Inhibition of ATP Citrate Lyase by Hydroxycitrate-Loaded Exosomes Suppresses the Survival of Lung Adenocarcinoma Cells.

Abstract

The metabolic enzyme ATP citrate lyase is overexpressed in several cancers and links glucose metabolism with de novo fatty acid synthesis pathway by catalyzing the conversion of citrate into acetyl CoA and oxaloacetate. Potassium hydroxycitrate, its natural inhibitor, exhibits anticancer activity; however, its use is limited due to low bioavailability. This study aims to improve the efficacy of hydroxycitrate by its encapsulation in bovine milk exosome surface conjugated with folate for targeting lung cancer cells. The mean particle size of potassium hydroxycitrate-loaded exosomes (Exo-KH) and paclitaxel exosomes (Exo-Pac) was 183 nm and 174 nm; they had spherical morphology and encapsulation efficiency of 16.87 ± 2.78% and 27.65 ± 3.23%, respectively. In the in vitro study, Exo-KH suppressed the proliferation of A549 cells and significantly reduced ACLY mRNA expression. In addition to ACLY, EXO-KH also downregulated the mRNA expression of other crucial metabolic enzymes such as fatty acid synthase and isocitrate dehydrogenase 1. EXO-KH formulation caused significant increase in apoptosis rate (< 75%) and reactive oxygen species production and reduced ACLY protein expression in A549 cells. Moreover, the pharmacokinetic study revealed the sustained release of hydroxycitrate (half-life 22.74 h and clearance 0.13 µg/ml) from the exoformulation. Altogether, the study findings highlight the beneficial role of EXO-KH formulation against lung cancer.