Pro-haloacetate Nanoparticles for Efficient Cancer Therapy via Pyruvate Dehydrogenase Kinase Modulation.
Anticancer agents based on haloacetic acids are developed for inhibition of pyruvate dehydrogenase kinase (PDK), an enzyme responsible for reversing the suppression of mitochondria-dependent apoptosis. Through molecular docking studies mono- and dihaloacetates are identified as potent PDK2 binders and matched their efficiency with dichloroacetic acid. In silico screening directed their conversion to phospholipid prodrugs, which were subsequently self-assembled to pro-haloacetate nanoparticles. Following a thorough physico-chemical characterization, the functional activity of these novel agents was established in wide ranges of human cancer cell lines in vitro and in vivo in rodents. Results indicated that the newly explored PDK modulators can act as efficient agent for cancer regression. A Pyruvate dehydrogenase (PDH) assay mechanistically confirmed that these agents trigger their activity through the mitochondria-dependent apoptosis.
Departments of Bioengineering, Materials Science and Engineering and Beckman Institute, University of Illinois at Urbana-Champaign, Mills Breast Cancer Institute, and Carle Foundation Hospital, Urbana, Illinois 61801, USA.
Santosh K
SK
Misra
Departments of Bioengineering, Materials Science and Engineering and Beckman Institute, University of Illinois at Urbana-Champaign, Mills Breast Cancer Institute, and Carle Foundation Hospital, Urbana, Illinois 61801, USA.
Mao
M
Ye
Departments of Bioengineering, Materials Science and Engineering and Beckman Institute, University of Illinois at Urbana-Champaign, Mills Breast Cancer Institute, and Carle Foundation Hospital, Urbana, Illinois 61801, USA.
Fatemeh
F
Ostadhossein
Departments of Bioengineering, Materials Science and Engineering and Beckman Institute, University of Illinois at Urbana-Champaign, Mills Breast Cancer Institute, and Carle Foundation Hospital, Urbana, Illinois 61801, USA.
Dipanjan
D
Pan
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D053758:Nanoparticles / Q000706:statistics & numerical data*; D010088:Oxidoreductases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C000631430:PDK2 protein, human; C000631435:Pdk2 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003999:Dichloroacetic Acid; D010088:Oxidoreductases; D017346:Protein Serine-Threonine Kinases