scholarly journals Metabolic Reprogramming: A Friend or Foe to Cancer Therapy?

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3351
Author(s):  
Christopher McCann ◽  
Emma M. Kerr
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Cancer Metabolism ◽  
Response To Therapy ◽  
Metabolic Reprogramming ◽  
Response To Treatment ◽  
Multiple Cancer ◽  
Cellular Survival ◽  
Cancer Hallmarks ◽  
Cytotoxic Stress

Drug resistance is a major cause of cancer treatment failure, effectively driven by processes that promote escape from therapy-induced cell death. The mechanisms driving evasion of apoptosis have been widely studied across multiple cancer types, and have facilitated new and exciting therapeutic discoveries with the potential to improve cancer patient care. However, an increasing understanding of the crosstalk between cancer hallmarks has highlighted the complexity of the mechanisms of drug resistance, co-opting pathways outside of the canonical “cell death” machinery to facilitate cell survival in the face of cytotoxic stress. Rewiring of cellular metabolism is vital to drive and support increased proliferative demands in cancer cells, and recent discoveries in the field of cancer metabolism have uncovered a novel role for these programs in facilitating drug resistance. As a key organelle in both metabolic and apoptotic homeostasis, the mitochondria are at the forefront of these mechanisms of resistance, coordinating crosstalk in the event of cellular stress, and promoting cellular survival. Importantly, the appreciation of this role metabolism plays in the cytotoxic response to therapy, and the ability to profile metabolic adaptions in response to treatment, has encouraged new avenues of investigation into the potential of exploiting metabolic addictions to improve therapeutic efficacy and overcome drug resistance in cancer. Here, we review the role cancer metabolism can play in mediating drug resistance, and the exciting opportunities presented by imposed metabolic vulnerabilities.

scholarly journals The use of hyperpolarised 13C-MRI in clinical body imaging to probe cancer metabolism

2021 ◽  
Author(s):  
Ramona Woitek ◽  
Ferdia A. Gallagher
Keyword(s):  
Cancer Metabolism ◽  
Signal To Noise Ratio ◽  
Response Assessment ◽  
Early Response ◽  
Multiparametric Mri ◽  
Metabolic Reprogramming ◽  
Response To Treatment ◽  
Additional Information ◽  
Positron Emission ◽  
Breast And Prostate Cancer

AbstractMetabolic reprogramming is one of the hallmarks of cancer and includes the Warburg effect, which is exhibited by many tumours. This can be exploited by positron emission tomography (PET) as part of routine clinical cancer imaging. However, an emerging and alternative method to detect altered metabolism is carbon-13 magnetic resonance imaging (MRI) following injection of hyperpolarised [1-13C]pyruvate. The technique increases the signal-to-noise ratio for the detection of hyperpolarised 13C-labelled metabolites by several orders of magnitude and facilitates the dynamic, noninvasive imaging of the exchange of 13C-pyruvate to 13C-lactate over time. The method has produced promising preclinical results in the area of oncology and is currently being explored in human imaging studies. The first translational studies have demonstrated the safety and feasibility of the technique in patients with prostate, renal, breast and pancreatic cancer, as well as revealing a successful response to treatment in breast and prostate cancer patients at an earlier stage than multiparametric MRI. This review will focus on the strengths of the technique and its applications in the area of oncological body MRI including noninvasive characterisation of disease aggressiveness, mapping of tumour heterogeneity, and early response assessment. A comparison of hyperpolarised 13C-MRI with state-of-the-art multiparametric MRI is likely to reveal the unique additional information and applications offered by the technique.

