bims-kracam 2021-07-18 papers

on K-Ras in cancer metabolism

Issue of 2021–07–18
seventeen papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development

Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment.
Cancer metabolism: looking forward.
Metabolic reprogramming in prostate cancer.
The Role of Tumour Metabolism in Cisplatin Resistance.
Physiological impact of in vivo stable isotope tracing on cancer metabolism.
Breast cancer fibroblasts and cross-talk.
Hypoxia Signaling in Cancer: From Basics to Clinical Practice.
Autophagy and Tumorigenesis.
Amino Acids in Autophagy: Regulation and Function.
Vitamin C (ascorbate) and redox topics in cancer.
p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage.
Gastric Cancer Stem Cells: A Glimpse on Metabolic Reprogramming.
Glucose Metabolism: The Metabolic Signature of Tumor Associated Macrophage.
Regulatory Mechanisms of LncRNAs in Cancer Glycolysis: Facts and Perspectives.
SI-MOIRAI: A new method to identify and quantify the metabolic fate of nucleotides.
Exploration of therapeutic applicability and different signaling mechanism of various phytopharmacological agents for treatment of breast cancer.
Valproic acid Suppresses Breast Cancer Cell Growth Through Triggering Pyruvate Kinase M2 Isoform Mediated Warburg Effect.

Nat Rev Cancer. 2021 Jul 09.

Metabolic networks in mutant KRAS-driven tumours: tissue specificities and the microenvironment.

Samuel A Kerk, Thales Papagiannakopoulos, Yatrik M Shah, Costas A Lyssiotis.

Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.

DOI: https://doi.org/10.1038/s41568-021-00375-9
Nat Rev Cancer. 2021 Jul 16.

Cancer metabolism: looking forward.

Inmaculada Martínez-Reyes, Navdeep S Chandel.

Tumour initiation and progression requires the metabolic reprogramming of cancer cells. Cancer cells autonomously alter their flux through various metabolic pathways in order to meet the increased bioenergetic and biosynthetic demand as well as mitigate oxidative stress required for cancer cell proliferation and survival. Cancer driver mutations coupled with environmental nutrient availability control flux through these metabolic pathways. Metabolites, when aberrantly accumulated, can also promote tumorigenesis. The development and application of new technologies over the last few decades has not only revealed the heterogeneity and plasticity of tumours but also allowed us to uncover new metabolic pathways involved in supporting tumour growth. The tumour microenvironment (TME), which can be depleted of certain nutrients, forces cancer cells to adapt by inducing nutrient scavenging mechanisms to sustain cancer cell proliferation. There is growing appreciation that the metabolism of cell types other than cancer cells within the TME, including endothelial cells, fibroblasts and immune cells, can modulate tumour progression. Because metastases are a major cause of death of patients with cancer, efforts are underway to understand how metabolism is harnessed by metastatic cells. Additionally, there is a new interest in exploiting cancer genetic analysis for patient stratification and/or dietary interventions in combination with therapies that target metabolism. In this Perspective, we highlight these main themes that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing questions that remain unanswered.

DOI: https://doi.org/10.1038/s41568-021-00378-6
Br J Cancer. 2021 Jul 14.

Metabolic reprogramming in prostate cancer.

Fahim Ahmad, Murali Krishna Cherukuri, Peter L Choyke.

Although low risk localised prostate cancer has an excellent prognosis owing to effective treatments, such as surgery, radiation, cryosurgery and hormone therapy, metastatic prostate cancer remains incurable. Existing therapeutic regimens prolong life; however, they are beset by problems of resistance, resulting in poor outcomes. Treatment resistance arises primarily from tumour heterogeneity, altered genetic signatures and metabolic reprogramming, all of which enable the tumour to serially adapt to drugs during the course of treatment. In this review, we focus on alterations in the metabolism of prostate cancer, including genetic signatures and molecular pathways associated with metabolic reprogramming. Advances in our understanding of prostate cancer metabolism might help to explain many of the adaptive responses that are induced by therapy, which might, in turn, lead to the attainment of more durable therapeutic responses.

DOI: https://doi.org/10.1038/s41416-021-01435-5
Front Mol Biosci. 2021 ;8 691795

The Role of Tumour Metabolism in Cisplatin Resistance.

Lude Wang, Xiaoya Zhao, Jianfei Fu, Wenxia Xu, Jianlie Yuan.

