Phutela Kanika, Ahlawat Priyanca, Kaur Jyotdeep, Bal Amanjit, Singh Navneet, Singh Harkant, Sharma Sadhna
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Madhya Marg, Sector 12, Chandigarh, 160012, India.
Centre for Immuno-Biology and Immunotherapy, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, Faridabad, Haryana, 121001, India.
Appl Biochem Biotechnol. 2025 Mar 1. doi: 10.1007/s12010-025-05204-5.
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.
代谢酶ATP柠檬酸裂解酶在多种癌症中过表达，并通过催化柠檬酸转化为乙酰辅酶A和草酰乙酸，将葡萄糖代谢与从头脂肪酸合成途径联系起来。其天然抑制剂羟基柠檬酸钾具有抗癌活性；然而，由于生物利用度低，其应用受到限制。本研究旨在通过将羟基柠檬酸盐封装在与叶酸缀合的牛乳外泌体表面来提高其疗效，以靶向肺癌细胞。负载羟基柠檬酸钾的外泌体（Exo-KH）和紫杉醇外泌体（Exo-Pac）的平均粒径分别为183nm和174nm；它们具有球形形态，封装效率分别为16.87±2.78%和27.65±3.23%。在体外研究中，Exo-KH抑制了A549细胞的增殖，并显著降低了ACLY mRNA表达。除ACLY外，Exo-KH还下调了其他关键代谢酶如脂肪酸合酶和异柠檬酸脱氢酶1的mRNA表达。Exo-KH制剂导致A549细胞凋亡率显著增加（<75%）和活性氧产生增加，并降低了ACLY蛋白表达。此外，药代动力学研究表明，外泌体制剂中羟基柠檬酸盐具有缓释作用（半衰期22.74小时，清除率0.13μg/ml）。总之，研究结果突出了Exo-KH制剂对肺癌的有益作用。
