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Stimulatory effects of the multi‐kinase inhibitor sorafenib on human bladder cancer cells
Author(s) -
Rose A,
Grandoch M,
vom Dorp F,
Rübben H,
Rosenkranz A,
Fischer JW,
Weber AA
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.00838.x
Subject(s) - sorafenib , mapk/erk pathway , cancer research , bladder cancer , apoptosis , cell growth , kinase , cancer , cancer cell , medicine , intracellular , cell culture , pharmacology , biology , hepatocellular carcinoma , microbiology and biotechnology , biochemistry , genetics
BACKGROUND AND PURPOSE Sorafenib is an inhibitor of several intracellular signalling kinases with anti‐proliferative, anti‐angiogenic and pro‐apoptotic effects in tumour cells. Sorafenib is used in the therapy of advanced renal cell carcinoma, and several phase II clinical trials are being carried out in patients with urothelial carcinomas. EXPERIMENTAL APPROACH Using a panel of human bladder cancer cell lines (RT4, T24, J82), we characterized systematically the effects of sorafenib on intracellular signalling, migration, proliferation and apoptosis. KEY RESULTS We demonstrated that at low concentrations (<1 µM), sorafenib is capable of significantly stimulating migration and proliferation of the bladder cancer cells. We hypothesize that these stimulatory effects on tumour cell functions might be explained by an activation of the Ras/ERK‐1/2 signal transduction pathway. In addition, the comparison of different bladder cancer cell lines not only revealed a different biology (e.g. cell migration), but also a differential susceptibility to the anti‐apoptotic effects of sorafenib. Finally, we confirmed in different bladder cancer cell lines the known inhibitory actions of sorafenib in pharmacological concentrations (≥3 µM) on ERK‐1/2 phosphorylation, migration and proliferation, as well as the pro‐apoptotic effects of the compound. CONCLUSIONS AND IMPLICATIONS Taken together, these findings suggest that although sorafenib has the potential to be used in the treatment of urothelial carcinoma, this compound might also activate bladder cancer cells at low concentrations. This should be relevant for dosing regiments to optimize the treatment with this promising anti‐tumour drug.