bims-kracam 2021-08-01 papers

on K-Ras in cancer metabolism

Issue of 2021‒08‒01
twenty-two papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development

Stopping the beating heart of cancer: KRAS reviewed.
Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells.
Cell death in pancreatic cancer: from pathogenesis to therapy.
UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth.
Vitamin D affects the Warburg effect and stemness maintenance of non-small-cell lung cancer cells by regulating PI3K/AKT/mTOR signaling pathway.
Two transition states of the glycogen shunt and two steady states of gene expression support metabolic flexibility and the Warburg effect in cancer.
Arginine depriving enzymes: applications as emerging therapeutics in cancer treatment.
Metabolism in the Tumour-Bone Microenvironment.
Histone Acetylation in the Epigenetic Regulation of Bone Metabolism and Related Diseases.
Multiple functions of pyruvate kinase M2 in various cell types.
Role of metformin and other metabolic drugs in the prevention and therapy of endocrine-related cancers.
Role of reactive oxygen species in tumors based on the 'seed and soil' theory: A complex interaction (Review).
Morpho-metabotyping the oxidative stress response.
Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.
Current cancer therapies and their influence on glucose control.
Anticancer mechanisms of phytochemical compounds: focusing on epigenetic targets.
Emerging role of nutritional short-chain fatty acids (SCFAs) against cancer via modulation of hematopoiesis.
Ketogenic Diet Prevents Paclitaxel-Induced Neuropathic Nociception through Activation of PPARγ Signaling Pathway and Inhibition of Neuroinflammation in Rat Dorsal Root Ganglion.
Therapeutic targeting of the hypoxic tumour microenvironment.
Mitochondrial regulation of ferroptosis.
Ferroptosis in the tumor microenvironment: perspectives for immunotherapy.
Monitoring autophagy-dependent ferroptosis.

Curr Opin Struct Biol. 2021 Jul 22. pii: S0959-440X(21)00097-X. [Epub ahead of print]71 136-147

Stopping the beating heart of cancer: KRAS reviewed.

Lorenz Herdeis, Daniel Gerlach, Darryl B McConnell, Dirk Kessler.

  It has taken four decades of research to see the first major breakthrough for KRAS-driven cancers. In particular, the last decade has seen a paradigm shift with the discovery of druggable pockets on KRAS and clinical efficacy with covalent KRASG12C inhibitors, culminating in the first approval of sotorasib monotherapy as second-line treatment in KRASG12C-driven non-small-cell lung cancer. Nevertheless, 85% of all KRAS-mutated cancers still lack novel agents. In this review, we will outline the structure, function, and post-translational modifications of KRAS and highlight the various approaches being adopted to drug KRAS, ranging from selective to pan concepts. The range of molecular modalities being explored, including PROTACs and glues, will also be described. Finally, an outlook toward the next wave of KRAS drugs and the challenges of resistance will be given.

Keywords:  KRAS, Protein-Protein Interaction, Cancer, Oncology, Resistance

DOI:  https://doi.org/10.1016/j.sbi.2021.06.013
Biochem Biophys Res Commun. 2021 Jul 26. pii: S0006-291X(21)01106-2. [Epub ahead of print]571 118-124

Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells.

Selahattin C Ozcan, Aydan Mutlu, Tugba H Altunok, Yunus Gurpinar, Aybike Sarioglu, Sabire Guler, Robertino J Muchut, Alberto A Iglesias, Serap Celikler, Paul M Campbell, Abdullah Yalcin.

  Activating mutations of the oncogenic KRAS in pancreatic ductal adenocarcinoma (PDAC) are associated with an aberrant metabolic phenotype that may be therapeutically exploited. Increased glutamine utilization via glutaminase-1 (GLS1) is one such feature of the activated KRAS signaling that is essential to cell survival and proliferation; however, metabolic plasticity of PDAC cells allow them to adapt to GLS1 inhibition via various mechanisms including activation of glycolysis, suggesting a requirement for combinatorial anti-metabolic approaches to combat PDAC. We investigated whether targeting the glycolytic regulator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) in combination with GLS1 can selectively prevent the growth of KRAS-transformed cells. We show that KRAS-transformation of pancreatic duct cells robustly sensitizes them to the dual targeting of GLS1 and PFKFB3. We also report that this sensitivity is preserved in the PDAC cell line PANC-1 which harbors an activating KRAS mutation. We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.

