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Glycolysis inhibitors

D A Korshunov, I A Klimov, V V Ivanov, I V Kondakova
Antitumor effects of glycolysis inhibitors monoiodoacetate and 2-deoxyglucose were studied on Lewis lung carcinoma model. Monoiodoacetate exhibited antitumor and antimetastatic activities, being not inferior of methotrexate (reference drug); however, the preparation also demonstrated high systemic toxicity. 2-Deoxyglucose exhibited only antitumor effect, while its antimetastatic activity did not differ from the result in the group without treatment.
September 17, 2018: Bulletin of Experimental Biology and Medicine
Ting Tao, Qiongli Su, Simeng Xu, Jun Deng, Sichun Zhou, Yu Zhuang, Yanjun Huang, Caimei He, Shanping He, Mei Peng, Berthold Hocher, Xiaoping Yang
Fatty acid synthase (FASN) catalyzing the terminal steps in the de novo biogenesis of fatty acids is correlated with low survival and high disease recurrence in patients with bladder cancer. Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels and provides a growth advantage to tumors. However, it is unclear whether the change of PKM2 has an effect on FASN and what is the mechanisms underlying. Here we describe a novel function of PKM2 in control of lipid metabolism by mediating transcriptional activation of FASN, showing the reduced expression of sterol regulatory element binding protein 1c (SREBP-1c)...
September 17, 2018: Journal of Cellular Physiology
Zheng Yang, Shaolin Zhang, Xiaohui Hu, Kin Yip Tam
Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired-resistance inevitably occurs after long-term exposure to the treatment of EGFR inhibitors. Glycolysis is a predominant process for most cancer cells to utilize glucose, which referred to as the Warburg Effect. Targeting critical enzymes, such as pyruvate dehydrogenase kinase 1 (PDK1) that inversely regulating the process of glycolysis could be a promising approach to work alone or in combination with other treatments for cancer therapy...
September 10, 2018: European Journal of Pharmacology
Lu Ding, Wan Zhang, Lili Yang, Helene Pelicano, Kaiwen Zhou, Ran Yin, Ruibin Huang, Junyi Zeng
Background: The bone marrow microenvironment constitutes a sanctuary for leukemia cells. Recent evidence indicates that environment-mediated drug resistance arises from a reciprocal influence between tumor cells and the surrounding stroma. The present study aimed to investigate the effect of chronic lymphocytic leukemia (CLL) cells on the metabolism of bone marrow stroma, to determine the role of this metabolic change in the stroma in vorinostat resistance of CLL cells, and thus to assess a novel strategy to target stroma and achieve the maximum therapeutic effect of vorinostat...
2018: OncoTargets and Therapy
Gaurav Pathria, David A Scott, Yongmei Feng, Joo Sang Lee, Yu Fujita, Gao Zhang, Avinash D Sahu, Eytan Ruppin, Meenhard Herlyn, Andrei L Osterman, Ze'ev A Ronai
Nutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD+ and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth...
September 12, 2018: EMBO Journal
Jared Klarquist, Alisha Chitrakar, Nathan D Pennock, Augustus M Kilgore, Trevor Blain, Connie Zheng, Thomas Danhorn, Kendra Walton, Li Jiang, Jie Sun, Christopher A Hunter, Angelo D'Alessandro, Ross M Kedl
In contrast to responses against infectious challenge, T cell responses induced via adjuvanted subunit vaccination are dependent on interleukin-27 (IL-27). We show that subunit vaccine-elicited cellular responses are also dependent on IL-15, again in contrast to the infectious response. Early expression of interferon regulatory factor 4 (IRF4) was compromised in either IL-27- or IL-15-deficient environments after vaccination but not infection. Because IRF4 facilitates metabolic support of proliferating cells via aerobic glycolysis, we expected this form of metabolic activity to be reduced in the absence of IL-27 or IL-15 signaling after vaccination...
September 7, 2018: Science Immunology
Jing-Hua Pan, Hong Zhou, Sheng-Bin Zhu, Jin-Lian Huang, Xiao-Xu Zhao, Hui Ding, Li Qin, Yun-Long Pan
Colorectal cancer (CRC) is the third most common malignancy, and the metabolic properties of CRC cells include enhanced aerobic glycolysis (the Warburg effect). Nicotinamide phosphoribosyl transferase (NAMPT) is one of the crucial enzymes that regulate the activity of nicotinamide adenine dinucleodinucleotide dependent enzymes. Targeting NAMPT is a potential method of CRC therapy. Nevertheless, the underlying clinical implications and regulatory mechanisms of NAMPT in CRC remain unclear. In this study, we showed that NAMPT protein expression was increased in subjects with rectal localization compared with those with colon localization, and NAMPT was a poor prognostic marker for the overall survival rate in patients with CRC...
