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Inhibition of Prostaglandin E2 receptor EP1 in combination with sorafenib for liver cancer therapy
Author(s) -
Lu Lu,
Han Chang,
Wu Tong
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.442.9
Previous studies from our lab revealed that the prostaglandin receptor, EP 1 , plays a key role in cPLA 2 alpha/COX‐2/PGE 2 ‐mediated liver cancer cell growth. These findings lead us to hypothesize that EP 1 receptor may represent a promising new target in liver cancer therapy. Given that the multikinase inhibitor, sorafenib, has been approved by the FDA for the treatment of hepatocellular carcinoma, we will evaluate the effect of targeting EP 1 in combination with sorafenib for molecular targeted therapeutics of liver cancer. For in vitro studies, human hepatoma cell lines (Sk‐Hep‐1 and Huh‐7) were treated with EP 1 competitive antagonist ONO8711 and/or sorafenib to evaluate the effect on cell proliferation. For in vivo studies, an orthotopic mouse liver cancer model will be used to study the effect of combination treatment of EP 1 antagonist ONO8711 and sorafenib. We found that the combination treatment showed much greater inhibition on cell growth in Sk‐hep‐1 and Huh‐7 cells than the treatment with either sorafenib or ONO8711 (p < 0.001). In Sk‐Hep‐1 cells, co‐treatment of sorafenib and ONO8711 showed stronger inhibition on ERK phosphorylation and STAT3 activation. The combination treatment also significantly downregulated anti‐apoptotic proteins including Mcl‐1, Survivin and cyclinD1. Our data indicates that the synergistic effect of targeting EP 1 in combination with sorafenib for liver cancer therapy and the mechanisms for the synergistic effect are through inhibition of either ERK phosphorylation or STAT3 activation.