Targeting tumor metabolism: biguanides as anti-neoplastic agents

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14592-e14592
Author(s):  
R. E. Knoblauch ◽  
C. B. Thompson
Keyword(s):  
Tumor Cell ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
K562 Cells ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Metabolic Effects ◽  
Imatinib Treatment ◽  
Targeted Agents ◽  
Erythroleukemia Cell

e14592 Background: During the process of malignant transformation, the tumor cell adopts a new form of metabolism, characterized by aerobic glycolysis and altered TCA cycle flux, that enable it to meet the energetic and biosynthetic demands of proliferation. This shift to anabolic metabolism results from oncogene-driven activation of signaling pathways, and therefore represents a potential therapeutic target that lies downstream of these genetic events. Methods: We have characterized the proliferative and metabolic effects of phenformin, a member of the biguanide family of compounds used in the treatment of diabetes, on the bcr-abl expressing K562 erythroleukemia cell line, and compared the resulting phenotype to those of imatinib and rapamycin, two targeted agents used in the treatment of malignant disease. Results: Phenformin induced the most profound growth inhibition of K562 cells, in a manner distinct from the targeted agents. Phenformin treatment eliminated the mitochondrial contribution to anabolic metabolism, through inhibition of Complex I of the Electron Transport Chain, as demonstrated by reduced oxygen consumption and intracellular ATP levels. Glutamine metabolism was also inhibited, consistent with TCA cycle inhibition as a secondary effect. The phenformin-induced mitochondrial dysfunction made K562 cells dependent upon glycolysis for survival. In contrast, the growth arrest resulting from imatinib treatment was associated with a complete reversion from the anabolic phenotype, as demonstrated by dramatically decreased glucose and glutamine consumption. Rapamycin, a poor inhibitor of K562 proliferation, decreased glycolysis but left mitochondrial function intact. Conclusions: Our results confirm the importance of metabolism to the proliferation of malignant cells, thereby validating anabolic metabolism's potential for therapeutic intervention. The direct inhibition of tumor cell metabolism by phenformin warrants further clinical study as a promising new approach to cancer therapy. No significant financial relationships to disclose.

scholarly journals SARS-CoV-2 infection rewires host cell metabolism and is potentially susceptible to mTORC1 inhibition

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Peter J. Mullen ◽  
Gustavo Garcia ◽  
Arunima Purkayastha ◽  
Nedas Matulionis ◽  
Ernst W. Schmid ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Host Cell ◽  
Cell Metabolism ◽  
Tca Cycle ◽  
Building Blocks ◽  
Glutamine Metabolism ◽  
Glucose Carbon ◽  
Mechanism Of Inhibition ◽  
Show Evidence ◽  
Kidney Epithelial Cells

AbstractViruses hijack host cell metabolism to acquire the building blocks required for replication. Understanding how SARS-CoV-2 alters host cell metabolism may lead to potential treatments for COVID-19. Here we profile metabolic changes conferred by SARS-CoV-2 infection in kidney epithelial cells and lung air-liquid interface (ALI) cultures, and show that SARS-CoV-2 infection increases glucose carbon entry into the TCA cycle via increased pyruvate carboxylase expression. SARS-CoV-2 also reduces oxidative glutamine metabolism while maintaining reductive carboxylation. Consistent with these changes, SARS-CoV-2 infection increases the activity of mTORC1 in cell lines and lung ALI cultures. Lastly, we show evidence of mTORC1 activation in COVID-19 patient lung tissue, and that mTORC1 inhibitors reduce viral replication in kidney epithelial cells and lung ALI cultures. Our results suggest that targeting mTORC1 may be a feasible treatment strategy for COVID-19 patients, although further studies are required to determine the mechanism of inhibition and potential efficacy in patients.

scholarly journals Troglitazone suppresses glutamine metabolism through a PPAR-independent mechanism

2015 ◽  
Vol 396 (8) ◽  
pp. 937-947
Author(s):  
Miriam R. Reynolds ◽  
Brian F. Clem
Keyword(s):  
Cell Growth ◽  
Tumor Cell ◽  
Tca Cycle ◽  
Viable Cell ◽  
Cell Number ◽  
Glutamine Metabolism ◽  
Viable Cell Number ◽  
Tumor Cell Growth ◽  
Pparγ Agonist ◽  
Glutamine Uptake

