Nano delivery of juglone causes cell cycle arrest and apoptosis for hepatocellular carcinoma therapy

Abstract

Chemotherapy remains the standard protocol for cancers, but the amount of chemotherapeutic agents used for hepatocellular carcinoma (HCC) is still low. For this reason, development of chemotherapeutic drugs for HCC therapy gains increasing attention. Recently, a better understanding in pharmacological activities of phytoconstituents has revealed their anticancer capacity, thereby providing promising therapeutic strategies for HCC. In this study, Juglone (JUN, a natural naphthoquinone in walnut trees) induced HCC cell cycle arrest, which was confirmed by the upregulation of p21 and the downregulation of Cyclin A and CDK2. JUN also caused HCC cell apoptosis, which was confirmed by the downregulation of Bcl-2, the upregulation of Bax, and the activation of caspase 9 and 3. In addition, a galactose-targeted polyethylene glycol-grafted poly(lactic-co-glycolic acid) was utilized in this study to prepare the nanoparticle for in vitro and in vivo JUN delivery. The obtained nanoformulation (termed PLGA-PEG-GAL.JUN) demonstrated favorable physicochemical profiles, in terms of morphology, particle size (110 nm), surface charge (-32 mV), particle stability, and pH-sensitive drug release. PLGA-PEG-GAL.JUN profoundly extended half-life and enhanced tumor accumulation in mice allografted by orthotopic HCC, without causing toxic signs. Consequently, it significantly suppressed tumor growth and prolonged animal survival. This study unveils the anti-HCC capacity of JUN and provides a promising chemotherapeutic regimen against HCC.