Keywords:  AZ PFKFB3 26; CB-839; GLS1; KRAS; PFKFB3; Pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.1016/j.bbrc.2021.07.070
Nat Rev Gastroenterol Hepatol. 2021 Jul 30.

Cell death in pancreatic cancer: from pathogenesis to therapy.

Xin Chen, Herbert J Zeh, Rui Kang, Guido Kroemer, Daolin Tang.

Pancreatic cancer is a devastating gastrointestinal cancer characterized by late diagnosis, limited treatment success and dismal prognosis. Exocrine tumours account for 95% of pancreatic cancers and the most common pathological type is pancreatic ductal adenocarcinoma (PDAC). The occurrence and progression of PDAC involve multiple factors, including internal genetic alterations and external inflammatory stimuli. The biology and therapeutic response of PDAC are further shaped by various forms of regulated cell death, such as apoptosis, necroptosis, ferroptosis, pyroptosis and alkaliptosis. Cell death induced by local or systemic treatments suppresses tumour proliferation, invasion and metastasis. However, unrestricted cell death or tissue damage might result in an inflammation-related immunosuppressive microenvironment, which is conducive to tumour progression or recurrence. The precise extent to which cell death affects PDAC is not yet well described. A growing body of preclinical and clinical studies document significant correlations between mutations (for example, in KRAS and TP53), stress responses (such as hypoxia and autophagy), metabolic reprogramming and chemotherapeutic responses. Here, we describe the molecular machinery of cell death, discuss the complexity and multifaceted nature of lethal signalling in PDAC cells, and highlight the challenges and opportunities for activating cell death pathways through precision oncology treatments.

DOI: https://doi.org/10.1038/s41575-021-00486-6
Proc Natl Acad Sci U S A. 2021 Aug 03. pii: e2103592118. [Epub ahead of print]118(31):

UDP-glucose pyrophosphorylase 2, a regulator of glycogen synthesis and glycosylation, is critical for pancreatic cancer growth.

Andrew L Wolfe, Qingwen Zhou, Eneda Toska, Jacqueline Galeas, Angel A Ku, Richard P Koche, Sourav Bandyopadhyay, Maurizio Scaltriti, Carlito B Lebrilla, Frank McCormick, Sung Eun Kim.

  UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models. We found that transcription of UGP2 is directly regulated by the Yes-associated protein 1 (YAP)-TEA domain transcription factor (TEAD) complex, identifying UGP2 as a bona fide YAP target gene. Loss of UGP2 leads to decreased intracellular glycogen levels and defects in N-glycosylation targets that are important for the survival of PDACs, including the epidermal growth factor receptor (EGFR). These critical roles of UGP2 in cancer maintenance, metabolism, and protein glycosylation may offer insights into therapeutic options for otherwise intractable PDACs.

Keywords:  N-glycosylation; PDAC; UDP-glucose; UGP2; glycogen

DOI:  https://doi.org/10.1073/pnas.2103592118
Curr Cancer Drug Targets. 2021 Jul 28.

Vitamin D affects the Warburg effect and stemness maintenance of non-small-cell lung cancer cells by regulating PI3K/AKT/mTOR signaling pathway.

Yiyan Song Yang, Songyisha Yang, Dejia Li, Wen Li.

  BACKGROUND: Non-small-cell lung cancer (NSCLC) is the most prevalent form of lung cancer, accounting for approximately 85% of all lung cancer cases and resulting in high morbidity and mortality. Previous studies have demonstrated that 1,25-dihydroxy-vitamin-D3 (vitamin D) exhibited anti-cancer activity against breast and prostate cancer.OBJECTIVES: The aim of the current study is to investigate the effect of vitamin D on NSCLC and its underlying mechanism.
METHODS: The effects of vitamin D on stemness maintenance and the Warburg effect in NSCLC cells were investigated both in vitro and in vivo.
RESULTS & DISCUSSION: In vitro experiments revealed that vitamin D inhibited glycolysis and stemness maintenance in A549 and NCI-H1975 cells. Both in vitro and in vivo experiments indicated that vitamin D attenuated the expression of metabolism-related enzymes associated with the Warburg effect (GLUT1, LDHA, HK2, and PKM2). In addition, vitamin D down-regulated the expression of stemness-related genes (Oct-4, SOX-2, and Nanog) and the expression of PI3K, AKT, and mTOR.
CONCLUSION: Overall, these findings suggest that vitamin D suppresses the Warburg effect and stemness maintenance in NSCLC cells via the inactivation of PI3K/AKT/mTOR signaling, thereby inhibiting the progression of NSCLC. The current study indicates that vitamin D is a potential candidate in therapeutic strategies against NSCLC.

