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Glycolysis inhibitors

Biying Zhu, Xiuye Cao, Wenqiang Zhang, Guoping Pan, Qing Yi, Wenbin Zhong, Daoguang Yan
The enhanced expression of miR-31 has been observed in many human malignancies including lung cancer, and this microRNA regulates several aspects of oncogenesis. However, the role of miR-31-5p in energy metabolism remains elusive. Here, we confirm that H1299 and A549 cells, 2 lung cancer cell lines, relay on aerobic glycolysis as main source of ATP. Inhibition of miR-31-5p leads to decreased glycolysis and ATP production, while miR-31-5p overexpression increases them. Hypoxia inducible factor 1 (HIF-1) up-regulates the expression of glycolytic enzymes, and the HIF-1α inhibitor (FIH) inhibits HIF-1 activity...
July 13, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Dehong Chen, Xiaosong Sun, Xuejun Zhang, Jun Cao
Targeting mitochondria respiration is an effective therapeutic strategy in renal cell carcinoma (RCC). Atovaquone is a FDA-approved antibiotic but is also known as a mitochondrial inhibitor. We found that atovaquone inhibited proliferation and induced apoptosis of RCC cells. Mechanistically, atovaquone inhibits mitochondrial respiration in a concentration-dependent and time-dependent manner, via targeting mitochondrial respiratory complex III. Although increased glycolysis was observed in atovaquone-treated cells, atovaquone decreased ATP levels...
July 13, 2018: Journal of Biochemical and Molecular Toxicology
Rui Ju, Kailun Fei, Siang Li, Chen Chen, Lei Zhu, Juan Li, Dechang Zhang, Lei Guo, Caiying Ye
The anti-cancer and anti-inflammatory effects of carboxyamidotriazole (CAI) have been demonstrated in several studies, but the underlying mechanisms remain to be elucidated. This study showed that CAI caused metabolic reprogramming of pancreatic cancer cells. The inhibition of mitochondrial oxidative metabolism by CAI led to increased glutamine-dependent reductive carboxylation and enhanced glycolytic metabolism. The presence of environmental substances that affect cellular metabolism, such as glutamine and pyruvate, attenuated the anti-cancer efficacy of CAI...
July 12, 2018: Journal of Pharmacology and Experimental Therapeutics
Sabrina G R Mota, Gustavo F Mercaldi, José G C Pereira, Paulo S L Oliveira, Ana Rodriguez, Artur T Cordeiro
Human African trypanosomiasis, Chagas disease, and leishmaniasis are human infections caused by kinetoplastid parasites of the genera Trypanosoma and Leishmania. Besides their severity and global impact, treatments are still challenging. Currently available drugs have important limitations, highlighting the urgent need to develop new drugs. Phosphoglucose isomerase (PGI) is considered a promising target for the development of antiparasitic drugs, as it acts on two essential metabolic pathways, glycolysis and gluconeogenesis...
July 1, 2018: SLAS Discovery
Shili Xu, Arthur Catapang, Daniel Braas, Linsey Stiles, Hanna M Doh, Jason T Lee, Thomas G Graeber, Robert Damoiseaux, Orian Shirihai, Harvey R Herschman
Background: Precision medicine therapies require identification of unique molecular cancer characteristics. Hexokinase (HK) activity has been proposed as a therapeutic target; however, different hexokinase isoforms have not been well characterized as alternative targets. While HK2 is highly expressed in the majority of cancers, cancer subtypes with differential HK1 and HK2 expression have not been characterized for their sensitivities to HK2 silencing. Methods: HK1 and HK2 expression in the Cancer Cell Line Encyclopedia dataset was analyzed...
2018: Cancer & Metabolism
Tingting Yang, Chune Ren, Pengyun Qiao, Xue Han, Li Wang, Shijun Lv, Yonghong Sun, Zhijun Liu, Yu Du, Zhenhai Yu
Hexokinase-II (HK2) is a key enzyme involved in glycolysis, which is required for breast cancer progression. However, the underlying post-translational mechanisms of HK2 activity are poorly understood. Here, we showed that Proviral Insertion in Murine Lymphomas 2 (PIM2) directly bound to HK2 and phosphorylated HK2 on Thr473. Biochemical analyses demonstrated that phosphorylated HK2 Thr473 promoted its protein stability through the chaperone-mediated autophagy (CMA) pathway, and the levels of PIM2 and pThr473-HK2 proteins were positively correlated with each other in human breast cancer...
July 9, 2018: Oncogene
Ramon Bartrons, Ana Rodríguez-García, Helga Simon-Molas, Esther Castaño, Anna Manzano, Àurea Navarro-Sabaté
It has been known for over half a century that tumors exhibit an increased demand for nutrients to fuel their rapid proliferation. Interest in targeting cancer metabolism to treat the disease has been renewed in recent years with the discovery that many cancer-related pathways have a profound effect on metabolism. Considering the recent increase in our understanding of cancer metabolism and the enzymes and pathways involved, the question arises as to whether metabolism is cancer's Achilles heel. Areas covered: This review summarizes the role of 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in glycolysis, cell proliferation and tumor growth, discussing PFKFB3 gene and isoenzyme regulation and the changes that occur in cancer and inflammatory diseases...
