期刊
ONCOTARGET
卷 6, 期 25, 页码 21614-21627出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.4308
关键词
TGF-beta inhibition; hepatocellular carcinoma; galunisertib; sorafenib; SMAD
资金
- Eli Lilly and Company
- Foundation Nelia & Amadeo Barleta (FNAB)
- Association d'Aide a la Recherche et a l'Enseignement en Cancerologie (AAREC)
Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-beta receptor (T beta R)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK-Suni). Exogenous stimulation of all HCC cell lines with TGF-beta yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 mu M and 10 mu M galunisertib, 5 mu M sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-beta signaling. Immunohistochemistry analysis of galunisertib and sorafenib-exposed samples showed a significant decrease of the proliferative marker Ki67 and increase of the apoptotic marker caspase-3. In combination, galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis. Our data suggest that galunisertib may be active in patients with HCC and could potentiate the effects of sorafenib.
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