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

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

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Targeting Cellular Metabolism Modulates Head and Neck Oncogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms20163960 ◽

2019 ◽

Vol 20 (16) ◽

pp. 3960 ◽

Cited By ~ 1

Author(s):

Yi-Ta Hsieh ◽

Yi-Fen Chen ◽

Shu-Chun Lin ◽

Kuo-Wei Chang ◽

Wan-Chun Li

Keyword(s):

Head And Neck ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Molecular Level ◽

Review Article ◽

Metabolic Reprogramming ◽

Prognostic Indicators ◽

Normal Cells ◽

Anti Cancer ◽

Great Energy

Considering the great energy and biomass demand for cell survival, cancer cells exhibit unique metabolic signatures compared to normal cells. Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. Recent findings have shown that environmental challenges, as well as intrinsic metabolic manipulations, could modulate HNSCC experimentally and serve as clinic prognostic indicators, suggesting that a better understanding of dynamic metabolic changes during HNSCC development could be of great benefit for developing adjuvant anti-cancer schemes other than conventional therapies. However, the following questions are still poorly understood: (i) how does metabolic reprogramming occur during HNSCC development? (ii) how does the tumorous milieu contribute to HNSCC tumourigenesis? and (iii) at the molecular level, how do various metabolic cues interact with each other to control the oncogenicity and therapeutic sensitivity of HNSCC? In this review article, the regulatory roles of different metabolic pathways in HNSCC and its microenvironment in controlling the malignancy are therefore discussed in the hope of providing a systemic overview regarding what we knew and how cancer metabolism could be translated for the development of anti-cancer therapeutic reagents.

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Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

British Journal of Cancer ◽

10.1038/s41416-019-0666-4 ◽

2019 ◽

Vol 122 (1) ◽

pp. 1-3 ◽

Cited By ~ 4

Author(s):

Adrian L. Harris

Keyword(s):

Metabolic Pathways ◽

Trial Design ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Critical Role ◽

Therapeutic Approaches ◽

Preclinical Models ◽

Wide Range ◽

Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

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Role of dendritic cell metabolic reprogramming in tumor immune evasion

International Immunology ◽

10.1093/intimm/dxaa036 ◽

2020 ◽

Vol 32 (7) ◽

pp. 485-491 ◽

Cited By ~ 2

Author(s):

Michael P Plebanek ◽

Michael Sturdivant ◽

Nicholas C DeVito ◽

Brent A Hanks

Keyword(s):

Dendritic Cell ◽

Metabolic Pathways ◽

Checkpoint Inhibitor ◽

Therapeutic Strategies ◽

Metabolic Reprogramming ◽

Combination Immunotherapy ◽

Tumor Immune Evasion ◽

Effector T Cell ◽

Cell Responses

Abstract The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.

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Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Cancers ◽

10.3390/cancers12020404 ◽

2020 ◽

Vol 12 (2) ◽

pp. 404 ◽

Cited By ~ 6

Author(s):

Guo ◽

Tan ◽

Chen ◽

Wang ◽

Feng

Keyword(s):

Chinese Medicine ◽

Cancer Therapy ◽

Traditional Chinese Medicine ◽

Cancer Cells ◽

Metabolic Pathways ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Traditional Chinese Medicines ◽

Chinese Medicines ◽

Incidence And Mortality

Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

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Peroxisome Metabolism in Cancer

Cells ◽

10.3390/cells9071692 ◽

2020 ◽

Vol 9 (7) ◽

pp. 1692 ◽

Cited By ~ 1

Author(s):

Jung-Ae Kim

Keyword(s):

Metabolic Pathways ◽

Cancer Metabolism ◽

Cell Metabolism ◽

Critical Role ◽

Acid Oxidation ◽

Metabolic Dysregulation ◽

Human Disorders ◽

Peroxisomal Function ◽

Target Cancer

Peroxisomes are metabolic organelles involved in lipid metabolism and cellular redoxbalance. Peroxisomal function is central to fatty acid oxidation, ether phospholipid synthesis, bile acidsynthesis, and reactive oxygen species homeostasis. Human disorders caused by genetic mutations inperoxisome genes have led to extensive studies on peroxisome biology. Peroxisomal defects are linkedto metabolic dysregulation in diverse human diseases, such as neurodegeneration and age-relateddisorders, revealing the significance of peroxisome metabolism in human health. Cancer is a diseasewith metabolic aberrations. Despite the critical role of peroxisomes in cell metabolism, the functionaleects of peroxisomes in cancer are not as well recognized as those of other metabolic organelles,such as mitochondria. In addition, the significance of peroxisomes in cancer is less appreciated thanit is in degenerative diseases. In this review, I summarize the metabolic pathways in peroxisomesand the dysregulation of peroxisome metabolism in cancer. In addition, I discuss the potential ofinactivating peroxisomes to target cancer metabolism, which may pave the way for more eectivecancer treatment.

