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Preclinical reports have demonstrated that 3-BrPA inhibits tumor growth upon intra-arterial or intratumoral administration. For example, 3-bromopyruvate (3-BrPA) is a glycolytic inhibitor that targets energy metabolism ( 6) and is an inhibitor of hexokinase ( 7, 8).
SHIRIN IN SHAHRZAD SERIES DRIVER
Collectively, this evidence supports that HK2 is a key driver of metabolic regulation in GBMs as it regulates tumor growth and proliferation and is in part responsible for resistance to chemoradiation.Ĭurrently, no direct inhibitors of HK2 have been tested in human patients with GBM due to the inability of the drugs to cross the blood–brain barrier (BBB) or concern for their toxicity in patients. We have proven that the function of HK2 is independent of its isoform HK1 ( 5). Furthermore, we have shown that decreased HK2 expression results in sensitization of tumor cells to radiation and chemotherapy, concomitant with increased survival of GBM mouse models. Specifically, we have also shown that downregulation of HK2 inhibits aerobic glycolysis, while promoting oxidative phosphorylation (OXPHOS), as demonstrated by increased O 2 consumption, decreased extracellular lactate, and increased expression of genes involved in OXPHOS ( 5). We have shown that the glycolytic enzyme, hexokinase II (HK2), plays an important role in glucose flux into glycolysis or the pentose phosphate pathway (PPP) and its transcription is tightly regulated in part by HIF1α, glucose, cAMP, insulin, glucagon, and p53 ( 4). Our group and others have shown that metabolic reprogramming plays an important role in tumor progression in GBM.
![shirin in shahrzad series shirin in shahrzad series](https://m.media-amazon.com/images/M/MV5BMTYxYjc2YTAtMzVjMi00NzViLThmYWItNTAwMzE0Nzc4Njg0XkEyXkFqcGdeQXVyMjU0MTE3OTg@._V1_.jpg)
To date, there has been no advance in targeted therapies for GBMs. Glioblastoma (GBM) is the most common primary brain tumor in adults, displaying high therapeutic resistance and poor median survival of 12–18 months ( 3). However, metabolic reprogramming is utilized even under sufficient supply of oxygen and nutrients, suggesting that there are other advantages of metabolic reprogramming for cancer cell survival ( 1). It was originally thought that solid tumors benefit from the Warburg effect through enhanced glycolytic flux and faster ATP production per glucose molecule, ensuring sufficient supply of ATP for rapidly proliferating tumor cells, in particular under hypoxic conditions ( 2).
![shirin in shahrzad series shirin in shahrzad series](https://1.bp.blogspot.com/-hxqin_hFifg/WZofeSxCoxI/AAAAAAAAABI/mpgVJd-Ac-IwuY1IgoyGZvnB7uWo_fpJwCLcBGAs/s1600/Shahrzad.jpg)
This metabolic remodeling seen in cancer cells results in alteration of synthesis and utilization of metabolites. This process is referred to as the “Warburg effect” or aerobic glycolysis ( 1). Cancer cells generate more than 50% of their ATP from glycolysis rather than oxidative phosphorylation (OXPHOS), even under high oxygen conditions. Asterisks on graphs denote a significant difference (*p < 0.05).Ĭancer cells exhibit a key distinguishing feature compared with normal cells in how they generate ATP. The amount of compounds in normal brain, U87 and GSC8-18 derived tumor samples were normalized to the Control sample. Amount of Posaconazole in tumor (U87 and GSC8-18) was compared to untreated normal brain tissue (Control) and normalized per gram of tissue as baseline. Detection of Posaconazole in U87 mouse tumor tissue was performed using mass spectrometry as described in ‘ Materials and Methods’ section. (C) Ki-67 quantification was performed to estimate the proportion of proliferating tumor cells in drug versus control treated U87 mouse GBM models. (B) Immunohistochemical analysis of Ki67 was performed to determine tumor cell proliferation upon treatment with Ketoconazole and Posaconazole. (A) Kaplan-Meier survival curve of vehicle-treated, Ketoconazole-treated (25mg/kg), and Posaconazole-treated (25mg/kg) U87 GBM xenograft models. Ketoconazole and Posaconazole inhibit GBM growth in a U87 xenograft model.