Cancer poses a significant threat to human health and life. Chemotherapy, immunotherapy and chemodynamic therapy (CDT) are effective treatments for cancer. However, the presence of metabolic reprogramming via glutamine in tumor cells limits their therapeutic effectiveness. Herein, we propose an effective assembly strategy to synthesize a novel metal-polyphenolic based multifunctional nanomedicine (Fe-DBEF) containing Pluronic F127 stable ferric ion crosslinked epigallocatechin gallate (EGCG) nanoparticles loaded with GLS1 inhibitor bis-2-(5-phenylacetamino-1,3,4-thiadiazole-2-yl) ethyl sulfide (BPTES) and chemotherapy drug doxorubicin (DOX). Our study demonstrates that Fe-DBEF nanomedicine exhibits high efficiency anti-proliferation properties in pancreatic cancer through a combination of in vitro cell experiments, human organoid experiments and KPC animal experiments. Notably, Fe-DBEF nanomedicine can reduce the production of glutathione (GSH) in tumor cells, thereby reducing their resistance to ROS therapy. Additionally, excessive ROS production also aggravates DNA damage caused by DOX, synergistically sensitizing chemotherapy and promoting apoptosis for efficient treatment of pancreatic cancer. Overall, our findings suggest that inhibiting glutamine metabolism to increase the sensitivity of chemotherapy/CDT using metal-polyphenolic based multifunctional nanomedicine provides a promising combination of multiple therapeutic means for treating pancreatic cancer.

Cancer metabolism is now a key area for therapeutic intervention, targeting unique metabolic reprogramming crucial for tumor growth and survival. This article reviews the therapeutic potential of addressing metabolic vulnerabilities through glycolysis and glutaminase inhibitors, which disrupt cancer cell metabolism. Challenges such as tumor heterogeneity and adaptive resistance are discussed, with strategies including personalized medicine and predictive biomarkers to enhance treatment efficacy. Additionally, integrating diet and lifestyle changes with metabolic targeting underscores a holistic approach to improving therapy outcomes. The article also examines the benefits of incorporating these strategies into standard care, highlighting the potential for more tailored, safer treatments. In conclusion, exploiting metabolic vulnerabilities promises a new era in oncology, positioning metabolic targeting at the forefront of personalized cancer therapy and transforming patient care.

Targeted therapies have revolutionized the treatment of renal cell carcinoma (RCC). The VHL/HIF pathway is responsible for the regulation of oxygen homeostasis and is frequently altered in RCC. Targeting this pathway as well as the mTOR pathway have yielded remarkable advances in the treatment of RCC. Here, we review the most promising novel targeted therapies for the treatment of RCC, including HIF2α, MET, metabolic targeting, and epigenomic reprogramming.

Glutamine metabolism is an important hallmark of several cancers with demonstrated antitumor activity in glioblastoma cancer cells (GBM). GBM cells regulate glutamine and use it as a major energy source for their proliferation through the glutaminolysis process. Enzymes, such as glutaminase in glutaminolysis, can be targeted by small-molecule inhibitors, thus exhibiting promising anticancer properties. The resistance to glutaminolysis demands the development of new therapeutic molecules to overcome drug resistance. Herein, we have reported a novel library of constrained methanodibenzo[b,f][1,5]dioxocin derivatives as glutaminase (GLS) inhibitors and their anti-GBM potential. The library consisting of seven molecules was obtained through self-condensation of 2\'-hydroxyacetophenones, out of which three molecules, namely compounds 3, 5, and 6, were identified with higher binding energy values ranging between -10.2 and -9.8 kcal/mol with GLS (PDB ID; 4O7D). Pharmacological validation of these compounds also showed a higher growth inhibition effect in GBM cells than the standard drug temozolomide (TMZ). The most promising compound, 6, obeyed Lipinski\'s rule of five and was identified to interact with key residues Arg307, Asp326, Lys328, Lys399, and Glu403 of GLS. This compound exhibited the best cytotoxic effect with IC50 values of 63 µM and 83 µM in LN229 and SNB19 cells, respectively. The potential activation of GLS by the best-constrained dibenzo[b,f][1,5]dioxocin in the tested series increased apoptosis via reactive oxygen species production in both GBM cells, and exhibited anti-migratory and anti-proliferative properties over time in both cell lines. Our results highlight the activation mechanism of a dibenzo[b,f][1,5]dioxocin from the structural basis and demonstrate that inhibition of glutaminolysis may facilitate the pharmacological intervention for GBM treatment.

Breast cancer (BC) is a heterogeneous cancer with multiple subtypes affecting women worldwide. Triple-negative breast cancer (TNBC) is a prominent subtype of BC with poor prognosis and an aggressive phenotype. Recent understanding of metabolic reprogramming supports its role in the growth of cancer cells and their adaptation to their microenvironment. The Warburg effect is characterized by the shift from oxidative to reductive metabolism and external secretion of lactate. The Warburg effect prevents the use of the required pyruvate in the tricarboxylic acid (TCA) cycle progressing through pyruvate dehydrogenase inactivation. Therefore, it is a major regulatory mechanism to promote glycolysis and disrupt the TCA cycle. Glutamine (Gln) can supply the complementary energy for cancer cells. Additionally, it is the main substrate to support bioenergetics and biosynthetic activities in cancer cells and plays a vital role in a wide array of other processes such as ferroptosis. Thus, the switching of glucose to Gln in the TCA cycle toward reductive Gln metabolism is carried out by hypoxia-inducible factors (HIFs) conducted through the Warburg effect. The literature suggests that the addiction of TNBC to Gln could facilitate the proliferation and invasiveness of these cancers. Thus, Gln metabolism inhibitors, such as CB-839, could be applied to manage the carcinogenic properties of TNBC. Such inhibitors, along with conventional chemotherapy agents, can potentially improve the efficiency and efficacy of TNBC treatment. In this review, we discuss the associations between glucose and Gln metabolism and control of cancer cell growth from the perspective that Gln metabolism inhibitors could improve the current chemotherapy drug effects.