July 9, 2018: Expert Opinion on Therapeutic Targets
Ming Luo, Li Shang, Michael D Brooks, Evelyn Jiagge, Yongyou Zhu, Johanna M Buschhaus, Sarah Conley, Melissa A Fath, April Davis, Elizabeth Gheordunescu, Yongfang Wang, Ramdane Harouaka, Ann Lozier, Daniel Triner, Sean McDermott, Sofia D Merajver, Gary D Luker, Douglas R Spitz, Max S Wicha
Although breast cancer stem cells (BCSCs) display plasticity transitioning between quiescent mesenchymal-like (M) and proliferative epithelial-like (E) states, how this plasticity is regulated by metabolic or oxidative stress remains poorly understood. Here, we show that M- and E-BCSCs rely on distinct metabolic pathways and display markedly different sensitivities to inhibitors of glycolysis and redox metabolism. Metabolic or oxidative stress generated by 2DG, H2 O2 , or hypoxia promotes the transition of ROSlo M-BCSCs to a ROShi E-state...
July 3, 2018: Cell Metabolism
Audrey Berthe, Marie Zaffino, Claire Muller, François Foulquier, Marine Houdou, Céline Schulz, Frédéric Bost, Elia De Fay, Sabine Mazerbourg, Stéphane Flament
PURPOSE: Cancer cells often elicit a higher glycolytic rate than normal cells, supporting the development of glycolysis inhibitors as therapeutic agents. 2-Deoxyglucose (2-DG) is used in this context due to its ability to compete with glucose. However, many studies do not take into account that 2-DG inhibits not only glycolysis but also N-glycosylation. Since there are limited publications on 2-DG mechanism of action in breast cancer, we studied its effects in breast cancer cell lines to determine the part played by glycolysis inhibition and N-linked glycosylation interference...
July 3, 2018: Breast Cancer Research and Treatment
Robert J Henning, Marie Bourgeois, Raymond D Harbison
Poly(ADP-ribosyl)ation is an immediate cellular repair response to DNA damage and is catalyzed primarily by poly(ADP-ribose)polymerase-1 (PARP1), which is the most abundant of the 18 different PARP isoforms and accounts for more than 90% of the catalytic activity of PARP in the cell nucleus. Upon detection of a DNA strand break, PARP1 binds to the DNA, cleaves nicotinamide adenine dinucleotide between nicotinamide and ribose and then modifies the DNA nuclear acceptor proteins by formation of a bond between the protein and the ADP-ribose residue...
July 2, 2018: Cardiovascular Toxicology
Yota Yasumizu, Hiroshi Hongo, Takeo Kosaka, Shuji Mikami, Koshiro Nishimoto, Eiji Kikuchi, Mototsugu Oya
The aim of this study was to explore the efficacy of mTOR inhibitor for castration-resistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic condition further induced expression of these proteins. These results indicate hypoxic environment elevated PI3K/Akt/mTOR pathway in aggressive prostate cancer. However, C4-2AT6 cells treated with mTOR inhibitor under hypoxia less decreased compared to cells treated with the same dose drugs under normoxia...
June 12, 2018: Oncotarget
Erwin Woff, Alain Hendlisz, Lieveke Ameye, Camilo Garcia, Tarek Kamoun, Thomas Guiot, Marianne Paesmans, Patrick Flamen
This study aimed to validate the prognostic value of baseline whole-body metabolic active tumor volume (WB-MATV) and total lesion glycolysis (WB-TLG) measured with [18 F]fluorodeoxyglucose positron emission tomography-computed tomography (18 F-FDG PET/CT) in a large cohort of chemorefractory metastatic colorectal cancer (mCRC) patients treated with multikinase inhibitors (MKI). The secondary objective of this study was to compare WB-MATV and WB-TLG respective prognostic values to commonly used clinical prognostic factors...
June 29, 2018: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Sergiy M Nadtochiy, Yves T Wang, Keith Nehrke, Josh Munger, Paul S Brookes
Stimulation of the cytosolic NAD+ dependent deacetylase SIRT1 is cardioprotective against ischemia-reperfusion (IR) injury. NAD+ precursors including nicotinamide mononucleotide (NMN) are thought to induce cardioprotection via SIRT1. Herein, while NMN protected perfused hearts against IR (functional recovery: NMN 42 ± 7% vs. vehicle 11 ± 3%), this protection was insensitive to the SIRT1 inhibitor splitomicin (recovery 47 ± 8%). Although NMN-induced cardioprotection was absent in Sirt3-/- hearts (recovery 9 ± 5%), this was likely due to enhanced baseline injury in Sirt3-/- (recovery 6 ± 2%), since similar injury levels in WT hearts also blunted the protective efficacy of NMN...