Abstract Enhanced glutamine metabolism is required for tumor cell growth and survival, which suggests that agents targeting glutaminolysis may have utility within anti-cancer therapies. Troglitazone, a PPARγ agonist, exhibits significant anti-tumor activity and can alter glutamine metabolism in multiple cell types. Therefore, we examined whether troglitazone would disrupt glutamine metabolism in tumor cells and whether its action was reliant on PPARγ activity. We found that troglitazone treatment suppressed glutamine uptake and the expression of the glutamine transporter, ASCT2, and glutaminase. In addition, troglitazone reduced 13C-glutamine incorporation into the TCA cycle, decreased [ATP], and resulted in an increase in reactive oxygen species (ROS). Further, troglitazone treatment decreased tumor cell growth, which was partially rescued with the addition of the TCA-intermediate, α-ketoglutarate, or the antioxidant N-acetylcysteine. Importantly, troglitazone’s effects on glutamine uptake or viable cell number were found to be PPARγ-independent. In contrast, troglitazone caused a decrease in c-Myc levels, while the proteasomal inhibitor, MG132, rescued c-Myc, ASCT2 and GLS1 expression, as well as glutamine uptake and cell number. Lastly, combinatorial treatment of troglitazone and metformin resulted in a synergistic decrease in cell number. Therefore, characterizing new anti-tumor properties of previously approved FDA therapies supports the potential for repurposing of these agents.

scholarly journals Interplay Between Glucose Metabolism and Chromatin Modifications in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Rui Ma ◽  
Yinsheng Wu ◽  
Shanshan Li ◽  
Xilan Yu
Keyword(s):  
Glucose Metabolism ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Tca Cycle ◽  
The Novel ◽  
Chromatin Modifications ◽  
Cancer Treatments ◽  
Cancer Cell Metabolism ◽  
Effect Of Glucose

Cancer cells reprogram glucose metabolism to meet their malignant proliferation needs and survival under a variety of stress conditions. The prominent metabolic reprogram is aerobic glycolysis, which can help cells accumulate precursors for biosynthesis of macromolecules. In addition to glycolysis, recent studies show that gluconeogenesis and TCA cycle play important roles in tumorigenesis. Here, we provide a comprehensive review about the role of glycolysis, gluconeogenesis, and TCA cycle in tumorigenesis with an emphasis on revealing the novel functions of the relevant enzymes and metabolites. These functions include regulation of cell metabolism, gene expression, cell apoptosis and autophagy. We also summarize the effect of glucose metabolism on chromatin modifications and how this relationship leads to cancer development. Understanding the link between cancer cell metabolism and chromatin modifications will help develop more effective cancer treatments.

scholarly journals Propranolol Promotes Glucose Dependence and Synergizes with Dichloroacetate for Anti-Cancer Activity in HNSCC

Cancers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 476 ◽  
Author(s):  
Christopher Lucido ◽  
W. Miskimins ◽  
Paola Vermeer
Keyword(s):  
Tumor Cell ◽  
Metabolic Pathways ◽  
Cellular Response ◽  
Cell Metabolism ◽  
Single Agent ◽  
Metabolic Effects ◽  
Anti Cancer ◽  
Tumor Cell Metabolism ◽  
Glucose Dependence ◽  
Cancer Activity

Tumor cell metabolism differs from that of normal cells, conferring tumors with metabolic advantages but affording opportunities for therapeutic intervention. Accordingly, metabolism-targeting therapies have shown promise. However, drugs targeting singular metabolic pathways display limited efficacy, in part due to the tumor’s ability to compensate by using other metabolic pathways to meet energy and growth demands. Thus, it is critical to identify novel combinations of metabolism-targeting drugs to improve therapeutic efficacy in the face of compensatory cellular response mechanisms. Our lab has previously identified that the anti-cancer activity of propranolol, a non-selective beta-blocker, is associated with inhibition of mitochondrial metabolism in head and neck squamous cell carcinoma (HNSCC). In response to propranolol, however, HNSCC exhibits heightened glycolytic activity, which may limit the effectiveness of propranolol as a single agent. Thus, we hypothesized that propranolol’s metabolic effects promote a state of enhanced glucose dependence, and that propranolol together with glycolytic inhibition would provide a highly effective therapeutic combination in HNSCC. Here, we show that glucose deprivation synergizes with propranolol for anti-cancer activity, and that the rational combination of propranolol and dichloroacetate (DCA), a clinically available glycolytic inhibitor, dramatically attenuates tumor cell metabolism and mTOR signaling, inhibits proliferation and colony formation, and induces apoptosis. This therapeutic combination displays efficacy in both human papillomavirus-positive (HPV(+)) and HPV(−) HNSCC cell lines, as well as a recurrent/metastatic model, while leaving normal tonsil epithelial cells relatively unaffected. Importantly, the combination significantly delays tumor growth in vivo with no evidence of toxicity. Additionally, the combination of propranolol and DCA enhances the effects of chemoradiation and sensitizes resistant cells to cisplatin and radiation. This novel therapeutic combination represents a promising treatment strategy which may overcome some of the limitations of targeting individual metabolic pathways in cancer.

