Combination of Metformin and Sorafenib Induces Ferroptosis of Hepatocellular Carcinoma Through p62-Keap1-Nrf2 Pathway

Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E...

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Bibliographic Details
Published in:Journal of Cancer 2022-01, Vol.13 (11), p.3234-3243
Main Authors: Tang, Kezhong, Chen, Qing, Liu, Yanmo, Wang, Lantian, Lu, Wenjie
Format: Article
Language:English
Subjects:
Antibodies
Antidiabetics
Apoptosis
Cancer therapies
Chemotherapy
Drug resistance
Ferroptosis
Kinases
Laboratory animals
Lipid peroxidation
Liver cancer
Manufacturers
Medical prognosis
Oral administration
Oxidative stress
Patients
Proteins
Research Paper
Signal transduction
Targeted cancer therapy
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Summary:Hepatocellular carcinoma (HCC) is one of the most lethal cancers in the world. Sorafenib is the first small-molecule multi-kinase inhibitors approved by FDA for treatment of advanced HCC. Metformin has been demonstrated to have benefit for preventing cancer progression. In human recurrent HCCs, NF-E2-related factor 2 (Nrf2) was overexpressed and associated with poor survival. Nrf2 related signaling pathway plays central role to mediate cellular resistance to sorafenib through protecting HCC cells from ferroptosis. The effect of Combination treatment for HCC cells and the intrinsic mechanism have not been reported. In this study, metformin augmented the anti-tumor effect of sorafenib for HCC through ferroptosis induction by inhibiting Nrf2 related pathway. Based on the results of Nrf2 knockdown and p62 knockdown study, the combination of sorafenib and metformin suppressed proliferation of HCC cells through p62-Keap1-Nrf2/HO1 signaling way. Size of xenografts treated with the combination of sorafenib and metformin was smaller than other groups in vivo. Moreover, the combination treatment greatly induced ferroptosis in HCC cells through inhibiting Nrf2 expression. Based on our findings, the combination treatment suppressed proliferation of HCC cells through ferroptosis induction, by p62-Keap1-Nrf2/HO1 signaling way.
ISSN:1837-9664
1837-9664
DOI:10.7150/jca.76618