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Lin, S.
Involvement of the mitogen-activated protein kinase pathway in drug resistance in hepatocellular carcinoma cells
[ Dissertation ] Universitaet Heidelberg; 2012.
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Authors Med Uni Graz:
Advisor:: Schemmer Peter
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Abstract:: Systemic treatment options for hepatocellular carcinoma are rare, since it exhibits strong intrinsic and acquired drug resistance. The overexpression of A BC transporters hampers the effects of chemotherapy and c orrelate s with MAPK pathway activation in HCCs. In this study, we systematically investigated the role of MAPK pathway inhibition on mediating HCC cell proliferation and ABC transporter expression in vitro We demonstrated that Raf1 and MEK inhibitors could inhibit HCC cell growth. In particular, the combination of the MEK inhibitor with gemcitabine o r doxorubicin resulted in additional growth inhibition of HCC cells. Furthermore, we detected that MEK inhibition increased the chemosensitivity of HCC cells by enhanced intracellular doxorubicin accumulation. Furthermore MEK inhibition deactivated phosph orylated ERK and decreased the endogenous expression of the MRP1. Additionally, the treatment with MEK inhibitors reversed gemcitabine and doxorubicin induced up regulation of MRP1 and MRP3. In conclusion, these results indicate that MEK inhibition increases intracellular chemo drug accumulation and reverses drug resistance through the down regulation of MRP1 and MRP3 expression.