Therapeutic Targeting of Cancer Cell Metabolism in Lymphoid Neoplasia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. SCI-27-SCI-27
Author(s):  
Chi Van Dang
Keyword(s):  
Cancer Metabolism ◽  
Cell Metabolism ◽  
Biomass Accumulation ◽  
Tca Cycle ◽  
Glutamine Metabolism ◽  
Myc Oncogene ◽  
Xenograft Growth ◽  
The Tca Cycle ◽  
Cancer Cell Metabolism ◽  
The Warburg Effect

Abstract Abstract SCI-27 The MYC oncogene plays a pivotal role in human lymphoid neoplasias, specifically in lymphomas and acute leukemias, which are characterized by altered glucose metabolism, termed the Warburg effect. The Warburg effect or elevated conversion glucose to lactate by cancer cells has been a prevailing model of cancer metabolism. Since the 1980’s, genetic alterations of oncogenes and tumor suppressors have provided insights into tumorigenesis. However, whether metabolism contributes to tumorigenesis was highly debated. In 1997, we reported that the MYC oncogene product, the Myc transcription factor, regulates the lactate dehydrogenase A (LDHA)gene. Myc also activates many glycolytic enzymes, mitochondrial biogenesis, and glutamine metabolism by inducing glutaminase (GLS) and glutamine transporters, thereby providing not only ATP through the TCA cycle but also anapleurotic building blocks. Myc also induces biomass accumulation by stimulating ribosomal biogenesis. It stimulates the cell cycle machinery and DNA replication. Deregulated MYC in cancer results in enforced biomass accumulation, such that cell death occurs when bioenergetic demands exceed nutrient availability. In this regard, we have exploited this conceptual framework and targeted LDHA and GLS with small molecular inhibitors as proof-of- concept that altered cancer metabolism could be targeted for cancer therapy. Specifically, we documented that a drug-like inhibitor of LDHA could decreased tumor xenograft growth, providing evidence that metabolic therapy is feasible. We further found in a human Burkitt lymphoma model that Myc induces a genetic program that drives glutamine metabolism both under aerobic and hypoxic conditions. Inhibition of glutaminase, which converts glutamine to glutamate for its catabolism by the TCA cycle, by a drug-like molecule also diminished lymphoma xenograft growth in vivo. These studies indicate that targeting cancer cell metabolism could constitute a novel strategy to treat lymphoid neoplasias. Disclosures: Dang: Agios Pharmaceuticals, Inc.: Consultancy, Honoraria.

Recent Development of Small Molecule Glutaminase Inhibitors

2018 ◽  
Vol 18 (6) ◽  
pp. 432-443 ◽  
Author(s):  
Minsoo Song ◽  
Soong-Hyun Kim ◽  
Chun Young Im ◽  
Hee-Jong Hwang
Keyword(s):  
Small Molecule ◽  
Cell Metabolism ◽  
Phase 1 ◽  
Vital Role ◽  
Glutamine Metabolism ◽  
Inhibition Mechanism ◽  
Tumor Cell Growth ◽  
X Ray ◽  
New Class ◽  
Preclinical And Clinical Studies

Glutaminase (GLS), which is responsible for the conversion of glutamine to glutamate, plays a vital role in up-regulating cell metabolism for tumor cell growth and is considered to be a valuable therapeutic target for cancer treatment. Based on this important function of glutaminase in cancer, several GLS inhibitors have been developed in both academia and industry. Most importantly, Calithera Biosciences Inc. is actively developing the glutaminase inhibitor CB-839 for the treatment of various cancers, and it is currently being evaluated in phase 1 and 2 clinical trials. In this review, recent efforts to develop small molecule glutaminase inhibitors that target glutamine metabolism in both preclinical and clinical studies are discussed. In particular, more emphasis is placed on CB-839 because it is the only small molecule GLS inhibitor being studied in a clinical setting. The inhibition mechanism is also discussed based on X-ray structure studies of thiadiazole derivatives present in glutaminase inhibitor BPTES. Finally, recent medicinal chemistry efforts to develop a new class of GLS inhibitors are described in the hopes of providing useful information for the next generation of GLS inhibitors.