June 26, 2018: Journal of Molecular and Cellular Cardiology
Jin G Jung, Anne Le
Considering metabolic cross talk between CAFs and cancer as a metabolic target for cancer therapy Targeting the reverse Warburg effects via disruption of the "lactate shuttle" by MCT1/MCT 4 inhibitors Blocking the function of CAFs, which promote cancer cell growth, by metformin Using metformin to inhibit glycolysis of CAFs Targeting glutaminolysis by blocking the glutamine uptake of cancer cells from CAFs Targeting ketone bodies and ketosis in CAFs Targeting fatty acid metabolism, as a nutrient reservoir for cancer cell growth, from cancer-associated adipocytes (CAAs)...
2018: Advances in Experimental Medicine and Biology
Jingwen Yao, Shuli Man, Honghong Dong, Li Yang, Long Ma, Wenyuan Gao
Sorafenib, as a multi-kinase inhibitor, was the first FDA-approved anti- hepatocellular carcinoma (HCC) drug. Rhizoma Paridis saponins (RPS) as natural products have shown antitumor activity through regulation of glycolytic and lipid metabolism which was regarded as the side effect limited the utility of sorafenib. In this research, we tried to use metabolomics to verify the probability of combinatorial treatment of RPS and Sorafenib. As a result, Sorafenib + RPS increased the antitumor effect of sorafenib and RPS in H22 mice...
June 19, 2018: Journal of Steroid Biochemistry and Molecular Biology
Young Kyuen Im, Ouafa Najyb, Simon-Pierre Gravel, Shawn McGuirk, Ryuhjin Ahn, Daina Avizonis, Valérie Chénard, Valerie Sabourin, Jesse Hudson, Tony Pawson, Ivan Topisirovic, Michael N Pollak, Julie St-Pierre, Josie Ursini-Siegel
The ShcA adaptor protein transduces oncogenic signals downstream of receptor tyrosine kinases. We show here that breast tumors engage the ShcA pathway to increase their metabolism. ShcA signaling enhanced glucose catabolism through glycolysis and oxidative phosphorylation, rendering breast cancer cells critically dependent on glucose. ShcA signaling simultaneously increased the metabolic rate and flexibility of breast cancer cells by inducing the PGC-1α transcription factor, a central regulator of mitochondrial metabolism...
June 21, 2018: Cancer Research
Kairui Zhang, Michael W Hast, Soutarou Izumi, Yu Usami, Snehal Shetye, Ngozi Akabudike, Nancy J Philp, Masahiro Iwamoto, Itzhak Nissim, Louis J Soslowsky, Motomi Enomoto-Iwamoto
BACKGROUND: Tendon injuries are common problems among athletes. Complete recovery of the mechanical structure and function of ruptured tendons is challenging. It has been demonstrated that upregulation of glycolysis and lactate production occurs in wounds, inflammation sites, and cancerous tumors, and these metabolic changes also control growth and differentiation of stem and progenitor cells. Similar metabolic changes have been reported in human healing tendons. In addition, lactate production has increased in progenitors isolated from injured tendons after treatment with IL-1β...
June 1, 2018: American Journal of Sports Medicine
Chie Araki, Nobuyuki Okahashi, Kousuke Maeda, Hiroshi Shimizu, Fumio Matsuda
Cancer cells often respond to chemotherapeutic inhibitors by redirecting carbon flow in the central metabolism. To understand the metabolic redirections of inhibitor treatment on cancer cells, this study established a 13 C-metabolic flux analysis (13 C-MFA)-based method to evaluate metabolic redirection in MCF-7 breast cancer cells using mass spectrometry. A metabolic stationary state necessary for accurate 13 C-MFA was confirmed during an 8-24 h window using low-dose treatments of various metabolic inhibitors...
2018: Mass Spectrometry
Yu Wu, Miaomiao Wang, Kefan Zhang, Yingjiang Li, Manlin Xu, Shaidi Tang, Xiuxia Qu, Chunping Li
Osteoblast uses aerobic glycolysis to meet the metabolic needs in differentiation process. Lactate, the end product of glycolysis, presents in the environment with elevated PTH and osteoblast differentiation. Although previous findings showed that lactate promoted osteoblast differentiation, whether lactate affects PTH-mediated osteoblast differentiation is unclear. To investigate this, pre-osteoblast cell line MC3T3-E1 was treated PTH with or without physiological dose of lactate. Lactate increases ALP positive cell formation, increases ALP activity and expression of differentiation related markers, enriches the CREB transcriptional factor target genes in PTH treated cells...
June 15, 2018: Biochemical and Biophysical Research Communications
Raphaela Fritsche-Guenther, Christin Zasada, Guido Mastrobuoni, Nadine Royla, Roman Rainer, Florian Roßner, Matthias Pietzke, Edda Klipp, Christine Sers, Stefan Kempa
Metabolic reprogramming is as a hallmark of cancer, and several studies have reported that BRAF and KRAS tumors may be accompanied by a deregulation of cellular metabolism. We investigated how BRAFV600E and KRASG12V affect cell metabolism, stress resistance and signaling in colorectal carcinoma cells driven by these mutations. KRASG12V expressing cells are characterized by the induction of glycolysis, accumulation of lactic acid and sensitivity to glycolytic inhibition. Notably mathematical modelling confirmed the critical role of MCT1 designating the survival of KRASG12V cells...
June 15, 2018: Scientific Reports
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