High Raf-1 kinase activity protects human tumor cells against paclitaxel-induced cytotoxicity.

Paclitaxel (Taxol) is becoming increasingly important in the treatment of many tumors, although a large proportion of tumors fail to respond to this drug. The identification of the processes that confer cellular paclitaxel resistance could provide potential targets for novel therapies that may help to eliminate paclitaxel-resistant tumors. Recent reports suggest that the Raf-1 protein kinase may have a profound influence on the level of paclitaxel-induced apoptosis. We have critically evaluated the relationship between Raf-1 kinase activity and de novo paclitaxel resistance in early-passage human cervical tumors. In the 12 cell lines studied, Raf-1 kinase activity was inversely correlated (P = 0.0016) with the level of cytotoxicity induced by 60 nM paclitaxel. The relationship between these two parameters seems to be more than an epiphenomenon, because genetic down-regulation of Raf-1 kinase activity led to an approximately 4-fold increase in paclitaxel-induced cytotoxicity. The data from both our transfection studies and those on the 12 unperturbed cell lines are consistent with Raf-1 kinase being a negative determinant of paclitaxel-induced cytotoxicity. Because the cytotoxicity of paclitaxel is primarily attributable to apoptosis, these data suggest that Raf-1 kinase acts to suppress paclitaxel-induced apoptosis. These data suggest that the clinical effectiveness of paclitaxel could be substantially improved by the use of Raf-1 kinase inhibitors, provided that a similar relationship between Raf-1 kinase activity and paclitaxel cytotoxicity exists in the clinic, especially in those tumor sites where paclitaxel is the current treatment of choice e.g., ovarian and breast cancer.