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Wnt Signaling in Cancer Metabolism and Immunity

Cancers ◽

10.3390/cancers11070904 ◽

2019 ◽

Vol 11 (7) ◽

pp. 904 ◽

Cited By ~ 23

Author(s):

Sara El-Sahli ◽

Ying Xie ◽

Lisheng Wang ◽

Sheng Liu

Keyword(s):

Wnt Signaling ◽

Cancer Cells ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Tumor Initiating Cells ◽

Tumor Plasticity ◽

Anti Cancer ◽

Wnt Ligands ◽

Canonical Wnt

The Wingless (Wnt)/β-catenin pathway has long been associated with tumorigenesis, tumor plasticity, and tumor-initiating cells called cancer stem cells (CSCs). Wnt signaling has recently been implicated in the metabolic reprogramming of cancer cells. Aberrant Wnt signaling is considered to be a driver of metabolic alterations of glycolysis, glutaminolysis, and lipogenesis, processes essential to the survival of bulk and CSC populations. Over the past decade, the Wnt pathway has also been shown to regulate the tumor microenvironment (TME) and anti-cancer immunity. Wnt ligands released by tumor cells in the TME facilitate the immune evasion of cancer cells and hamper immunotherapy. In this review, we illustrate the role of the canonical Wnt/β-catenin pathway in cancer metabolism and immunity to explore the potential therapeutic approach of targeting Wnt signaling from a metabolic and immunological perspective.

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Extracellular Vesicles in Cancer Metabolism: Implications for Cancer Diagnosis and Treatment

Technology in Cancer Research & Treatment ◽

10.1177/15330338211037821 ◽

2021 ◽

Vol 20 ◽

pp. 153303382110378

Author(s):

Qian Zhang ◽

Xiangling Yang ◽

Huanliang Liu

Keyword(s):

Cancer Cells ◽

Extracellular Vesicles ◽

Cancer Diagnosis ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Bioactive Molecules ◽

Diagnosis And Treatment ◽

Existing Problems ◽

Non Coding Rnas

Metabolic reprogramming is one of the most common characteristics of cancer cells. The metabolic alterations of glucose, amino acids and lipids can support the aggressive phenotype of cancer cells. Exosomes, a kind of extracellular vesicles, participate in the intercellular communication through transferring bioactive molecules. Increasing evidence has demonstrated that enzymes, metabolites and non-coding RNAs in exosomes are responsible for the metabolic alteration of cancer cells. In this review, we summarize the past and recent findings of exosomes in altering cancer metabolism and elaborate on the role of the specific enzymes, metabolites and non-coding RNAs transferred by exosomes. Moreover, we give evidence of the role of exosomes in cancer diagnosis and treatment. Finally, we discuss the existing problems in the study and application of exosomes in cancer diagnosis and treatment.

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Cancer and metabolism

Oxford Textbook of Oncology ◽

10.1093/med/9780199656103.003.0013_update_001 ◽

2016 ◽

pp. 119-124

Author(s):

Cameron Snell ◽

Kevin C. Gatter ◽

Adrian L. Harris ◽

Francesco Pezzella

Keyword(s):

Tumour Growth ◽

Glycogen Synthesis ◽

Metabolic Reprogramming ◽

Suppressor Activity ◽

Metabolic Switch ◽

Metabolic Genes ◽

Tumour Suppressor Activity ◽

Metabolic Transformation ◽

The Relationship

This chapter covers the relationship between cancer and metabolism. It discusses the role of angiogenesis and metabolic reprogramming in influencing tumour growth. The transcription factors that orchestrate the metabolic switch are discussed. The chapter presents an overview of the contribution of tumour suppressors to increased glycolysis. The metabolic changes that support uncontrolled proliferation such as lactate and pH levels, hypoxia, and reactive oxygen species are discussed. The chapter also covers the contribution of metabolic genes with oncogenic or tumour suppressor activity to metabolic transformation, the upregulation of lipid biosynthesis in cancer, and glycogen synthesis in cancer. The chapter concludes with a description of the potential strategies for targeting metabolic transformation.

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

British Journal of Cancer ◽

10.1038/s41416-021-01335-8 ◽

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.

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Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

Cells ◽

10.3390/cells9010161 ◽

2020 ◽

Vol 9 (1) ◽

pp. 161 ◽

Cited By ~ 5

Author(s):

Lonneke V. Nouwen ◽

Bart Everts

Keyword(s):

Immune Response ◽

Dendritic Cells ◽

Amino Acid ◽

Immune Responses ◽

Metabolic Pathways ◽

Immune Escape ◽

Mammalian Target Of Rapamycin ◽

Metabolic Reprogramming ◽

First Line

Myeloid cells, including macrophages and dendritic cells, represent an important first line of defense against infections. Upon recognition of pathogens, these cells undergo a metabolic reprogramming that supports their activation and ability to respond to the invading pathogens. An important metabolic regulator of these cells is mammalian target of rapamycin (mTOR). During infection, pathogens use host metabolic pathways to scavenge host nutrients, as well as target metabolic pathways for subversion of the host immune response that together facilitate pathogen survival. Given the pivotal role of mTOR in controlling metabolism and DC and macrophage function, pathogens have evolved strategies to target this pathway to manipulate these cells. This review seeks to discuss the most recent insights into how pathogens target DC and macrophage metabolism to subvert potential deleterious immune responses against them, by focusing on the metabolic pathways that are known to regulate and to be regulated by mTOR signaling including amino acid, lipid and carbohydrate metabolism, and autophagy.

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