Keywords:  1; 25-dihydroxy-vitamin-D3; Cancer stem cell; Non-small cell lung cancer; PI3K/AKT/mTOR; Warburg effect; stemness maintenance

DOI:  https://doi.org/10.2174/1568009621666210729100300
Neoplasia. 2021 Jul 21. pii: S1476-5586(21)00046-4. [Epub ahead of print]23(9): 879-886

Two transition states of the glycogen shunt and two steady states of gene expression support metabolic flexibility and the Warburg effect in cancer.

Douglas L Rothman, Robert G Shulman.

  Previously we suggested that the early Warburg effect can be explained by the use by cancer cells the glycogen shunt during a rapid increase in glucose concentration. In analogy to the Crabtree effect in yeast, the shunt plays a critical role in maintaining homeostasis of glycolytic intermediate levels during these transitions. We extend this analysis here, and propose that the recently appreciated flexibility of cancer cell glucose and glycogen metabolism involves 4 metabolic states that we recently identified in metabolic control analysis studies of yeast. Under stable conditions of low glucose and normal O2 yeast, and by analogy cancer, cells are in the Respiration State in which through gene expression for oxidizing non glucose substrates. When their environment changes to high glucose with reduced O2 levels, such as occur in tumors, they transition to the Glycolysis State due to gene expression of new glycolytic enzyme isoforms such as PKM2. These isoforms optimize metabolism to sustain the Warburg effect. When the changes in glucose and O2 levels are rapid there may be insufficient time for gene expression to adapt. The metabolic flexibility conferred by 2 states of the glycogen shunt allow the cells to survive these transitions. The model explains experimental observations in cancer such as the function of the glycogen shunt and the frequent expression of PKM2 in cells undergoing the Warburg Effect. A surprising conclusion is that the function of PKM2 is to maintain glycolytic intermediate homeostasis rather than controlling the glycolytic flux. The glycogen shunt may also have an important role in cancer metabolic reprogramming by allowing cancer cells to survive large glucose and oxygen changes during the selection of mutations that lead to the Warburg phenotype.

Keywords:  Glycogen Shunt; Homeostasis; Metabolic Flexibility; Oncogenesis; Warburg Effect

DOI:  https://doi.org/10.1016/j.neo.2021.06.004
Cancer Chemother Pharmacol. 2021 Jul 26.

Arginine depriving enzymes: applications as emerging therapeutics in cancer treatment.

Neha Kumari, Saurabh Bansal.

  Cancer is the second leading cause of death globally. Chemotherapy and radiation therapy and other medications are employed to treat various types of cancer. However, each treatment has its own set of side effects, owing to its low specificity. As a result, there is an urgent need for newer therapeutics that do not disrupt healthy cells' normal functioning. Depriving nutrient or non/semi-essential amino acids to which cancerous cells are auxotrophic remains one such promising anticancer strategy. L-Arginine (Arg) is a semi-essential vital amino acid involved in versatile metabolic processes, signaling pathways, and cancer cell proliferation. Hence, the administration of Arg depriving enzymes (ADE) such as arginase, arginine decarboxylase (ADC), and arginine deiminase (ADI) could be effective in cancer therapy. The Arg auxotrophic cancerous cells like hepatocellular carcinoma, human colon cancer, leukemia, and breast cancer cells are sensitive to ADE treatment due to low expression of crucial enzymes argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and ornithine transcarbamylase (OCT). These therapeutic enzyme treatments induce cell death through inducing autophagy, apoptosis, generation of oxidative species, i.e., oxidative stress, and arresting the progression and expansion of cancerous cells at certain cell cycle checkpoints. The enzymes are undergoing clinical trials and could be successfully exploited as potential anticancer agents in the future.