Implication of BMP7 in Human Mantle Cell Lymphoma (MCL) Secondary Drug Resistance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2589-2589
Author(s):  
Valerie Camara-Clayette ◽  
Serge Koscielny ◽  
Thierry Lamy ◽  
Thierry Fest ◽  
Marc Bernard ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Rna Interference ◽  
Cell Line ◽  
Fold Change ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Reverse Direction ◽  
Dna Chips ◽  
Absolute Value ◽  
Two Samples

Abstract Despite a high response rate to 1st line chemotherapy, the probability of cure is very low in MCL. Secondary drug resistance invariably develops and the identification of mechanisms involved in this secondary drug resistance is a major challenge. We choose to track at a tumor level which genes are associated to the appearance of secondary drug resistance. The strategy was based on the use of paired samples from the same patient in order to control inter-patients variability. Five MCL patients had tumor samples collected from the same tissue before therapy and after failure. Two patients had refractory disease (non responders) and three achieved an objective response to therapy (responders). For each patient, pairs of samples from the same patient were co-hybridized on Agilent dual color DNA chips. Four DNA-chips were processed per patient (dye swap + replicate). The statistical analysis concentrated on variations in gene expression between the two samples from each patient. Each gene was analysed independently from the others. A multiple regression model (GLM procedure, SAS 8.2, Cary, NC, USA) was used to analyse the relation between the fold change in expression between the two samples of the same patient and several parameters including the response to treatment. Genes were selected on the basis of the absolute value of the coefficient associated to response to treatment. This absolute value was then expressed as a fold-change ratio (FCR), or ratio between the mean fold changes in responders and in non responders. Nineteen genes with a FCR greater than 2 and a P value < 10–6 were selected. FCR values larger than 5 were observed for CD69 (FCR=7.7) and BMP7 (FCR=7.0). Seventeen of the selected genes (89%) had a decreased expression at relapse in responders and an increased expression in non responders. The variation in expression according to response to therapy was in the reverse direction for the two remaining genes (BMP7 and TRAF5). The expression of TRAF5 decreased in non responders and remained unchanged in responders. In responders, the expression of BMP7, which was very low before treatment, was multiplied by about 8 after relapse, and did not vary in non responders. Because of this increase in expression, observed only in responders, BMP7 was considered as a major gene probably involved in secondary drug resistance. The possibility to interfere with its activity using miRNA was tested on JEKO cell line. JEKO cell line (EBV - MCL cell line) spontaneously express BMP7 and do not show growth inhibition when exposed in vitro to high concentration of BMP7. BMP7 RNA interference markedly increased necrosis (from 8.3% to 31.5%; P<0.05) of JEKO exposed to Bortezomide pointing BMP7 as a key gene involved in drug resistance. In conclusion, the patient oriented strategy is extremely powerful and permits relevant gene selection with a limited number of samples. Biologic validation with RNA interference confirms the relevance of this approach. Further investigations concerning the role of BMP7 and its possible use as a target for therapy are under investigation.

scholarly journals The amino acid metabolism is essential for evading physical plasma-induced tumour cell death

2021 ◽  
Author(s):  
Rajesh Kumar Gandhirajan ◽  
Dorothee Meyer ◽  
Sanjeev Kumar Sagwal ◽  
Klaus-Dieter Weltmann ◽  
Thomas von Woedtke ◽  
...  
Keyword(s):  
Cell Death ◽  
Amino Acid ◽  
Plasma Treatment ◽  
Tumour Cell ◽  
Cancer Metabolism ◽  
Tumour Cells ◽  
Metabolic Reprogramming ◽  
Metabolic Substrates ◽  
Physical Plasma

Abstract Background Recent studies have emphasised the important role of amino acids in cancer metabolism. Cold physical plasma is an evolving technology employed to target tumour cells by introducing reactive oxygen species (ROS). However, limited understanding is available on the role of metabolic reprogramming in tumour cells fostering or reducing plasma-induced cancer cell death. Methods The utilisation and impact of major metabolic substrates of fatty acid, amino acid and TCA pathways were investigated in several tumour cell lines following plasma exposure by qPCR, immunoblotting and cell death analysis. Results Metabolic substrates were utilised in Panc-1 and HeLa but not in OVCAR3 and SK-MEL-28 cells following plasma treatment. Among the key genes governing these pathways, ASCT2 and SLC3A2 were consistently upregulated in Panc-1, Miapaca2GR, HeLa and MeWo cells. siRNA-mediated knockdown of ASCT2, glutamine depletion and pharmacological inhibition with V9302 sensitised HeLa cells to the plasma-induced cell death. Exogenous supplementation of glutamine, valine or tyrosine led to improved metabolism and viability of tumour cells following plasma treatment. Conclusion These data suggest the amino acid influx driving metabolic reprogramming in tumour cells exposed to physical plasma, governing the extent of cell death. This pathway could be targeted in combination with existing anti-tumour agents.

