Myocardial Steatosis and Necrosis in Atria and Ventricles of Rats Given Pyruvate Dehydrogenase Kinase Inhibitors

2014 ◽  
Vol 42 (8) ◽  
pp. 1250-1266 ◽  
Author(s):  
Huw Bowen Jones ◽  
Jaimini Reens ◽  
Elizabeth Johnson ◽  
Simon Brocklehurst ◽  
Ian Slater
2013 ◽  
Vol 289 (7) ◽  
pp. 4432-4443 ◽  
Author(s):  
Shih-Chia Tso ◽  
Xiangbing Qi ◽  
Wen-Jun Gui ◽  
Cheng-Yang Wu ◽  
Jacinta L. Chuang ◽  
...  

RSC Advances ◽  
2016 ◽  
Vol 6 (82) ◽  
pp. 78762-78767 ◽  
Author(s):  
Shao-Lin Zhang ◽  
Wen Zhang ◽  
Qingpin Xiao ◽  
Zheng Yang ◽  
Xiaohui Hu ◽  
...  

The synthesis and biological assays were described herein to firstly identify a novel PDK1 inhibitor.


2005 ◽  
Vol 33 (2) ◽  
pp. 367-370 ◽  
Author(s):  
R.M. Mayers ◽  
B. Leighton ◽  
E. Kilgour

The pyruvate dehydrogenase multienzyme complex catalyses the oxidative decarboxylation of pyruvate, which is an important regulatory step in oxidative metabolism. Phosphorylation of the E1 (pyruvate decarboxylase) subunit on one of three specific serine residues results in loss of enzyme activity. Four dedicated PDHK (pyruvate dehydrogenase kinase) isoenzymes have been identified, each of which display a distinct tissue-specific expression profile, and have differential regulatory properties. Thus PDHK play a key role in controlling the balance between glucose and lipid oxidation according to substrate supply. Increasing glucose oxidation by inhibiting PDHK may be an effective mechanism to increase glucose utilization; additionally, increasing pyruvate oxidation may further contribute to lowering of glucose level by decreasing the supply of gluconeogenic substrates. A number of PDHK inhibitors are now available to enable this mechanism to be evaluated as a therapy for diabetes. The isoenzyme selectivity profile of AZD7545 and related compounds will be described and evidence for their non-ATP-competitive mode of action presented. These compounds increase PDH activity in vivo, and when dosed chronically, improve glycaemic control in Zucker rats. Furthermore, glucose lowering has been demonstrated in the hyperglycaemic Zucker diabetic fatty rat. This result supports the hypothesis that inhibition of PDHK may be an effective therapy for Type II diabetes.


2017 ◽  
Vol 60 (3) ◽  
pp. 1142-1150 ◽  
Author(s):  
Shih-Chia Tso ◽  
Mingliang Lou ◽  
Cheng-Yang Wu ◽  
Wen-Jun Gui ◽  
Jacinta L. Chuang ◽  
...  

MedChemComm ◽  
2018 ◽  
Vol 9 (11) ◽  
pp. 1843-1849 ◽  
Author(s):  
Ronghua Yang ◽  
Caihong Guo

Targeting pyruvate dehydrogenase kinases (PDKs) reverses the Warburg effect, which could be a potential therapeutic target for anti-cancer drug discovery.


2021 ◽  
pp. 116514
Author(s):  
Yuki Bessho ◽  
Tatsuo Akaki ◽  
Yoshinori Hara ◽  
Maki Yamakawa ◽  
Shingo Obika ◽  
...  

2003 ◽  
Vol 31 (6) ◽  
pp. 1168-1170 ◽  
Author(s):  
J.A. Morrell ◽  
J. Orme ◽  
R.J. Butlin ◽  
T.E. Roche ◽  
R.M. Mayers ◽  
...  

The PDH (pyruvate dehydrogenase) multi-enzyme complex catalyses a key regulatory step in oxidative glycolysis. Phosphorylation of the E1 subunit of the complex on serine residues results in the inactivation of enzyme activity. A family of four dedicated PDH kinase isoenzymes exists, each of which displays a distinct tissue-specific expression profile. AZD7545 is one of a series of PDH kinase inhibitors developed for the treatment of type 2 diabetes. The isoenzyme-selectivity profile of AZD7545 and related compounds is described and the consequences for their in vivo mode of action are discussed.


2020 ◽  
Author(s):  
Sissel Elisabeth Dyrstad ◽  
Maria Lie Lotsberg ◽  
Tuan Zea Tan ◽  
Ina Katrine Nitschke Pettersen ◽  
Silje Hjellbrekke ◽  
...  

Abstract Background Non-small cell lung cancer (NSCLC) patients harboring oncogenic mutations in the epidermal growth factor receptor (EGFR) inevitably develop resistance to targeted therapy. Drug resistance is an example of cancer cell plasticity where cells change according to diverse microenvironmental pressure, which can be described as a way of evolution by natural selection. Metabolic rewiring during cancer development may support several malignant features and facilitate emergence of therapy resistant clones. Results Analysis of transcriptome data from two independent NSLSC patient cohorts identified upregulated markers of glucose metabolism and ROS defense in tumors compared to normal tissue. We show that these alterations were associated with increased expression of pyruvate dehydrogenase kinase 1 (PDK1). We established relevant in vitro models to study metabolic alterations in the context of resistance to EGFR TKIs to determine if targeted metabolic intervention would prevent development of resistance to EGFR tyrosine kinase inhibitors (EGFR TKIs) in NSCLC cells. The PDK inhibitor dichloroacetate (DCA) was shown to reduce cell growth. This mechanism was associated with redirected metabolism towards pyruvate and lactate oxidation, and reduced lactate production, both in EGFR TKI sensitive and resistant NSCLC cells. Conclusion We propose that the intracellular stress created by redirecting pyruvate metabolism can prevent EGFR TKI resistance in NSCLC.


Sign in / Sign up

Export Citation Format

Share Document