Inhibition of Metabolic Shift can Decrease Therapy Resistance in Human High-Grade Glioma Cells

Abstract

The high-grade brain malignancy, glioblastoma multiforme (GBM), is one of the most aggressive tumours in central nervous system. The developing resistance against recent therapies and the recurrence rate of GBMs are extremely high. In spite several new ongoing trials, GBM therapies could not significantly increase the survival rate of the patients as significantly. The presence of inter-and intra-tumoral heterogeneity of GBMs arise the problem to find both the pre-existing potential resistant clones and the cellular processes which promote the adaptation mechanisms such as multidrug resistance, stem cell-ness or metabolic alterations, etc. In our work, the in situ metabolic heterogeneity of high-grade human glioblastoma cases were analysed by immunohistochemistry using tissue-microarray. The potential importance of the detected metabolic heterogeneity was tested in three glioma cell lines (grade III-IV) using protein expression analyses (Western blot and WES Simple) and therapeutic drug (temozolomide), metabolic inhibitor treatments (including glutaminase inhibitor) to compare the effects of rapamycin (RAPA) and glutaminase inhibitor combinations in vitro (Alamar Blue and SRB tests). The importance of individual differences and metabolic alterations were observed in mono-therapeutic failures, especially the enhanced Rictor expressions after different monotreatments in correlation to lower sensitivity (temozolomide, doxycycline, etomoxir, BPTES). RAPA combinations with other metabolic inhibitors were the best strategies except for RAPA+glutaminase inhibitor. These observations underline the importance of multi-targeting metabolic pathways. Finally, our data suggest that the detected metabolic heterogeneity (the high mTORC2 complex activity, enhanced expression of Rictor, p-Akt, p-S6, CPT1A, and LDHA enzymes in glioma cases) and the microenvironmental or treatment induced metabolic shift can be potential targets in combination therapy. Therefore, it should be considered to map tissue heterogeneity and alterations with several cellular metabolism markers in biopsy materials after applying recently available or new treatments.

In Situ Metabolic Characterisation of Breast Cancer and Its Potential Impact on Therapy

“…Experimental studies of highly malignant tumours (e.g., gliomas and hepatocellular carcinomas) indicate that the antitumour effect of rapalogs is significantly enhanced by inhibitors of glycolysis or OXPHOS/mitochondrial biogenesis [ 14 , 39 ]. Additional approaches such as autophagy, lipid oxidation/synthesis or other OXPHOS inhibitors, combined with current targeted therapies, have been successfully tested in malignancies other than breast cancer [ 40 , 41 , 42 ]. The results of these studies coincide with the observations that metformin treatment lowers, whereas obesity and insulin resistance increase, the incidence of breast cancer [ 43 , 44 ].…”

“…DMSO (1%) was used as a vehicle and was added to control cells as required. Concentrations were determined and used based on previous experiments and publications [ 40 ].…”

Oxidative Stress—Part of the Solution or Part of the Problem in the Hypoxic Environment of a Brain Tumor

“…Several approaches have been applied to target metabolism in glioblastoma as well as other cancers [ 51 , 52 , 53 ]. Different studies showed that deletion/inhibition of LDHA combined with treatment with drugs such as tamoxifen, taxol, or use of drugs alone (oxamate, phenformin, gossypol, galloflavin) could impact tumorigenesis by affecting glucose uptake and increasing tumor apoptosis (reviewed in [ 51 , 52 , 53 ]). Gossypol, for instance, is well tolerated in clinical trials and has shown promise in recurrent malignant glioma trials [ 54 ].…”

“…Gossypol, for instance, is well tolerated in clinical trials and has shown promise in recurrent malignant glioma trials [ 54 ]. Combinations of rapamycin with chemotherapy (temozolomide, doxycycline, etomoxir) were shown to be effective strategies in GBM [ 53 ]. However, the common problem with drugs is that they have limited cell penetration; therefore, relatively high doses are required to have any significant effect.…”

Hypoxia Signaling in Cancer: From Basics to Clinical Practice

“…Based on certain studies, their combination with chemotherapy could be effective, but it could significantly enhance the effect of anti-angiogenic therapy (bevacizumab) without increasing the severity of side effects (e.g. in metastatic NSCLC) [105][106][107].…”