Keywords:  Arginase; Arginine decarboxylase; Arginine deiminase; Argininosuccinate synthetase; Auxotrophic cancer; Deprivation therapy; Therapeutic enzyme

DOI:  https://doi.org/10.1007/s00280-021-04335-w
Curr Osteoporos Rep. 2021 Jul 28.

Metabolism in the Tumour-Bone Microenvironment.

Jessica Whitburn, Claire M Edwards.

  PURPOSE OF REVIEW: For solid tumours such as breast and prostate cancer, and haematological malignancies such as myeloma, bone represents a supportive home, where the cellular crosstalk is known to underlie both tumour growth and survival, and the development of the associated bone disease. The importance of metabolic reprogramming is becoming increasingly recognised, particularly within cancer biology, enabling tumours to adapt to changing environments and pressures. This review will discuss our current understanding of metabolic requirements and adaptations within the tumour-bone microenvironment.RECENT FINDINGS: The bone provides a unique metabolic microenvironment, home to highly energy-intensive processes such as bone resorption and bone formation, both of which are dysregulated in the presence of cancer. Approaches such as metabolomics demonstrate metabolic plasticity in patients with advanced disease. Metabolic crosstalk between tumour cells and surrounding stroma supports disease pathogenesis. There is increasing evidence for a key role for metabolic reprogramming within the tumour-bone microenvironment to drive disease progression. As such, understanding these metabolic adaptations should reveal new therapeutic targets and approaches.

Keywords:  Bone; Cancer; Glycolysis; Metabolism; Metastasis; Microenvironment

DOI:  https://doi.org/10.1007/s11914-021-00695-7
Stem Cells Int. 2021 ;2021 8043346

Histone Acetylation in the Epigenetic Regulation of Bone Metabolism and Related Diseases.

Qinglu Tian, Shiqi Gao, Xuedong Zhou, Liwei Zheng, Yachuan Zhou.

As the earliest studied epigenetic modification, acetylation has been explored a lot through the years. While bone tissue acts as an indispensable part of body, researches aimed at the relationship between the bone and acetylation became necessary. Some environmental factors like diet may affect the metabolism status that some metabolites especially nicotinamide adenine dinucleotide (NAD) were found able to regulate intracellular histone acetylation in bone metabolism. This review focuses on representing the interaction among acetylation, metabolism, and the bone. The results showed that acetylation connects a lot with bone metabolism, while the explorations about related metabolites like acetyl-CoA or different environmental exposures are still limited. Some acetylation-related therapy methods of bone diseases based on metabolic regulation or epigenetic enzymes were also reviewed.

DOI: https://doi.org/10.1155/2021/8043346
J Cell Physiol. 2021 Jul 26.

Multiple functions of pyruvate kinase M2 in various cell types.

Yoon-Beom Lee, Jung K Min, Jae-Gyu Kim, Kim Cuong Cap, Rokibul Islam, Abu J Hossain, Oyungerel Dogsom, Amir Hamza, Shohel Mahmud, Dae R Choi, Yong-Sun Kim, Young-Ho Koh, Hyun-A Kim, Won-Suk Chung, Sang W Suh, Jae-Bong Park.

  Glucose metabolism is a mechanism by which energy is produced in form of adenosine triphosphate (ATP) by mitochondria and precursor metabolites are supplied to enable the ultimate enrichment of mature metabolites in the cell. Recently, glycolytic enzymes have been shown to have unconventional but important functions. Among these enzymes, pyruvate kinase M2 (PKM2) plays several roles including having conventional metabolic enzyme activity, and also being a transcriptional regulator and a protein kinase. Compared with the closely related PKM1, PKM2 is highly expressed in cancer cells and embryos, whereas PKM1 is dominant in mature, differentiated cells. Posttranslational modifications such as phosphorylation and acetylation of PKM2 change its cellular functions. In particular, PKM2 can translocate to the nucleus, where it regulates the transcription of many target genes. It is notable that PKM2 also acts as a protein kinase to phosphorylate several substrate proteins. Besides cancer cells and embryonic cells, astrocytes also highly express PKM2, which is crucial for lactate production via expression of lactate dehydrogenase A (LDHA), while mature neurons predominantly express PKM1. The lactate produced in cancer cells promotes tumor progress and that in astrocytes can be supplied to neurons and may act as a major source for neuronal ATP energy production. Thereby, we propose that PKM2 along with its different posttranslational modifications has specific purposes for a variety of cell types, performing unique functions.