September 7, 2018: Journal of Cellular Physiology
Young Eun Kim, Hyo Jin Jeon, Dahee Kim, Sun Young Lee, Ki Young Kim, Jongki Hong, Pil Jae Maeng, Kwang-Rok Kim, Dukjin Kang
Recently there has been a growing interest in three-dimensional (3D) cell culture systems for drug discovery and development. These 3D culture systems better represent the in vivo cellular environment compared to two-dimensional (2D) cell culture, thereby providing more physiologically reliable information on drug screening and testing. Here we present the quantitative profiling of a drug-induced proteome in 2D- and 3D-cultured colorectal cancer SW480 cells using 2D nanoflow liquid chromatography-tandem mass spectrometry (2D-nLC-MS/MS) integrated with isobaric tags for relative and absolute quantitation (iTRAQ)...
September 5, 2018: Scientific Reports
Vishak Raman, Uma K Aryal, Victoria Hedrick, Rodrigo Mohallem Ferreira, Jorge Luis Fuentes Lorenzo, Elena E Stashenko, Morris Levy, Maria M Levy, Ignacio G Camarillo
Triple-negative breast cancer is an aggressive subtype of breast cancer with low 5-year survival rates, high 3-year recurrence rates, and no known therapeutic targets. Recent studies have indicated that triple-negative breast cancers possess an altered metabolic state with higher rates of glycolysis, mitochondrial oxidative phosphorylation, and increased generation and utilization of tricarboxylic acid cycle intermediates. Here, we utilized label-free quantitative proteomics to gain insight into the anticancer mechanisms of a methanolic extract from the Central American plant Lippia origanoides on MDA-MB-231 triple-negative breast cancer cells...
September 18, 2018: Journal of Proteome Research
John J Wilson, Kin-Hoe Chow, Nathan J Labrie, Jane A Branca, Thomas J Sproule, Bryant R A Perkins, Elise E Wolf, Mauro Costa, Grace Stafford, Christine Rosales, Kevin D Mills, Derry C Roopenian, Muneer G Hasham
Targeting the early steps of the glycolysis pathway in cancers is a well-established therapeutic strategy; however, the doses required to elicit a therapeutic effect on the cancer can be toxic to the patient. Consequently, numerous preclinical and clinical studies have combined glycolytic blockade with other therapies. However, most of these other therapies do not specifically target cancer cells, and thus adversely affect normal tissue. Here we first show that a diverse number of cancer models - spontaneous, patient-derived xenografted tumor samples, and xenografted human cancer cells - can be efficiently targeted by 2-deoxy-D-Glucose (2DG), a well-known glycolytic inhibitor...
September 5, 2018: Cancer Biology & Therapy
Xiaochen He, Heng Zeng, Richard J Roman, Jian-Xiong Chen
BACKGROUND: Diastolic dysfunction is emerging as a leading cause of heart failure in aging population. Induction of hypoxia tolerance and reprogrammed cell metabolism have emerged as novel therapeutic strategies for the treatment of cardiovascular diseases. METHODS AND RESULTS: In the present study, we showed that deletion of sirtuin 3 (SIRT3) resulted in a diastolic dysfunction together with a significant increase in the expression of prolyl hydroxylases (PHD) 1 and 2...
August 24, 2018: International Journal of Cardiology
Jing Tong, Jieqiong Yang, Hong Lv, Shijian Lv, Cong Zhang, Zi-Jiang Chen
OBJECTIVES: Normal decidualization is essential for normal pregnancy and abnormal decidualization is thought to cause preeclampsia (PE). Phosphoglycerate kinase 1 (PGK1) is an enzyme involved in the glycolytic pathway which is the main metabolism process decidual cells exhibit. Phosphoglycerate kinase 1, pseudogene 2 (PGK1P2), which is also a long non-coding RNA (lncRNA), has a high sequence similarity to PGK1 and therefore acquires an ability for sequence-specific regulation. METHODOLOGY: The expression of PGK1 and PGK1P2 in human decidua, as well as their relationship and functions during decidualization was investigated using in vitro cultured human endometrial stromal cell lines (hESCs) and primary ESCs by real-time PCR, immunohistochemistry, western blotting, siRNA techniques and miRNA inhibitor or mimic transfection...
July 2018: Pregnancy Hypertension
Xiangbing Mao, Man Ren, Daiwen Chen, Bing Yu, Lianqiang Che, Jun He, Junqiu Luo, Yuheng Luo, Jianping Wang, Hui Sun
Leucine can affect intestinal protein expressions, and improve mucosal immune function. However, little study has been conducted to determine the change of protein component by leucine treatment in intestine epithelial cells. The present study was to cover the key proteins and cell pathways that could be regulated by leucine treatment in porcine intestinal epithelial cell line (IPEC-J2) cells with the approach of proteome analysis. A total number of 3,211 proteins were identified in our approach by searching the database of Uniprot sus scrofa ...
September 2018: Animal nutrition
Maria Apicella, Elisa Giannoni, Stephany Fiore, Karin Johanna Ferrari, Daniel Fernández-Pérez, Claudio Isella, Carlotta Granchi, Filippo Minutolo, Antonino Sottile, Paolo Maria Comoglio, Enzo Medico, Filippo Pietrantonio, Marco Volante, Diego Pasini, Paola Chiarugi, Silvia Giordano, Simona Corso
The microenvironment influences cancer drug response and sustains resistance to therapies targeting receptor-tyrosine kinases. However, if and how the tumor microenvironment can be altered during treatment, contributing to resistance onset, is not known. We show that, under prolonged treatment with tyrosine kinase inhibitors (TKIs), EGFR- or MET-addicted cancer cells displayed a metabolic shift toward increased glycolysis and lactate production. We identified secreted lactate as the key molecule instructing cancer-associated fibroblasts to produce hepatocyte growth factor (HGF) in a nuclear factor κB-dependent manner...
