Carcinogenesis, Vol. 23, No. 11, 1831-1838,
November 2002
© 2002 Oxford University Press
CANCER BIOLOGY |
The role of MAPK pathways in the action of chemotherapeutic drugs
1 The Beatson Institute for Cancer Research, Cancer Research UK, Bearsden, Glasgow G61 1BD, UK,
2 Roche Diagnostics GmbH, Pharma Research, Penzberg, Germany and
3 Institute for Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
In this study we have investigated the role of mitogen-induced and stress-activated MAP kinase pathways in the cellular response to taxol, etoposide and ceramide in three different human cancer cell lines: HeLa cervical carcinoma, MCF7 breast cancer and A431 squamous carcinoma cells. The mitogen-induced ERK MAPKs were linked to cell proliferation and survival, whereas the stress-activated MAPKs, p38 and JNK, were connected with apoptosis. Our results show that all drugs activated MAPKs, but that the extent and kinetics of activation were different. In order to assay the biological consequences of drug-induced MAPK activation we employed selective MAPK inhibitors and measured both long-term clonogenic survival as well as short-term parameters including apoptosis, mitochondrial metabolic integrity and cell cycle progression. Our results show that drug induced toxicity is not correlated with any singular parameter, but rather a combination of effects on cell cycle and apoptosis. In certain constellations the modulation of MAPK pathways could enhance or decrease drug efficacies. These effects mainly pertained to the regulation of apoptosis and clonogenic survival, but they were highly dependent on the combination of drug and cell line without any clear patterns of correlations emerging. These results suggest that the modulation of MAPK pathways to enhance the efficacy of chemotherapeutic drugs is of limited value unless it is tailored to the specific combination of drug and cancer.
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