Keywords:  PKM2; astrocyte; cancer cell; glycolysis

DOI:  https://doi.org/10.1002/jcp.30536
Curr Opin Pharmacol. 2021 Jul 23. pii: S1471-4892(21)00072-2. [Epub ahead of print]60 17-26

Role of metformin and other metabolic drugs in the prevention and therapy of endocrine-related cancers.

Antonio J León-González, Juan M Jiménez-Vacas, Antonio C Fuentes-Fayos, Andre Sarmento-Cabral, Aura D Herrera-Martínez, Manuel D Gahete, Raúl M Luque.

  Metabolic syndrome is associated with chronic diseases, including type 2 diabetes, cardiovascular diseases, and cancer. This review summarizes the current evidence on the antitumor effects of some relevant drugs currently used to manage metabolic-related pathologies (i.e. insulin and its analogs, metformin, statins, etc.) in endocrine-related cancers including breast cancer, prostate cancer, pituitary cancer, ovarian cancer, and neuroendocrine neoplasms. Although current evidence does not provide a clear antitumor role of several of these drugs, metformin seems to be a promising chemopreventive and adjuvant agent in cancer management, modulating tumor cell metabolism and microenvironment, through both AMP-activated protein kinase-dependent and -independent mechanisms. Moreover, its combination with statins might represent a promising therapeutic strategy to tackle the progression of endocrine-related tumors. However, further studies are needed to endorse the clinical relevance of these drugs as adjuvants for cancer chemotherapy.

Keywords:  Cancer; insulin; metabolic syndrome; metformin; statins

DOI:  https://doi.org/10.1016/j.coph.2021.06.002
Oncol Rep. 2021 Sep;pii: 208. [Epub ahead of print]46(3):

Role of reactive oxygen species in tumors based on the 'seed and soil' theory: A complex interaction (Review).

Wei Liang, Xinying He, Jianqiang Bi, Tingting Hu, Yunchuan Sun.

  Tumor microenvironment (TME) can serve as the 'soil' for the growth and survival of tumor cells and function synergically with tumor cells to mediate tumor progression and therapeutic resistance. Reactive oxygen species (ROS) is somewhat of a double‑edged sword for tumors. Accumulating evidence has reported that regulating ROS levels can serve an anti‑tumor role in the TME, including the promotion of cancer cell apoptosis, inhibition of angiogenesis, preventing immune escape, manipulating tumor metabolic reorganization and improving drug resistance. In the present review, the potential role of ROS in anti‑tumor therapy was summarized, including the possibility of directly or indirectly targeting the TME.

Keywords:  immune escape; metabolism recombination; reactive oxygen species; tumor angiogenesis; tumor drug resistance; tumor microenvironment

DOI:  https://doi.org/10.3892/or.2021.8159
Sci Rep. 2021 Jul 29. 11(1): 15471

Morpho-metabotyping the oxidative stress response.

Mate Rusz, Giorgia Del Favero, Yasin El Abiead, Christopher Gerner, Bernhard K Keppler, Michael A Jakupec, Gunda Koellensperger.

Oxidative stress and reactive oxygen species (ROS) are central to many physiological and pathophysiological processes. However, due to multiple technical challenges, it is hard to capture a comprehensive readout of the cell, involving both biochemical and functional status. We addressed this problem by developing a fully parallelized workflow for metabolomics (providing absolute quantities for > 100 metabolites including TCA cycle, pentose phosphate pathway, purine metabolism, glutathione metabolism, cysteine and methionine metabolism, glycolysis and gluconeogenesis) and live cell imaging microscopy. The correlative imaging strategy was applied to study morphological and metabolic adaptation of cancer cells upon short-term hydrogen peroxide (H2O2) exposure in vitro. The combination provided rich metabolic information at the endpoint of exposure together with imaging of mitochondrial effects. As a response, superoxide concentrations were elevated with a strong mitochondrial localization, and multi-parametric image analysis revealed a shift towards fragmentation. In line with this, metabolism reflected both the impaired mitochondrial function and shifts to support the first-line cellular defense and compensate for energy loss. The presented workflow combining high-end technologies demonstrates the applicability for the study of short-term oxidative stress, but it can be suitable for the in-depth study of various short-term oxidative and other cellular stress-related phenomena.

