Ketoconazole and Posaconazole Selectively Target HK2-expressing Glioblastoma Cells

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, patientderived 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.

Antifungal Agent Luliconazole Inhibits the Growth of Mouse Glioma-initiating Cells in Brain Explants

“…3A,B). Consistent with these morphological changes and with reports that ketoconazole and posaconazole induce apoptosis in glioblastoma xenograft models, 12 analysis revealed that the number of GICs positive for cleaved caspase-3, a marker of apoptosis, markedly increased in the luliconazole-treated tumors (Fig. 3C,D).…”

“…Clotrimazole, ketoconazole, miconazole, and econazole were found to reduce the viability of multiple glioma cell lines in vitro. 11,12 However, glioblastomas include fractions of cells with stemlike properties that contribute to the initiation or propagation (or both) of these tumors. To achieve an improvement in prognosis for glioblastoma, repositioned drugs would also need to be effective against such stemlike cells.…”

“…Ketoconazole and miconazole reduce the number of glioblastoma stemlike cells in vitro. 12 However, the activities of most imidazole antifungals against glioma-initiating cells (GICs) remain unclear. Consequently, we investigated the effects of luliconazole, an imidazole previously untested for anticancer properties, on mouse GICs in vitro and in brain explants.…”

A Novel Glycolysis-Related Gene Signature that can Predict the Prognosis of Glioblastoma Patients

“…where the inhibition of HK2 and activation of PINK1 in preclinical GBM models have shown therapeutic bene t [22,23].…”

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

“…206 Others such as 3-bromopyruvic acid (3-BrPA), ketoconazole and posaconazole can also affect tumor metabolism and growth by blocking HK. 207,208 Phosphofructokinase 1 (PFK1) is the second rate-limiting enzyme of glycolysis, and tumor formation can be impaired by the O-GlcNAcylation of PFK1 at serine 529. 209 Metformin can target the HIF-1α/PFKFB3/PFK1 pathway in hepatoma cells and reduce hepatoma cell proliferation by inhibiting glycolysis.…”