scholarly journals Cancer Metabolism and the Evasion of Apoptotic Cell Death

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1144 ◽  
Author(s):  
Aditi Sharma ◽  
Lawrence H. Boise ◽  
Mala Shanmugam
Keyword(s):  
Cell Death ◽  
Cancer Metabolism ◽  
Apoptotic Cell ◽  
Therapy Resistance ◽  
Nutrient Acquisition ◽  
Cellular Growth ◽  
Cancer Hallmarks ◽  
Primary Focus ◽  
Multicellular Organisms ◽  
Energy Dependent

Cellular growth and proliferation depend upon the acquisition and synthesis of specific metabolites. These metabolites fuel the bioenergy, biosynthesis, and redox potential required for duplication of cellular biomass. Multicellular organisms maintain tissue homeostasis by balancing signals promoting proliferation and removal of cells via apoptosis. While apoptosis is in itself an energy dependent process activated by intrinsic and extrinsic signals, whether specific nutrient acquisition (elevated or suppressed) and their metabolism regulates apoptosis is less well investigated. Normal cellular metabolism is regulated by lineage specific intrinsic features and microenvironment driven extrinsic features. In the context of cancer, genetic abnormalities, unconventional microenvironments and/or therapy engage constitutive pro-survival signaling to re-program and rewire metabolism to maintain survival, growth, and proliferation. It thus becomes particularly relevant to understand whether altered nutrient acquisition and metabolism in cancer can also contribute to the evasion of apoptosis and consequently therapy resistance. Our review attempts to dissect a causal relationship between two cancer hallmarks, i.e., deregulated cellular energetics and the evasion of programmed cell death with primary focus on the intrinsic pathway of apoptosis.

scholarly journals Glioblastoma-derived cells in vitro unveil the spectrum of drug resistance capability – comparative study of tumour chemosensitivity in different culture systems

2017 ◽  
Vol 37 (3) ◽  
Author(s):  
Monika Witusik-Perkowska ◽  
Magdalena Zakrzewska ◽  
Beata Sikorska ◽  
Wielislaw Papierz ◽  
Dariusz J. Jaskolski ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Death ◽  
Expression Pattern ◽  
Epithelial To Mesenchymal Transition ◽  
Experimental Models ◽  
Response To Treatment ◽  
Mesenchymal Transition ◽  
Serum Free ◽  
Culture Models

Resistance to cancer drugs is a complex phenomenon which could be influenced by in vitro conditions. However, tumour-derived cell cultures are routinely used for studies related to mechanisms of drug responsiveness or the search for new therapeutic approaches. The purpose of our work was to identify the potential differences in drug resistance and response to treatment of glioblastoma with the use of three in vitro models: traditional adherent culture, serum-free spheroid culture and novel adherent serum-free culture.The experimental models were evaluated according to ‘stemness state‘ and epithelial-to-mesenchymal transition (EMT) status, invasion capability and their expression pattern of genes related to the phenomenon of tumour drug resistance. Additionally, the response to drug treatments of three different culture models was compared with regard to the type of cell death.Multi-gene expression profiling revealed differences between examined culture types with regard to the expression pattern of the selected genes. Functionally, the examined genes were related to drug resistance and metabolism, DNA damage and repair and cell cycle control, and included potential therapeutic targets.Cytotoxicity analyses confirmed that environmental factors can influence not only the molecular background of glioblastoma drug-resistance and efficiency of treatment, but also the mechanisms/pathways of cell death, which was reflected by a distinct intensification of apoptosis and autophagy observed in particular culture models. Our results suggest that parallel exploitation of different in vitro experimental models can be used to reveal the spectrum of cancer cell resistance capability, especially regarding intra-heterogeneous glioblastomas.