DOI: https://doi.org/10.1038/s41598-021-94585-8
Front Oncol. 2021 ;11 697894

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.

Guofeng Ma, Chun Li, Zhilei Zhang, Ye Liang, Zhijuan Liang, Yuanbin Chen, Liping Wang, Dan Li, Manqin Zeng, Wenhong Shan, Haitao Niu.

  Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.

Keywords:  PD-1/PD-L1 immune checkpoint; combination therapy; glucose metabolism; glutamine metabolism; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.697894
World J Diabetes. 2021 Jul 15. 12(7): 1010-1025

Current cancer therapies and their influence on glucose control.

Carly Yim, Kerry Mansell, Nassrein Hussein, Terra Arnason.

  This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs. Both of these classes have been in use in cancer therapy since the 1950s. Also considered are the phosphatidyl inositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-inhibitors that provide cancer response advantages by disrupting cell growth, proliferation and survival signaling pathways, and have been in clinical use as early as 2007. The final class to be reviewed are the monoclonal antibodies selected to function as immune checkpoint inhibitors (ICIs). These were first used in 2011 for advanced melanoma and are rapidly becoming widely utilized in many solid tumors. For each drug class, the literature has been reviewed to answer relevant questions about these medications related specifically to the characteristics of the hyperglycemia that develops with use. The incidence of new glucose elevations in euglycemic individuals, as well as glycemic changes in those with established diabetes has been considered, as has the expected onset of hyperglycemia from their first use. This comparison emphasizes that some classes exhibit very immediate impacts on glucose levels, whereas other classes can have lengthy delays of up to 1 year. A comparison of the spectrum of severity of hyperglycemic consequences stresses that the appearance of diabetic ketoacidosis is rare for all classes except for the ICIs. There are distinct differences in the reversibility of glucose elevations after treatment is stopped, as the mTOR inhibitors and ICI classes have persistent hyperglycemia long term. These four highlighted drug categories differ in their underlying mechanisms driving hyperglycemia, with clinical presentations ranging from potent yet transient insulin resistant states [type 2 diabetes mellitus (T2DM) -like] to rare permanent insulin-deficient causes of hyperglycemia. Knowledge of the relative incidence of new onset hyperglycemia and the underlying causes are critical to appreciate how and when to best screen and treat patients taking any of these cancer drug therapies.

Keywords:  5-fluorouracil analogs; Cancer therapy; Diabetes mellitus; Glucocorticoids; Hyperglycemia; Immune checkpoint inhibitors; adverse drug effects; mTOR inhibitors

DOI:  https://doi.org/10.4239/wjd.v12.i7.1010
Environ Sci Pollut Res Int. 2021 Jul 26.

Anticancer mechanisms of phytochemical compounds: focusing on epigenetic targets.

Nasreddine El Omari, Mohamed Bakha, Hamada Imtara, Fatima-Ezzahrae Guaouguaoua, Abdelaali Balahbib, Gokhan Zengin, Abdelhakim Bouyahya.

  It has recently been proven that epigenetic dysregulation is importantly involved in cell transformation and therefore induces cancerous diseases. The development of molecules called epidrugs, which target specifically different epigenetic modifications to restore cellular memory and therefore the treatment, became a real challenge currently. Currently, bioactive compounds of medicinal plants as epidrugs have been can identified and explored in cancer therapy. Indeed, these molecules can target specifically different epigenetic modulators including DNMT, HDAC, HAT, and HMT. Moreover, some compounds exhibit stochastic epigenetic actions on different pathways regulating cell memory. In this work, pharmacodynamic actions of natural epidrugs belonging to cannabinoids, carotenoids, chalcones, fatty acids, lignans, polysaccharides, saponins, secoiridoids, steroids, tannins, tanshinones, and other chemical classes we reported and highlighted. In this review, the effects of several natural bioactive compounds of epigenetic medications on cancerous diseases were highlighted. Numerous active molecules belonging to different chemical classes such as cannabinoids, carotenoids, fatty acids, lignans, polysaccharides, saponins, secoiridoids, steroids, tannins, and tanshinones are discussed in this review.

