Article Dans Une Revue Molecular Pharmacology Année : 2021

Drug-drug interaction between metformin and sorafenib alters antitumor effect in hepatocellular carcinoma cells

Résumé

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is one of the leading causes of cancer-related deaths worldwide. The multi-target inhibitor sorafenib is a first-line treatment for patients with advanced unresectable HCC. Recent clinical studies have evidenced that patients treated with sorafenib together with the anti-diabetic drug metformin have a survival disadvantage compared to patients receiving sorafenib only. Here, we examined whether a clinically relevant dose of metformin (50 mg/kg/d) could influence the antitumoral effects of sorafenib (15 mg/kg/d) in a subcutaneous xenograft model of human HCC growth using two different sequences of administration, i.e concomitant versus sequential dosing regimens. We observed that the administration of metformin six hours prior to sorafenib was significantly less effective in inhibiting tumor growth (15.4% tumor growth inhibition) than concomitant administration of the two drugs (59.5% tumor growth inhibition). In vitro experiments confirmed that pretreatment of different human HCC cell lines with metformin reduced the effects of sorafenib on cell viability, proliferation and signaling. Transcriptomic analysis confirmed significant differences between xenografted tumors obtained under the concomitant and the sequential dosing regimens. Taken together, these observations call into question the benefit of parallel use of metformin and sorafenib in patients with advanced HCC and diabetes, as the interaction between the two drugs could ultimately compromise patient survival. Significance Statement When drugs are administrated sequentially, metformin alters the anti-tumor effect of sorafenib, the reference treatment for advanced hepatocellular carcinoma, in a preclinical murine xenograft model of liver cancer progression as well as in hepatic cancer cell lines. Defective activation of the AMPK pathway as well as major transcriptomic changes are associated with the loss of the anti-tumor effect. These results echo recent clinical work reporting a poorer prognosis for patients with liver cancer who were co-treated with metformin and sorafenib.
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Dates et versions

hal-03228343 , version 1 (18-05-2021)

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Rania Harati, Marc Vandamme, Benoit Blanchet, Christophe Bardin, Françoise Praz, et al.. Drug-drug interaction between metformin and sorafenib alters antitumor effect in hepatocellular carcinoma cells. Molecular Pharmacology, 2021, pp.MOLPHARM-AR-2020-000223. ⟨10.1124/molpharm.120.000223⟩. ⟨hal-03228343⟩
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