  Cisplatin is a chemotherapy drug commonly used in cancer treatment. Tumour cells are more sensitive to cisplatin than normal cells. Cisplatin exerts an antitumour effect by interfering with DNA replication and transcription processes. However, the drug-resistance properties of tumour cells often cause loss of cisplatin efficacy and failure of chemotherapy, leading to tumour progression. Owing to the large amounts of energy and compounds required by tumour cells, metabolic reprogramming plays an important part in the occurrence and development of tumours. The interplay between DNA damage repair and metabolism also has an effect on cisplatin resistance; the molecular changes to glucose metabolism, amino acid metabolism, lipid metabolism, and other metabolic pathways affect the cisplatin resistance of tumour cells. Here, we review the mechanism of action of cisplatin, the mechanism of resistance to cisplatin, the role of metabolic remodelling in tumorigenesis and development, and the effects of common metabolic pathways on cisplatin resistance.

Keywords:  DNA damage repair; ROS; cisplatin; resistance; tumour metabolism

DOI:  https://doi.org/10.3389/fmolb.2021.691795
Mol Metab. 2021 Jul 10. pii: S2212-8778(21)00139-3. [Epub ahead of print] 101294

Physiological impact of in vivo stable isotope tracing on cancer metabolism.

Manuel Grima-Reyes, Adriana Martinez-Turtos, Ifat Abramovich, Eyal Gottlieb, Johanna Chiche, Jean-Ehrland Ricci.

   BACKGROUND: There is growing interest in the analysis of tumor metabolism to identify cancer-specific metabolic vulnerabilities and therapeutic targets. The identification of such candidate metabolic pathways mainly relies on the highly sensitive identification and quantitation of numerous metabolites and metabolic fluxes using metabolomics and isotope tracing analyses. However, nutritional requirements and metabolic routes used by cancer cells cultivated in vitro do not always reflect the metabolic demands of malignant cells within the tumor milieu. Therefore, to be able to understand how the metabolism of a tumor cell in its physiological environment differs from that of normal cells, these analyses must be performed in vivo.
SCOPE OF REVIEW: This review covers the physiological impact of the exogenous administration of a stable isotope tracer into cancer animal models. We discuss specific aspects of in vivo isotope tracing protocols based on discrete bolus injections of a labeled metabolite: the tracer administration per se and the fasting period prior to tracer administration. In addition, we illustrate the complex physiological scenarios that arise when studying tumor metabolism by isotopic labeling in animal models fed with a diet restricted in a specific amino acid. Finally, we provide strategies to minimize those limitations.
MAJOR CONCLUSIONS: There is a growing evidence that metabolic dependencies in cancers are influenced by tissue environments, cancer lineage, and genetic events. More and more studies are describing discrepancies in tumor metabolic dependencies when studied in in vitro settings or in in vivo models, including cancer patients. Therefore, in depth in vivo profiling of tumor metabolic routes within the appropriate patho-physiological environment will be key to identifying relevant alterations that contribute to cancer onset and progression.

Keywords:  Fasting; Inter-organ exchange; Stable isotope tracing; Tracer administration; Tumor metabolism

DOI:  https://doi.org/10.1016/j.molmet.2021.101294
Clin Chim Acta. 2021 Jul 13. pii: S0009-8981(21)00242-4. [Epub ahead of print]

Breast cancer fibroblasts and cross-talk.

Priyanila Magesh, Sanu Thankachan, Thejaswini Venkatesh, Padmanaban S Suresh.

  The breast tumor microenvironment is one of the crucial elements supporting breast cancer tumor progression and metastasis. The fibroblasts are the chief cellular component of the stromal microenvironment and are pathologically activated and differentiated into breast cancer-associated fibroblasts (CAFs). The catabolic phenotype of breast CAFs arises due to metabolic reprogramming of these fibroblasts under pseudo-hypoxic conditions. The metabolic intermediates and ATP produced by the breast CAFs are exploited by the neighboring cancer cells for energy generation. The growth factors, cytokines, and chemokines secreted by the CAFs help fuel tumor growth, invasion, and dissemination. Moreover, the interplay between breast CAFs and cancer cells, mediated by the growth factors, ROS, metabolic intermediates, exosomes, and catabolite transporters, aids in building a favorable microenvironment that promotes cancer cell proliferation, tumor progression, and metastasis. Therefore, identifying effective means to target the reprogrammed metabolism of the breast CAFs and the cross-communication between CAFs and cancer cells serve as promising strategies to develop anti-cancer therapeutics. Henceforth, the scope of the present review ranges from discussing the underlying characteristics of breast CAFs, mechanisms of metabolic reprogramming in breast CAFs, and the nature of interactions between breast CAFs and cancer cells to studying the intricacies of reprogrammed metabolism targeted cancer therapy.