scholarly journals Glycolytic suppression dramatically changes the intracellular metabolic profile of multiple cancer cell lines in a mitochondrial metabolism-dependent manner

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Reika Shiratori ◽  
Kenta Furuichi ◽  
Masashi Yamaguchi ◽  
Natsumi Miyazaki ◽  
Haruna Aoki ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Mitochondrial Function ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Dependent Manner ◽  
Multiple Cancer ◽  
Cellular Survival ◽  
Pancreatic Cancer Cells ◽  
Tca Cycle Intermediates

AbstractMost cancer cells rely on glycolysis to generate ATP, even when oxygen is available. However, merely inhibiting the glycolysis is insufficient for the eradication of cancer cells. One main reason for this is that cancer cells have the potential to adapt their metabolism to their environmental conditions. In this study, we investigated how cancer cells modify their intracellular metabolism when glycolysis is suppressed, using PANC-1 pancreatic cancer cells and two other solid tumor cell lines, A549 and HeLa. Our study revealed that glycolytically suppressed cells upregulated mitochondrial function and relied on oxidative phosphorylation (OXPHOS) to obtain the ATP necessary for their survival. Dynamic changes in intracellular metabolic profiles were also observed, reflected by the reduced levels of TCA cycle intermediates and elevated levels of most amino acids. Glutamine and glutamate were important for this metabolic reprogramming, as these were largely consumed by influx into the TCA cycle when the glycolytic pathway was suppressed. During the reprogramming process, activated autophagy was involved in modulating mitochondrial function. We conclude that upon glycolytic suppression in multiple types of tumor cells, intracellular energy metabolism is reprogrammed toward mitochondrial OXPHOS in an autophagy-dependent manner to ensure cellular survival.

scholarly journals Metabolic Reprogramming of Triple-Negative Breast Cancer: The Role of miRNAs

2017 ◽  
Vol 3 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Amal Qattan
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Metabolism ◽  
Current Knowledge ◽  
Human Cancer ◽  
Tricarboxylic Acid Cycle ◽  
Locally Advanced ◽  
Mrna Translation ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype

AbstractMicroRNAs (miRNAs) are well known to influence the expression of the genes that regulate critical cellular functions. Various reports have suggested that they play critical roles in breast cancer metabolism through the regulation of various metabolic pathways, including the metabolism of glucose, lipids, glycolysis and the mitochondrial tricarboxylic acid cycle (TCA). miRNAs regulate the metabolic process by targeting key molecules (enzymes, kinases transporters) or by modifying the expression of key transcription molecules. In addition, miRNAs can indirectly regulate mRNA translation by targeting chromatin-remodeling enzymes. Furthermore, miRNAs influence the expression of both oncogenes and tumor suppressors and have a major impact on PI3K/AKT, HIF, and MYC signal transduction, which contributes to the metabolic phenotype in human cancer. Although human epidermal growth factor and endocrine therapies have been effective in treating breast cancer, for locally advanced and distant metastases mortality remains high. Drug resistance and recurrence remain major hurdles for advanced breast cancer therapy. Given the critical influence of metabolic reprogramming in the progression of neoplasm, tumorigenesis and metastasis, research should focus on novel targets of metabolic enzymes to reverse drug resistance and improve overall survival rates. Blocking the miRNAs that contribute to metabolic reprogramming or the use of exogenous miRNAs as antisense oligonucleotides, may be an effective way to treat aggressive, chemo-resistant cancers. This review summarizes current knowledge on the mechanism of action of miRNAs in altering the metabolism of cancer cells and presents possible therapeutic approaches to treating breast cancers that are resistant to current drugs.

