肝细胞癌
伦瓦提尼
天然产物
抗药性
药理学
调节器
癌症研究
医学
候选药物
体外
药品
生物
肿瘤科
生物化学
基因
遗传学
索拉非尼
作者
Lei Zhao,Heyao Ma,Yuhui Jiang,Yingying Li,Qiao Li,Yu Chen,Xiaowen Jiang,Lihui Wang,Sheng Wang,Xinyu Fan
标识
DOI:10.1021/acs.jnatprod.4c00406
摘要
Hepatocellular carcinoma (HCC) is an aggressive cancer that has an effect on human health. As a first-line drug for HCC, despite its excellent efficacy, lenvatinib (Len) is prone to developing drug resistance in HCC patients. The N6-methyladenosine (m6A) modification is not only related to the development of HCC but also shows great potential in overcoming HCC resistance. Using Dot Blot, our group first screened a small molecule m6A regulator, lobeline (Lob), from a library of 390 compounds (mostly natural products). In vitro experiments demonstrated that Lob could significantly enhance the sensitivity to Len of Len-resistant HCC (HCC/Len) and inhibit migration of resistant cells. In Len-resistant cell-derived and patient-derived xenograft models, Lob could reverse the resistant phenotype, with reductions in tumor volume of 68% and 60%, respectively. Furthermore, MeRIP-m6A sequencing results indicated that the underlying molecular mechanism of Lob reversal of HCC drug resistance was related to UBE3B. Taken together, this study highlighted that Lob, a plant derived natural product, could reverse the resistance of HCC to Len by regulating the m6A levels. It is hoped that this will provide a pharmacological research basis for the clinical treatment of HCC patients.
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