Identification of an m6A Natural Inhibitor, Lobeline, That Reverses Lenvatinib Resistance in Hepatocellular Tumors

  • J Nat Prod. 2024 Aug 23;87(8):1983-1993. doi: 10.1021/acs.jnatprod.4c00406.
Lei Zhao  1 ,  Heyao Ma  2 ,  Yuhui Jiang  3 ,  Yingying Li  3 ,  Li Qiao  3 ,  Yu Chen  3 ,  Xiaowen Jiang  4 ,  Lihui Wang  3 ,  Shu Wang  5 ,  Xinyu Fan  6
Affiliations
  • 1. Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
  • 2. Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China.
  • 3. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 4. Department of Analysis and Pharmacology of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 5. Department of Nuclear Medicine, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
  • 6. Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China.
PMID: 39136667 DOI: 10.1021/acs.jnatprod.4c00406
Abstract

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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