Keywords:  Cancer-associated fibroblasts; G-protein estrogen receptor; Warburg effect; exosomes; extracellular matrix; metabolism

DOI:  https://doi.org/10.1016/j.cca.2021.07.011
Pathol Oncol Res. 2021 ;27 1609802

Hypoxia Signaling in Cancer: From Basics to Clinical Practice.

Anna Sebestyén, László Kopper, Titanilla Dankó, József Tímár.

  Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes. Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient (frequently induced by anemia), leading to a unique form of genetic reprogramming by hypoxia induced transcription factors (HIF). However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply. The consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile and the immunosuppressive microenvironment. Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance. Accordingly, it seems inevitable to combine various therapeutic modalities of cancer patients by existing anti-hypoxic agents such as anti-angiogenics, anti-anemia therapies or specific signaling pathway inhibitors. It is evident that there is an unmet need in cancer patients to develop targeted therapies of hypoxia to improve efficacies of various anti-cancer therapeutic modalities. The case has been opened recently due to the approval of the first-in-class HIF2α inhibitor.

Keywords:  angiogenesis; cancer; hypoxia; metabolism; therapy

DOI:  https://doi.org/10.3389/pore.2021.1609802
FEBS J. 2021 Jul 16.

Autophagy and Tumorigenesis.

Michael Rangel, Jerry Kong, Vrushank Bhatt, Khoosheh Khayati, Jessie Yanxiang Guo.

  Autophagy is a catabolic process that captures cellular waste and degrades them in the lysosome. The main function of autophagy is quality control of cytosolic proteins and organelles, and intracellular recycling of nutrients in order to maintain cellular homeostasis. Autophagy is upregulated in many cancers to promote cell survival, proliferation and metastasis. Both cell-autonomous autophagy (also known as tumor autophagy) and non-cell autonomous autophagy (also known as host autophagy) supports tumorigenesis through different mechanisms, including inhibition of p53 activation, sustaining redox homeostasis, maintenance of essential amino acids levels in order to support energy production and biosynthesis, and inhibition of anti-tumor immune responses. Therefore, autophagy may serve as a tumor-specific vulnerability and targeting autophagy could be a novel strategy in cancer treatment.

Keywords:  Autophagy; Cancer; Cancer Metabolism; Immune Response; Metastasis; p53

DOI:  https://doi.org/10.1111/febs.16125
Adv Exp Med Biol. 2021 ;1332 51-66

Amino Acids in Autophagy: Regulation and Function.

James Z Shen, Guoyao Wu, Shaodong Guo.

  Autophagy is a dynamic process in which the eukaryotic cells break down intracellular components by lysosomal degradation. Under the normal condition, the basal level of autophagy removes damaged organelles, misfolded proteins, or protein aggregates to keep cells in a homeostatic condition. Deprivation of nutrients (e.g., removal of amino acids) stimulates autophagy activity, promoting lysosomal degradation and the recycling of cellular components for cell survival. Importantly, insulin and amino acids are two main inhibitors of autophagy. They both activate the mTOR complex 1 (mTORC1) signaling pathway to inhibit the autophagy upstream of the uncoordinated-51 like kinase 1/2 (ULK1/2) complex that triggers autophagosome formation. In particular, insulin activates mTORC1 via the PI3K class I-AKT pathway; while amino acids activate mTORC1 either through the PI3K class III (hVps34) pathway or through a variety of amino acid sensors located in the cytosol or lysosomal membrane. These amino acid sensors control the translocation of mTORC1 from the cytosol to the lysosomal surface where mTORC1 is activated by Rheb GTPase, therefore regulating autophagy and the lysosomal protein degradation.

Keywords:  Amino acids; Arginine; Autophagosome; Autophagy; Calcium/calmodulin-dependent protein kinase kinase; Leucine; Lysosome; Mammalian target of rapamycin complex 1; Rag GTPase; Rheb

DOI:  https://doi.org/10.1007/978-3-030-74180-8_4
Antioxid Redox Signal. 2021 Jul 13.

Vitamin C (ascorbate) and redox topics in cancer.

Christophe Glorieux, Pedro Buc Calderon.

