Pro-haloacetate Nanoparticles for Efficient Cancer Therapy via Pyruvate Dehydrogenase Kinase Modulation

Abstract

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.

Caffeic Acid Expands Anti-Tumor Effect of Metformin in Human Metastatic Cervical Carcinoma HTB-34 Cells: Implications of AMPK Activation and Impairment of Fatty Acids De Novo Biosynthesis

“…PDH is a key regulatory point of metabolic pathways, which are determinant for the overall glucose and lipid disposal within the cell. The activity state of PDH is precisely regulated by the covalent modification via specific kinase (PDK), which in turn was reported as a subject to anticancer intervention [ 20 , 24 ]. In present experiments, CA inhibits PDK activity in HTB-34 cells and the effect is opposite to that of Met.…”

Defined Host–Guest Chemistry on Nanocarbon for Sustained Inhibition of Cancer

“…Mechanistic studies of cell regression after incubation with free Nic and its nanoformulation were performed to investigate genomic DNA degradation after probable induction of apoptosis. A turned on suicidal switch of apoptosis leads to the degradation of genomic DNA, decreasing the intercalation of propidium iodide (PI) and also generating DNA fragments . Calculated cell population with fragmented genomic DNA with low PI intercalation were found ≈28% for the treatment of free Nic which increased to 37, 46% for CB6 Nic and CNP CB6 Nic while CNP and CB6 showed a nominal population of ≈5% and 11%, respectively (Figure B and Table 2 ).…”

“…A turned on suicidal switch of apoptosis leads to the degradation of genomic DNA, decreasing the intercalation of propidium iodide (PI) and also generating DNA fragments. [42] Calculated cell population with fragmented genomic DNA with low PI intercalation were found ≈28% for the treatment of free Nic which increased to 37, 46% for CB6 Nic and CNP CB6 Nic while CNP and CB6 showed a nominal population of ≈5% and 11%, respectively (Figure 6B and Table 2). Gel electrophoresis of extracted genomic DNA after incubating MCF-7 cells was analyzed for all cases—Lane 2: Cells alone; Lane 3: CNP; Lane 4: Nic; lane 5: CB6; Lane 6: CB6 Nic; Lane 7: CB6 CNP and CB6 CNP Nic (postfunctionalized) Lane 8.…”

Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery

“…Nevertheless, Mito-DCA contains three DCA moieties per molecule and an overall positive charge that enhances mitochondrial depolarization [ 24 ]. In other examples, the anticancer power of haloacetates has been enhanced by incorporating DCA and other derivatives in phospholipid nanoparticles [ 69 ]. Increasing the local concentration of the inhibitor through the nanoparticle ensured efficient delivery.…”