scholarly journals Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3018
Author(s):  
Marek Samec ◽  
Alena Liskova ◽  
Lenka Koklesova ◽  
Kevin Zhai ◽  
Elizabeth Varghese ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Glucose Transporter ◽  
Aerobic Glycolysis ◽  
Cell Metabolism ◽  
Lactate Production ◽  
Pentose Phosphate ◽  
Metabolic Reprogramming ◽  
Effective Prevention ◽  
Anti Cancer ◽  
Glucose 6 Phosphate Dehydrogenase

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

scholarly journals Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 396
Author(s):  
Timon A. Bloedjes ◽  
Guus de Wilde ◽  
Jeroen E. J. Guikema
Keyword(s):  
Multiple Myeloma ◽  
Cell Metabolism ◽  
Chromosomal Rearrangements ◽  
Chromosomal Translocations ◽  
Metabolic Effects ◽  
Aberrant Expression ◽  
Metabolic Functions ◽  
Complex Chromosomal Rearrangements ◽  
Cancer Cell Metabolism ◽  
The Many

Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells.

Tumor cell metabolism correlates with resistance to gas plasma treatment: The evaluation of three dogmas

2021 ◽  
Vol 167 ◽  
pp. 12-28
Author(s):  
Sander Bekeschus ◽  
Grit Liebelt ◽  
Jonas Menz ◽  
Julia Berner ◽  
Sanjeev Kumar Sagwal ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Plasma Treatment ◽  
Cell Metabolism ◽  
Gas Plasma ◽  
Tumor Cell Metabolism

scholarly journals Production of succinate by engineered strains of Synechocystis PCC 6803 overexpressing phosphoenolpyruvate carboxylase and a glyoxylate shunt

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Claudia Durall ◽  
Kateryna Kukil ◽  
Jeffrey A. Hawkes ◽  
Alessia Albergati ◽  
Peter Lindblad ◽  
...  
Keyword(s):  
Phosphoenolpyruvate Carboxylase ◽  
Isocitrate Lyase ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Tca Cycle ◽  
Malate Synthase ◽  
Glyoxylate Shunt ◽  
Control Strain ◽  
Genes Encoding ◽  
Pcc 6803

Abstract Background Cyanobacteria are promising hosts for the production of various industrially important compounds such as succinate. This study focuses on introduction of the glyoxylate shunt, which is naturally present in only a few cyanobacteria, into Synechocystis PCC 6803. In order to test its impact on cell metabolism, engineered strains were evaluated for succinate accumulation under conditions of light, darkness and anoxic darkness. Each condition was complemented by treatments with 2-thenoyltrifluoroacetone, an inhibitor of succinate dehydrogenase enzyme, and acetate, both in nitrogen replete and deplete medium. Results We were able to introduce genes encoding the glyoxylate shunt, aceA and aceB, encoding isocitrate lyase and malate synthase respectively, into a strain of Synechocystis PCC 6803 engineered to overexpress phosphoenolpyruvate carboxylase. Our results show that complete expression of the glyoxylate shunt results in higher extracellular succinate accumulation compared to the wild type control strain after incubation of cells in darkness and anoxic darkness in the presence of nitrate. Addition of the inhibitor 2-thenoyltrifluoroacetone increased succinate titers in all the conditions tested when nitrate was available. Addition of acetate in the presence of the inhibitor further increased the succinate accumulation, resulting in high levels when phosphoenolpyruvate carboxylase was overexpressed, compared to control strain. However, the highest succinate titer was obtained after dark incubation of an engineered strain with a partial glyoxylate shunt overexpressing isocitrate lyase in addition to phosphoenolpyruvate carboxylase, with only 2-thenoyltrifluoroacetone supplementation to the medium. Conclusions Heterologous expression of the glyoxylate shunt with its central link to the tricarboxylic acid cycle (TCA) for acetate assimilation provides insight on the coordination of the carbon metabolism in the cell. Phosphoenolpyruvate carboxylase plays an important role in directing carbon flux towards the TCA cycle.

Sign in / Sign up

Export Citation Format

Share Document