SIGNIFICANCE: Vitamin C (ascorbate), in regard to its effectiveness against malignancies, has had a controversial history in cancer treatment. It has been shown that in vitro and in vivo anticancer efficacy of ascorbate relies on its pro-oxidant effect mainly from an increased generation of reactive oxygen species (ROS). A growing understanding of its anticancer activities and pharmacokinetic properties has prompted scientists to reevaluate the significance of ascorbate in cancer treatment. Recent Advances: A recent resurge in ascorbate research emerged after discovering that, at high doses, ascorbate preferentially kills K-ras- and BRAF-mutant cancer cells. In addition, some of the main hallmarks of cancer cells, such as redox homeostasis and oxygen-sensing regulation (through inhibition of HIF-1α activity), are affected by vitamin C.
CRITICAL ISSUES: Currently, there is no clear consensus from literature in regards to the beneficial effects of antioxidants. Results from both human and animal studies provide no clear evidence about the benefit of antioxidant treatment in preventing or suppressing cancer development. Since pro-oxidants may affect both normal and tumor cells, the extremely low toxicity of ascorbate represents a main advantage. This guarantees the safe inclusion of ascorbate in clinical protocols to treat cancer patients.
FUTURE DIRECTIONS: Current research could focus on elucidating the wide array of reactions between ascorbate and reactive species, namely ROS, reactive nitrogen species (RNS) as well as reactive sulfide species (RSS), and their intracellular molecular targets. Unraveling these mechanisms could allow researchers to assess what could be the optimal combination of ascorbate with standard treatments.

DOI: https://doi.org/10.1089/ars.2020.8233
Proc Natl Acad Sci U S A. 2021 Jul 13. pii: e2019822118. [Epub ahead of print]118(28):

p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage.

Gen Li, Jun Wu, Le Li, Peng Jiang.

  Cancer cells acquire metabolic reprogramming to satisfy their high biogenetic demands, but little is known about how metabolic remodeling enables cancer cells to survive stress associated with genomic instability. Here, we show that the mitochondrial methylenetetrahydrofolate dehydrogenase (MTHFD2) is transcriptionally suppressed by p53, and its up-regulation by p53 inactivation leads to increased folate metabolism, de novo purine synthesis, and tumor growth in vivo and in vitro. Moreover, MTHFD2 unexpectedly promotes nonhomologous end joining in response to DNA damage by forming a complex with PARP3 to enhance its ribosylation, and the introduction of a PARP3-binding but enzymatically inactive MTHFD2 mutant (e.g., D155A) sufficiently prevents DNA damage. Notably, MTHFD2 depletion strongly restrains p53-deficient cell proliferation and sensitizes cells to chemotherapeutic agents, indicating a potential role for MTHFD2 depletion in the treatment of p53-deficient tumors.

Keywords:  MTHFD2; NHEJ; cell proliferation; folate metabolism; p53

DOI:  https://doi.org/10.1073/pnas.2019822118
Front Oncol. 2021 ;11 698394

Gastric Cancer Stem Cells: A Glimpse on Metabolic Reprogramming.

Martina Addeo, Giuseppina Di Paola, Henu Kumar Verma, Simona Laurino, Sabino Russi, Pietro Zoppoli, Geppino Falco, Pellegrino Mazzone.

  Gastric cancer (GC) is one of the most widespread causes of cancer-related death worldwide. Recently, emerging implied that gastric cancer stem cells (GCSCs) play an important role in the initiation and progression of GC. This subpopulation comprises cells with several features, such as self-renewal capability, high proliferating rate, and ability to modify their metabolic program, which allow them to resist current anticancer therapies. Metabolic pathway intermediates play a pivotal role in regulating cell differentiation both in tumorigenesis and during normal development. Thus, the dysregulation of both anabolic and catabolic pathways constitutes a significant opportunity to target GCSCs in order to eradicate the tumor progression. In this review, we discuss the current knowledge about metabolic phenotype that supports GCSC proliferation and we overview the compounds that selectively target metabolic intermediates of CSCs that can be used as a strategy in cancer therapy.

Keywords:  cancer stem cell (CSC); gastric cancer; metabolism; reprogramming; therapy

DOI:  https://doi.org/10.3389/fonc.2021.698394
Front Immunol. 2021 ;12 702580

Glucose Metabolism: The Metabolic Signature of Tumor Associated Macrophage.

Qi Zhang, Junli Wang, Dipesh Kumar Yadav, Xueli Bai, Tingbo Liang.

