Journal
MEDICAL ONCOLOGY
Volume 38, Issue 4, Pages -Publisher
HUMANA PRESS INC
DOI: 10.1007/s12032-021-01487-w
Keywords
CD133; Hedgehog signalling; Hepatocellular carcinoma; Lenvatinib therapeutic efficiency; GANT61
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Funding
- Key research and development project of the Department of Science and Technology of Zhejiang Province [2017C03051]
- Science Fund for Creative Research Groups of the National Natural Science Foundation of China [81721091]
- Zhejiang Provincial Education Department
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The study found that the Hedgehog signaling inhibitor GANT61 can reverse resistance to Lenvatinib in CD133-positive HCC cells, and the combination of both can enhance therapeutic efficacy.
Lenvatinib has been approved as a first-line treatment for advanced hepatocellular carcinoma (HCC) in recent years. However, Lenvatinib resistance hinders its therapeutic effect, and the underlying mechanism of action of Lenvatinib needs to be better understood. Increasing studies have suggested that cancer stem cells (CSCs) are an important driving force. Hedgehog signalling is important for the maintenance of hepatocellular carcinoma stemness. In the present study, we investigated the therapeutic role of the Hedgehog signalling inhibitor in reversing Lenvatinib resistance in CD133-positive HCC cells. First, we examined the inhibitory impact of Lenvatinib against CD133 expression in HCC cell lines through Western blot. The CCK8 assay showed that GANT61, a Hedgehog signalling inhibitor, has a suppression advantage over other CSCs-related signalling inhibitors regarding cell viability. Moreover, Lenvatinib and GANT61 combined had better inhibitory effects on cell viability and malignant properties, both in vivo and in vitro. In addition, GANT61 reversed the upregulation of CD133 and Hedgehog signalling caused by Lenvatinib in SK-Hep-1 and MHCC97H. Thus, our results suggested that GANT61 reversed Lenvatinib resistance by suppressing Hedgehog signalling in HCC cells, especially in CD133-positive cells and combining Lenvatinib with Hedgehog signalling inhibitors could improve its therapeutic efficacy in HCC patients with high CD133 expression levels.
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