Keywords:  Cannabinoids; Carotenoids; Chalcones; Epidrugs; Epigenetic, Cancer

DOI:  https://doi.org/10.1007/s11356-021-15594-8
Crit Rev Food Sci Nutr. 2021 Jul 28. 1-18

Emerging role of nutritional short-chain fatty acids (SCFAs) against cancer via modulation of hematopoiesis.

Muthu Thiruvengadam, Umadevi Subramanian, Baskar Venkidasamy, Prabhu Thirupathi, Ramkumar Samynathan, Mohammad Ali Shariati, Maksim Rebezov, Ill-Min Chung, Kannan R R Rengasamy.

  The understanding of gut microbiota has emerged as a significant frontier in development of strategies to maintain normal human body's homeostasis and preventing the disease development over the last decade. The composition of the gut microbiota influences the clinical benefit of immune checkpoints in patients with advanced cancer, but the mechanisms underlying this relationship are unclear. Cancer is among the leading causes of mortality worldwide. So far, there is no universal treatment for cancer and despite significant advances, a lot of improvement on cancer therapy is required. Owing to its role in preserving the host's health and maintaining cellular integrity, the human gut microbiome has recently drawn a lot of interest as a target for cancer treatment. Dietary fiber is fermented by the gut microbiota to generate short-chain fatty acids (SCFAs), such as acetate, butyrate, and propionate, which are physiologically active metabolites. SCFAs can modulate the pathophysiology of the tumor environment through various critical signaling pathways. In addition, SCFAs can bind to carcinogens and other toxic chemicals, thus facilitating their biotransformation and elimination through different excretory mechanisms. This review discusses the mechanisms of action of short-chain fatty acids in modulating hematopoiesis of various immune system cells and the resultant beneficial anti-cancer effects. It also provides future perspectives on cancer therapy.

Keywords:  Human nutrition; anticancer activities; erythropoiesis; hematopoiesis; histone deacetylase inhibitors; inflammatory signaling; short chain fatty acids

DOI:  https://doi.org/10.1080/10408398.2021.1954874
Eur J Neurosci. 2021 Jul 27.

Ketogenic Diet Prevents Paclitaxel-Induced Neuropathic Nociception through Activation of PPARγ Signaling Pathway and Inhibition of Neuroinflammation in Rat Dorsal Root Ganglion.

Shanshan Zhong, Zhike Zhou, Xinyu Lin, Fangxi Liu, Chang Liu, Zhouyang Liu, Wenyun Deng, Xiuchun Zhang, Hongtao Chang, Chuansheng Zhao.

  Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect during the course of cancer treatment, which is mainly manifested as a series of sensory abnormalities. At present, there are no recommended prevention or treatment strategies, and the underlying mechanisms are unclear. The ketogenic diet (KD), a special diet that is high in fat and low in carbohydrate intake, shows good therapeutic potential in children with epilepsy. In this study, it was found that KD significantly prevented paclitaxel-induced neuropathic nociception. Using the GSE113941 database, 281 differentially expressed genes (DEGs) were found in an animal model of CIPN and controls. The DEGs were mainly enriched in peroxisome proliferator activated receptor (PPAR) and oxidative phosphorylation signaling pathways. As a main regulatory pathway of lipid metabolism, the PPARγ signaling pathway was significantly upregulated in the KD model. In addition, KD also inhibited the expression of pro-inflammatory cytokines and the TLR4/NF-κB signaling pathway in the dorsal root ganglion (DRG) in paclitaxel-treated rats. In vitro, rat primary DRG neurons were used to investigate the role of PPARγ in paclitaxel-induced neurotoxicity. It was found that PPARγ agonist rosiglitazone significantly protected DRG neurons against cell apoptosis and reactive oxygen species generation induced by paclitaxel administration. Therefore, KD is a prospective treatment option when applied as a dietary intervention in the prevention and treatment of paclitaxel-induced neuropathic nociception, possibly through the activation of PPARγ and its neuroprotective functions.

Keywords:  Chemotherapy-induced peripheral neuropathy; Ketogenic diet; Neuroinflammation; Peroxisome proliferator activated receptor

DOI:  https://doi.org/10.1111/ejn.15397
Nat Rev Clin Oncol. 2021 Jul 29.

Therapeutic targeting of the hypoxic tumour microenvironment.

Dean C Singleton, Andrew Macann, William R Wilson.