  Macrophages exist in most tissues of the body, where they perform various functions at the same time equilibrating with other cells to maintain immune responses in numerous diseases including cancer. Recently, emerging investigations revealed that metabolism profiles control macrophage phenotypes and functions, and in turn, polarization can trigger metabolic shifts in macrophages. Those findings implicate a special role of metabolism in tumor-associated macrophages (TAMs) because of the sophisticated microenvironment in cancer. Glucose is the major energy source of cells, especially for TAMs. However, the complicated association between TAMs and their glucose metabolism is still unclearly illustrated. Here, we review the recent advances in macrophage and glucose metabolism within the tumor microenvironment, and the significant transformations that occur in TAMs during the tumor progression. Additionally, we have also outlined the potential implications for macrophage-based therapies in cancer targeting TAMs.

Keywords:  cancer; glucose metabolism; macrophage; polarization; therapy

DOI:  https://doi.org/10.3389/fimmu.2021.702580
Cancer Manag Res. 2021 ;13 5317-5336

Regulatory Mechanisms of LncRNAs in Cancer Glycolysis: Facts and Perspectives.

Peng Huang, Shaomi Zhu, Xin Liang, Qinxiu Zhang, Xiaohong Luo, Chi Liu, Linjiang Song.

  Cancer cells exhibit distinct metabolic characteristics that employ glycolysis to provide energy and intermediary metabolites. This aberrant metabolic phenotype favors cancer progression. LncRNAs are transcripts longer than 200 nucleotides that do not encode proteins. LncRNAs contribute to cancer progression and therapeutic resistance and affect aerobic glycolysis via multiple mechanisms, including modulating glycolytic transporters and enzymes. Further, dysregulated signaling pathways are vital for glycolysis. In this review, we highlight regulatory mechanisms for lncRNAs in aerobic glycolysis that provide novel insights into cancer development. Moreover, a comprehensive understanding of the regulatory mechanisms of lncRNAs in aerobic glycolysis can provide new strategies for clinical cancer management.

Keywords:  cancer progression; glycolysis; lncRNA; signaling pathway

DOI:  https://doi.org/10.2147/CMAR.S314502
J Biochem. 2021 Jul 09. pii: mvab077. [Epub ahead of print]

SI-MOIRAI: A new method to identify and quantify the metabolic fate of nucleotides.

Yoshiki Ikeda, Akiyoshi Hirayama, Satoshi Kofuji, Yoshihisa Hirota, Ryo Kamata, Natsuki Osaka, Yuki Fujii, Mika Sasaki, Satsuki Ikeda, Eric P Smith, Robert Bachoo, Tomoyoshi Soga, Atsuo T Sasaki.

  Since the discovery of nucleotides over 100 years ago, extensive studies have revealed the importance of nucleotides for homeostasis, health, and disease. However, there remains no established method to investigate quantitively and accurately intact nucleotide incorporation into RNA and DNA. Herein, we report a new method, Stable-Isotope Measure Of Influxed Ribonucleic Acid Index (SI-MOIRAI), for the identification and quantification of the metabolic fate of ribonucleotides and their precursors. SI-MOIRAI, named after Greek goddesses of fate, combines a stable isotope-labeling flux assay with mass spectrometry to enable quantification of the newly synthesized ribonucleotides into r/m/tRNA under a metabolic stationary state. Using glioblastoma U87MG cells and a patient-derived xenograft (PDX) glioblastoma mouse model, SI-MOIRAI analyses showed that newly synthesized GTP was particularly and disproportionally highly utilized for rRNA and tRNA synthesis but not for mRNA synthesis in glioblastoma (GBM) in vitro and in vivo. Furthermore, newly synthesized pyrimidine nucleotides exhibited a significantly lower utilization rate for RNA synthesis than newly synthesized purine nucleotides. The results reveal the existence of discrete pathways and compartmentalization of purine and pyrimidine metabolism designated for RNA synthesis, demonstrating the capacity of SI-MOIRAI to reveal previously unknown aspects of nucleotide biology.

Keywords:  cancer metabolism; flux analysis; glioblastoma (GBM); mass spectrometry; metabolomics; nucleotide metabolism

DOI:  https://doi.org/10.1093/jb/mvab077
Biomed Pharmacother. 2021 Jul;pii: S0753-3322(21)00369-3. [Epub ahead of print]139 111584

Exploration of therapeutic applicability and different signaling mechanism of various phytopharmacological agents for treatment of breast cancer.

