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Identification of an m6A Natural Inhibitor, Lobeline, That Reverses Lenvatinib Resistance in Hepatocellular Tumors
Lei Zhao1, Heyao Ma2, Yuhui Jiang3
1Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China.
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.
Insights
Lobeline, a natural product, reverses lenvatinib resistance in hepatocellular carcinoma (HCC) by regulating m6A levels. This finding offers a new strategy for treating resistant HCC tumors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) is a prevalent and aggressive cancer.
- Lenvatinib (Len) is a first-line treatment for HCC but drug resistance is a significant clinical challenge.
- N6-methyladenosine (m6A) modification plays a role in HCC development and resistance.
Purpose of the Study:
- To identify small molecules that can overcome lenvatinib resistance in HCC.
- To investigate the mechanism by which lobeline (Lob) affects lenvatinib-resistant HCC.
- To evaluate the therapeutic potential of lobeline in reversing drug resistance.
Main Methods:
- Screening of 390 compounds using Dot Blot to identify m6A regulators.
- In vitro experiments to assess lobeline's effect on lenvatinib-resistant HCC (HCC/Len) cell sensitivity and migration.
- In vivo studies using xenograft models (cell-derived and patient-derived) to evaluate lobeline's efficacy.
- MeRIP-m6A sequencing to elucidate the molecular mechanism.
Main Results:
- Lobeline was identified as a potent m6A regulator.
- Lobeline significantly enhanced lenvatinib sensitivity in HCC/Len cells and inhibited their migration in vitro.
- Lobeline treatment reduced tumor volume by 68% in cell-derived and 60% in patient-derived xenograft models.
- MeRIP-m6A sequencing revealed that lobeline's resistance-reversing effect is linked to UBE3B regulation.
Conclusions:
- Lobeline, a natural product, effectively reverses lenvatinib resistance in HCC.
- Lobeline acts by modulating m6A levels, potentially through UBE3B.
- This study provides a basis for developing lobeline-based therapies for lenvatinib-resistant HCC.
