Rapid discovery of a novel “green” and natural GST inhibitor for sensitizing hepatocellular carcinoma to Cisplatin by visual screening strategy

• Published in: Journal of pharmaceutical analysis 2024-05, Vol.14 (5), p.100923-14, Article 100923
• Main Authors: Mao, Linxi, Qin, Yan, Fan, Jialong, Yang, Wei, Li, Bin, Cao, Liang, Yuan, Liqin, Wang, Mengyun, Liu, Bin, Wang, Wei
• Format: Article
• Language: English
• Subjects: Antitumor activity; Apoptosis; Cancer therapies; Cell culture; Chinese medicine; Chromatography; Cisplatin; Clinical medicine; Drug resistance; Enzymes; Fluorescence; Glutathione transferase; GST; Hepatocarcinoma; Hepatocellular carcinoma; Hepatocytes; Liver cancer; Mass spectrometry; Monoclonal antibodies; Natural compound C1; NMR; Nuclear magnetic resonance; Overexpression; Scientific imaging; Temperature; “Green” GST inhibitor
• ISSN: 2095-1779; 2214-0883
• DOI: 10.1016/j.jpha.2023.12.013

Over-expression of glutathione S-transferase (GST) can promote Cisplatin resistance in hepatocellular carcinoma (HCC) treatment. Hence, inhibiting GST is an attractive strategy to improve Cisplatin sensitivity in HCC therapy. Although several synthesized GST inhibitors have been developed, the side effects and narrow spectrum for anticancer seriously limit their clinical application. Considering the abundance of natural compounds with anticancer activity, this study developed a rapid fluorescence technique to screen “green” natural GST inhibitors with high specificity. The fluorescence assay demonstrated that schisanlactone B (hereafter abbreviated as C1) isolated from Xue tong significantly down-regulated GST levels in Cisplatin-resistant HCC cells in vitro and in vivo. Importantly, C1 can selectively kill HCC cells from normal liver cells, effectively improving the therapeutic effect of Cisplatin on HCC mice by down-regulating GST expression. Considering the high GST levels in HCC patients, this compound demonstrated the high potential for sensitizing HCC therapy in clinical practice by down-regulating GST levels. [Display omitted] •Designed a visual fluorescent probe PM for the rapid screening GST natural inhibitors.•The natural and “green” GST inhibitor C1 showed high safety to normal liver cells but high toxicity to HCC cells.•The inhibitor C1 demonstrated an excellent sensitizing effect on Cisplatin-resistant and sensitive HCC.