Vandana Singh, Kuldeep Kumar, Deepika Purohit, Ravinder Verma, Parijat Pandey, Saurabh Bhatia, Vinay Malik, Vineet Mittal, Md Habibur Rahman, Ghadeer M Albadrani, Mohammed W Arafah, Fatma M El-Demerdash, Muhammad Furqan Akhtar, Ammara Saleem, Mohamed Kamel, Agnieszka Najda, Mohamed M Abdel-Daim, Deepak Kaushik.

   BACKGROUND: Cancer is one of the most dreaded diseases characterized by uncontrolled proliferation of abnormal cells that occurs due to impairment of cell division and apoptosis process. Cancer is categorized into several types on the basis of affected organs and breast cancer (BC) is the most predominant cause of mortality among women. Although, several synthetic and semi-synthetic therapies have been developed for the treatment of BC but they exhibit numerous serious adverse effects therefore; pharmacological agents with fewer/no side effects need to be explored. Plants and phytoconstituents perhaps fulfill the aforementioned requirement and could serve as a potential and alternative therapy for BC treatment. The ongoing biomedical research, clinical trials and number of patents granted have further boosted the acceptance of the plants and plant-derived constituents in the effective treatment of BC.
PURPOSE OF STUDY: Various treatment strategies such as checkpoint inhibitors, targeting micro RNA, apoptotic pathway, BRCA-1 gene, P53 protein, P13K/Akt/mTOR pathway, notch signaling pathway, hedgehog/gli-1 signaling pathway, poly-ADP ribose polymerase inhibitors, mitogen-activated protein kinase inhibitors etc. are available for BC. In addition to these synthetic and semi-synthetic drug therapies, several natural constituents such as alkaloids, sesquiterpenes, polyphenols, flavonoids and diterpenoids from medicinal plants, vegetables and fruits are reported to possess promising anti-cancer activity. The purpose of the present review is to highlight the various signaling pathways through which plants/herbs show the anti-cancer potential especially against the BC.
STUDY DESIGN: The literature for the present study was collected from various databases such as Pubmed, Scopus, Chemical Abstracts, Medicinal and aromatic plant abstracts, Web of Science etc. The different patent databases were also reviewed for the anti-cancer (BC) potential of the particular herbs/plants and their formulations.
RESULT AND CONCLUSION: In this review, we have discussed the number of plants along with their patents of different herbal formulations which are being used for the treatment of BC and other types of cancers. We have also delineated the different signaling mechanisms through which they inhibit the growth of BC cells. In nutshell, we can conclude that large numbers of herbs or their extracts are reported for the treatment of BC. But still, there is further need for research in-depth to translate the use of natural products clinically BC treatment.

Keywords:  Breast cancer; Herbal formulations; Mitogen-activated protein kinase; Phytochemicals; Poly-ADP ribose polymerase

DOI:  https://doi.org/10.1016/j.biopha.2021.111584
Cell Transplant. 2021 Jan-Dec;30:30 9636897211027524

Valproic acid Suppresses Breast Cancer Cell Growth Through Triggering Pyruvate Kinase M2 Isoform Mediated Warburg Effect.

Zhen Li, Lina Yang, Shuai Zhang, Jiaqi Song, Huanran Sun, Changliang Shan, Dan Wang, Shuangping Liu.

  Energy metabolism programming is a hallmark of cancer, and serves as a potent target of cancer therapy. Valproic acid (VPA), a broad Class I histone deacetylases (HDACs) inhibitor, has been used as a therapeutic agent for cancer. However, the detail mechanism about the potential role of VPA on the Warburg effect in breast cancer remains unclear. In this study, we highlight that VPA significantly attenuates the Warburg effect by decreasing the expression of pyruvate kinase M2 isoform (PKM2), leading to inhibited cell proliferation and reduced colony formation in breast cancer MCF-7 and MDA-MB-231 cells. Mechanistically, Warburg effect suppression triggered by VPA was mediated by inactivation of ERK1/2 phosphorylation through reduced HDAC1 expression, resulting in suppressing breast cancer growth. In summary, we uncover a novel mechanism of VPA in regulating the Warburg effect which is essential for developing the effective approach in breast cancer therapy.

Keywords:  Valproic acid; Warburg effect; breast cancer; cell proliferation; histone deacetylases; pyruvate kinase M2 isoform

DOI:  https://doi.org/10.1177/09636897211027524