Hypoxia is prevalent in human tumours and contributes to microenvironments that shape cancer evolution and adversely affect therapeutic outcomes. Historically, two different tumour microenvironment (TME) research communities have been discernible. One has focused on physicochemical gradients of oxygen, pH and nutrients in the tumour interstitium, motivated in part by the barrier that hypoxia poses to effective radiotherapy. The other has focused on cellular interactions involving tumour and non-tumour cells within the TME. Over the past decade, strong links have been established between these two themes, providing new insights into fundamental aspects of tumour biology and presenting new strategies for addressing the effects of hypoxia and other microenvironmental features that arise from the inefficient microvascular system in solid tumours. This Review provides a perspective on advances at the interface between these two aspects of the TME, with a focus on translational therapeutic opportunities relating to the elimination and/or exploitation of tumour hypoxia.

DOI: https://doi.org/10.1038/s41571-021-00539-4
J Cell Biol. 2021 Sep 06. pii: e202105043. [Epub ahead of print]220(9):

Mitochondrial regulation of ferroptosis.

Boyi Gan.

Ferroptosis is a form of iron-dependent regulated cell death driven by uncontrolled lipid peroxidation. Mitochondria are double-membrane organelles that have essential roles in energy production, cellular metabolism, and cell death regulation. However, their role in ferroptosis has been unclear and somewhat controversial. In this Perspective, I summarize the diverse metabolic processes in mitochondria that actively drive ferroptosis, discuss recently discovered mitochondria-localized defense systems that detoxify mitochondrial lipid peroxides and protect against ferroptosis, present new evidence for the roles of mitochondria in regulating ferroptosis, and outline outstanding questions on this fascinating topic for future investigations. An in-depth understanding of mitochondria functions in ferroptosis will have important implications for both fundamental cell biology and disease treatment.

DOI: https://doi.org/10.1083/jcb.202105043
Trends Mol Med. 2021 Jul 23. pii: S1471-4914(21)00181-7. [Epub ahead of print]

Ferroptosis in the tumor microenvironment: perspectives for immunotherapy.

Huanji Xu, Di Ye, Meiling Ren, Hongying Zhang, Feng Bi.

  Targeting ferroptosis, which provokes lipid peroxidation in cancer cells, presents potentially new avenues for anticancer therapy. Recent studies have begun to explore how immune cells in the tumor microenvironment (TME) respond and adapt to lethal lipid peroxides (LPOs). A better understanding of this process in the TME is likely to uncover another side of ferroptosis in cancer immunity and promote the development of ferroptosis-targeted therapy. This Opinion article overviews the main metabolic processes in ferroptosis, summarizes the emerging roles of ferroptosis not only in immune cells in the TME but also in the crosstalk between tumor cells and immune cells, and presents a perspective on the targeting of ferroptosis in cancer immunotherapy.

Keywords:  ferroptosis; immune cells; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.molmed.2021.06.014
Methods Cell Biol. 2021 ;pii: S0091-679X(20)30195-3. [Epub ahead of print]165 163-176

Monitoring autophagy-dependent ferroptosis.

Jingbo Li, Rui Kang, Daolin Tang.

  Ferroptosis is an iron-dependent form of regulated cell death, driven by the accumulation of lipid peroxidation. Autophagy is a lysosome-dependent degradation process that can be used to remove and recover intracellular components, such as dysfunctional proteins and damaged organelles. By regulating iron storage and oxidative stress, excessive autophagy is involved in the induction and execution of ferroptosis. In particular, several types of selective autophagy (e.g., ferritinophagy, lipophagy, clockophagy, and chaperone-mediated autophagy) increase the susceptibility to ferroptotic cell death by degrading anti-ferroptotic regulators (e.g., ferritin, GPX4, ARNTL, and lipid droplets). These two integrated biological processes play a pathological role in the occurrence and development of human diseases, such as cancer, neurodegenerative disorders, ischemia and reperfusion injury. Therefore, it is important to develop reliable methods to evaluate the kinetics of autophagosome formation, iron accumulation, and lipid peroxidation. Here, we introduce some protocols (such as western blotting, lipid peroxidation assay kits and probes, and iron probes) to monitor the process of autophagy-dependent ferroptosis.

Keywords:  Autophagy; Cell death; Ferroptosis; Lipid peroxidation; Metabolism

DOI:  https://doi.org/10.1016/bs.mcb.2020.10.012