (US)
Pages (from-to)844-855
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number2
DOIs
StatePublished - Jan 15 2019

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Ketoconazole
Glioblastoma
Azoles
Glioma
Neoplasms
Stem Cells
Cell Line
Hexokinase
Survival
Gene Targeting
posaconazole
Research Design
Therapeutics
Cell Proliferation
Clinical Trials
Growth
Pharmaceutical Preparations
Genes
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Agnihotri, S., Mansouri, S., Burrell, K., Li, M., Mamatjan, Y., Liu, J., ... Zadeh, G. (2019). Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells. Clinical Cancer Research, 25(2), 844-855. https://doi.org/10.1158/1078-0432.CCR-18-1854
Agnihotri, Sameer ; Mansouri, Sheila ; Burrell, Kelly ; Li, Mira ; Mamatjan, Yasin ; Liu, Jeff ; Nejad, Romina ; Kumar, Sushil ; Jalali, Shahrzad ; Singh, Sanjay K. ; Vartanian, Alenoush ; Chen, Eric Xueyu ; Karimi, Shirin ; Singh, Olivia ; Bunda, Severa ; Mansouri, Seyed Alireza ; Aldape, Kenneth D. ; Zadeh, Gelareh. / Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 2. pp. 844-855.
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Agnihotri, S, Mansouri, S, Burrell, K, Li, M, Mamatjan, Y, Liu, J, Nejad, R, Kumar, S, Jalali, S, Singh, SK, Vartanian, A, Chen, EX, Karimi, S, Singh, O, Bunda, S, Mansouri, SA, Aldape, KD & Zadeh, G 2019, 'Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells', Clinical Cancer Research, vol. 25, no. 2, pp. 844-855. https://doi.org/10.1158/1078-0432.CCR-18-1854

Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells. / Agnihotri, Sameer; Mansouri, Sheila; Burrell, Kelly; Li, Mira; Mamatjan, Yasin; Liu, Jeff; Nejad, Romina; Kumar, Sushil; Jalali, Shahrzad; Singh, Sanjay K.; Vartanian, Alenoush; Chen, Eric Xueyu; Karimi, Shirin; Singh, Olivia; Bunda, Severa; Mansouri, Seyed Alireza; Aldape, Kenneth D.; Zadeh, Gelareh.

In: Clinical Cancer Research, Vol. 25, No. 2, 15.01.2019, p. 844-855.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells

AU - Agnihotri, Sameer

AU - Mansouri, Sheila

AU - Burrell, Kelly

AU - Li, Mira

AU - Mamatjan, Yasin

AU - Liu, Jeff

AU - Nejad, Romina

AU - Kumar, Sushil

AU - Jalali, Shahrzad

AU - Singh, Sanjay K.

AU - Vartanian, Alenoush

AU - Chen, Eric Xueyu

AU - Karimi, Shirin

AU - Singh, Olivia

AU - Bunda, Severa

AU - Mansouri, Seyed Alireza

AU - Aldape, Kenneth D.

AU - Zadeh, Gelareh

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Purpose: Hexokinase II (HK2) protein expression is elevated in glioblastoma (GBM), and we have shown that HK2 could serve as an effective therapeutic target for GBM. Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient-derived glioma stem cells (GSCs), and mouse models of GBM. Experimental Design: We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2-associated gene signature. We next determined the EC 50 of the compounds by treating glioma cell lines and GSCs. Selected compounds showing significant impact in vitro were used to treat mice and examine their effect on survival and tumor characteristics. The effect of compounds on the metabolic activity in glioma cells was also assessed in vitro. Results: This screen identified the azole class of antifungals as inhibitors of tumor metabolism. Among the compounds tested, ketoconazole and posaconazole displayed the greatest inhibitory effect on GBM both in vitro and in vivo. Treatment of mice bearing GBM with ketoconazole and posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. In addition, treatment with azoles resulted in increased proportion of apoptotic cells. Conclusions: Overall, we provide evidence that azoles exert their effect by targeting genes and pathways regulated by HK2. These findings shed light on the action of azoles in GBM. Combined with existing literature and preclinical results, these data support the value of repurposing azoles in GBM clinical trials.

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