Metabolic reprogramming in cancer targets glutamine metabolism as a key mechanism to provide energy, biosynthetic precursors and redox requirements to allow the massive proliferation of tumor cells. Glutamine is also a signaling molecule involved in essential pathways regulated by oncogenes and tumor suppressor factors. Glutaminase isoenzymes are critical proteins to control glutaminolysis, a key metabolic pathway for cell proliferation and survival that directs neoplasms\' fate. Adaptive glutamine metabolism can be altered by different metabolic therapies, including the use of specific allosteric inhibitors of glutaminase that can evoke synergistic effects for the therapy of cancer patients. We also review other clinical applications of in vivo assessment of glutaminolysis by metabolomic approaches, including diagnosis and monitoring of cancer.

BACKGROUND: Metabolic reprogramming of tumours is a hallmark of cancer. Among the changes in the metabolic network of cancer cells, glutaminolysis is a key reaction altered in neoplasms. Glutaminase proteins control the first step in glutamine metabolism and their expression correlates with malignancy and growth rate of a great variety of cancers. The two types of glutaminase isoenzymes, GLS and GLS2, differ in their expression patterns and functional roles: GLS has oncogenic properties and GLS2 has been described as a tumour suppressor factor.
RESULTS: We have focused on glutaminase connections with key oncogenes and tumour suppressor genes. Targeting glutaminase isoenzymes includes different strategies aimed at deactivating the rewiring of cancer metabolism. In addition, we found a long list of metabolic enzymes, transcription factors and signalling pathways dealing with glutaminase. On the other hand, a number of chemicals have been described as isoenzyme-specific inhibitors of GLS and/or GLS2 isoforms. These molecules are being characterized as synergic and therapeutic agents in many types of tumours.
CONCLUSIONS: This review states the metabolic pathways that are rewired in cancer, the roles of glutaminase isoforms in cancer, as well as the metabolic circuits regulated by glutaminases. We also show the plethora of anticancer drugs that specifically inhibit glutaminase isoenzymes for treating several sets of cancer.

Altered cellular metabolism is a hallmark of cancer. Cancer cells express isoforms of metabolic enzymes that may constitute therapeutic targets. Glutaminase controls glutamine metabolism and their expression correlate with malignancy of tumours. The two types of glutaminase isoenzymes, GLS and GLS2, differ in their expression patterns and functional roles: GLS has oncogenic properties and GLS2 has been described as a tumour suppressor factor. Selective genomic and epigenomic intervention over glutaminase affects the metabolic reprogramming of cancer. This review highlights the molecular metabolic vulnerabilities in various types of cancer, to be used for biomarker development, drug design, and in personalized oncology.

Metabolomics, the newest of the omics sciences that also include genomics, transcriptomics and proteomics, has matured into a reliable high-throughput technology. Gas chromatography combined with time-of-flight mass spectrometry (GC-TOFMS) is a suitable method to analyze the central metabolism in fresh frozen tumor tissue samples. Bioinformatics methods, including the PROFILE clustering developed by us, permit integrated analysis and fast interpretation of metabolomics data in the context of enzymatic reactions and metabolic pathways. The metabolome analyses of three solid tumor types presented here, together with the results of other authors, show that metabolites are suitable as biomarkers and provide diverse options for translation into the clinical setting.

Ovarian cancer is characterized by an increase in cellular energy metabolism, which is predominantly satisfied by glucose and glutamine. Targeting metabolic pathways is an attractive approach to enhance the therapeutic effectiveness and to potentially overcome drug resistance in ovarian cancer. In platinum-sensitive ovarian cancer cell lines the metabolism of both, glucose and glutamine was initially up-regulated in response to platinum treatment. In contrast, platinum-resistant cells revealed a significant dependency on the presence of glutamine, with an upregulated expression of glutamine transporter ASCT2 and glutaminase. This resulted in a higher oxygen consumption rate compared to platinum-sensitive cell lines reflecting the increased dependency of glutamine utilization through the tricarboxylic acid cycle. The important role of glutamine metabolism was confirmed by stable overexpression of glutaminase, which conferred platinum resistance. Conversely, shRNA knockdown of glutaminase in platinum resistant cells resulted in re-sensitization to platinum treatment. Importantly, combining the glutaminase inhibitor BPTES with platinum synergistically inhibited platinum sensitive and resistant ovarian cancers in vitro. Apoptotic induction was significantly increased using platinum together with BPTES compared to either treatment alone. Our findings suggest that targeting glutamine metabolism together with platinum based chemotherapy offers a potential treatment strategy particularly in drug resistant ovarian cancer.