August 23, 2018: Cell Metabolism
Weidong Li, Xueying Sun
BACKGROUND: Solid tumors often contain hypoxic microenvironments due to abnormal vasculatures and outweighing demands of oxygen. Cancer cells rely on anaerobic respiration, leading to sequential acidic microenvironments. Hypoxic and acidic microenvironments cause genetic instability and activate signaling pathways, contributing to cancer progression and drug therapy resistance, and have become targets for developing novel anti-cancer agents. OBJECTIVE: This article reviews recent advances in the development of novel anti-cancer drugs targeting hypoxic and acidic microenvironments...
August 30, 2018: Recent Patents on Anti-cancer Drug Discovery
Ping Fan, Bo Wang, Zibo Meng, Jingyuan Zhao, Xin Jin
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. However, the mechanism underlying the tumorigenesis of HCC is still unclear. Improper recruitment of Pescadillo homologue 1 (PES1) can lead to tumorigenesis in multiple cancer types, such as gastric cancer and colon cancer. Here, we reported that PES1 was upregulated and associated with a poor prognosis in HCC specimens. Next, we found that PES1 promoted the growth of HCC in vivo and in vitro. Furthermore, we showed that the knockdown of PES1 decreased glycolysis via altering the gene expression of GLUT1, PKM2, ENO1, FBP1, and PCK1, which are related to glucose metabolism in HCC cells...
August 29, 2018: International Journal of Biochemistry & Cell Biology
Ruyuan Zhang, Ranran Li, Yiyun Liu, Lei Li, Yaoqing Tang
Endothelial cells play an important role in health and a variety of diseases. Recent evidences show that endothelial cells rely on glycolysis rather than on oxidative phosphorylation to generate energy to support cellular functions such as angiogenesis. However, the effect of endothelial glycolysis on vascular inflammation remains little known. Here, we investigate the role of key glycolytic enzyme PFKFB3 in tumor necrosis factor-α (TNF-α)-induced endothelial proinflammatory responses. siRNAs were used to knockdown the expression of PFKFB3...
August 31, 2018: Inflammation
Liangcai Zhao, Minjian Dong, Mengqian Ren, Chen Li, Hong Zheng, Hongchang Gao
Diabetes mellitus causes brain structure changes and cognitive decline, and it has been estimated that diabetes doubles the risk for dementia. Until now, the pathogenic mechanism of diabetes-associated cognitive decline (DACD) has remained unclear. Using metabolomics, we show that lactate levels increased over time in the hippocampus of rats with streptozotocin-induced diabetes, as compared to age-matched control rats. Additionally, mRNA levels, protein levels, and enzymatic activity of lactate dehydrogenase-A (LDH-A) were significantly up-regulated, suggesting increased glycolysis activity...
August 31, 2018: Molecular & Cellular Proteomics: MCP
Maša Ždralević, Almut Brand, Lorenza Di Ianni, Katja Dettmer, Jörg Reinders, Katrin Singer, Katrin Peter, Annette Schnell, Christina Bruss, Sonja-Maria Decking, Gudrun Koehl, Blanca Felipe-Abrio, Jérôme Durivault, Pascale Bayer, Marie Evangelista, Thomas O'Brien, Peter J Oefner, Kathrin Renner, Jacques Pouysségur, Marina Kreutz
Increased glucose consumption distinguishes cancer cells from normal cells and is known as the "Warburg effect" due to increased glycolysis. Lactate dehydrogenase A (LDHA) is a key glycolytic enzyme, a hallmark of aggressive cancers, and believed to be the major enzyme responsible for the pyruvate-to-lactate conversion. To elucidate its role in tumor growth, we disrupted both LDHA and LDHB genes in two cancer cell lines (human colon adenocarcinoma and murine melanoma). Surprisingly neither LDHA nor LDHB knockout strongly reduced lactate secretion...
August 29, 2018: Journal of Biological Chemistry
Simran S Sabharwal, David B Rosen, Jeff Grein, Dana Tedesco, Barbara Joyce-Shaikh, Roanna Ueda, Marie Semana, Michele Bauer, Kathy Bang, Christopher Stevenson, Daniel J Cua, Luis A Zuniga
GITR is a costimulatory receptor currently undergoing Phase I clinical trials. Efficacy of anti-GITR therapy in syngeneic mouse models requires regulatory T-cell depletion and CD8+ T-cell costimulation. It is increasingly appreciated that immune cell proliferation and function is dependent on cellular metabolism. Enhancement of diverse metabolic pathways leads to different immune cell fates. Little is known about the metabolic effects of GITR agonism; thus, we investigated whether costimulation via GITR altered CD8+ T-cell metabolism...
August 28, 2018: Cancer Immunology Research
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