Preclinical investigation of artesunate as a therapeutic agent for hepatocellular carcinoma via impairment of glucosylceramidase-mediated autophagic degradation

Abstract

Artesunate (ART) has been indicated as a candidate drug for hepatocellular carcinoma (HCC). Glucosylceramidase (GBA) is required for autophagic degradation. Whether ART regulates autophagic flux by targeting GBA in HCC remains to be defined. Herein, our data demonstrated that the dramatic overexpression of GBA was significantly associated with aggressive progression and short overall survival times in HCC. Subsequent experiments revealed an association between autophagic activity and GBA expression in clinical HCC samples, tumor tissues from a rat model of inflammation-induced HCC and an orthotopic mouse model, and human HCC cell lines. Interestingly, probe labeling identified GBA as an ART target, which was further verified by both a glutathione-S-transferase pulldown assay and surface plasmon resonance analysis. The elevated protein expression of LC3B, the increased numbers of GFP-LC3B puncta and double-membrane vacuoles, and the enhanced expression of SQSTM1/p62 indicated that the degradation of autophagosomes in HCC cells was inhibited by ART treatment. Both the in vitro and in vivo data revealed that autophagosome accumulation through targeting of GBA was responsible for the anti-HCC effects of ART. In summary, this preclinical study identified GBA as one of the direct targets of ART, which may have promising potential to inhibit lysosomal autophagy for HCC therapy.

Liver cancer: Anti-enzyme potential drug candidate

Confirmation that the malaria drug artesunate targets a key enzyme overexpressed in aggressive liver cancer suggests it may be a novel therapeutic option for the disease. High levels of an enzyme called glucosylceramidase (GBA) are associated with poor prognosis in liver cancer, according to research conducted by Yanqiong Zhang and Na Lin at the Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, and co-workers. In experiments on rat and mouse models and human cell lines, the team demonstrated that high GBA levels over activated autophagic flux, accelerated the rate at which cellular material may be degraded and recycled in balanced, healthy cells. This disturbance enables liver cancer to progress. The researchers found that artesunate can suppress GBA expression levels and restore normal autophagic flux, boosting the drug’s anticancer activity.