scholarly journals Phytochemicals targeting metabolic reprogramming in cancer: an assessment of role, mechanisms, pathways and therapeutic relevance

2020 ◽  
Author(s):  
Asifa Khan ◽  
Shumaila Siddiqui ◽  
Syed Husain ◽  
Sybille Mazurek ◽  
Mohammad Askandar Iqbal
Keyword(s):  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Therapeutic Benefit ◽  
Metabolic Reprogramming ◽  
Normal Cells ◽  
Cancer Hallmarks ◽  
Metabolic Transformation ◽  
Regulation Of Growth ◽  
Diverse Plant

The metabolism of cancer is remarkably different from that of normal cells and confers variety of benefits including the promotion of other cancer hallmarks. As the rewired metabolism is a near-universal property of cancer cells, efforts are underway to exploit metabolic vulnerabilities for therapeutic benefit. In the continued search for a safer and effective ways of cancer treatment, structurally diverse plant-based compounds have gained substantial attention. Here, we present an extensive assessment of the role of phytocompounds in modulating cancer metabolism and make a case for the use of plant-based compounds in targeting metabolic vulnerabilities of cancer. We discuss the interactions of phytocompounds with major metabolic pathways and evaluate the role of phytochemicals in the regulation of growth signaling and transcriptional programs involved in metabolic transformation of cancer. Lastly, we examine the potential of these compounds in clinical management of cancer along with limitations and challenges

scholarly journals Overcoming Glucocorticoid Resistance in Acute Lymphoblastic Leukemia: Repurposed Drugs Can Improve the Protocol

2021 ◽  
Vol 11 ◽  
Author(s):  
Miguel Olivas-Aguirre ◽  
Liliana Torres-López ◽  
Igor Pottosin ◽  
Oxana Dobrovinskaya
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Metabolic Reprogramming ◽  
Leukemic Cells ◽  
Response To Treatment ◽  
Remission Induction ◽  
Central Component ◽  
Apoptosis Resistance ◽  
Treatment Protocols

Glucocorticoids (GCs) are a central component of multi-drug treatment protocols against T and B acute lymphoblastic leukemia (ALL), which are used intensively during the remission induction to rapidly eliminate the leukemic blasts. The primary response to GCs predicts the overall response to treatment and clinical outcome. In this review, we have critically analyzed the available data on the effects of GCs on sensitive and resistant leukemic cells, in order to reveal the mechanisms of GC resistance and how these mechanisms may determine a poor outcome in ALL. Apart of the GC resistance, associated with a decreased expression of receptors to GCs, there are several additional mechanisms, triggered by alterations of different signaling pathways, which cause the metabolic reprogramming, with an enhanced level of glycolysis and oxidative phosphorylation, apoptosis resistance, and multidrug resistance. Due to all this, the GC-resistant ALL show a poor sensitivity to conventional chemotherapeutic protocols. We propose pharmacological strategies that can trigger alternative intracellular pathways to revert or overcome GC resistance. Specifically, we focused our search on drugs, which are already approved for treatment of other diseases and demonstrated anti-ALL effects in experimental pre-clinical models. Among them are some “truly” re-purposed drugs, which have different targets in ALL as compared to other diseases: cannabidiol, which targets mitochondria and causes the mitochondrial permeability transition-driven necrosis, tamoxifen, which induces autophagy and cell death, and reverts GC resistance through the mechanisms independent of nuclear estrogen receptors (“off-target effects”), antibiotic tigecycline, which inhibits mitochondrial respiration, causing energy crisis and cell death, and some anthelmintic drugs. Additionally, we have listed compounds that show a classical mechanism of action in ALL but are not used still in treatment protocols: the BH3 mimetic venetoclax, which inhibits the anti-apoptotic protein Bcl-2, the hypomethylating agent 5-azacytidine, which restores the expression of the pro-apoptotic BIM, and compounds targeting the PI3K-Akt-mTOR axis. Accordingly, these drugs may be considered for the inclusion into chemotherapeutic protocols for GC-resistant ALL treatments.

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