Antimitotic drugs cause increased tumorigenicity of multidrug resistant cells

Taxol and vinblastine are widely and effectively used in the treatment of cancer, but the initial response to chemotherapy is often hampered by the development of multidrug resistant (MDR) cells. The collateral effects of these two antimitotic drugs on MDA-435 human breast carcinoma cells were investigated. When used at concentrations below those required to depolymerize microtubules, both drugs increased cyclin dependent kinase activity and stimulated the MAPK signal transduction pathway. The activity of MAPK pathway elements and cyclin dependent kinases were found to be constitutively elevated in an MDR cell line that was selected with taxol and expresses high levels of P-glycoprotein. The MDR cells maintained these alterations and also overexpressed hyperphosphorylated RB. This was manifested in a higher growth rate for MDR cells in low serum and an increased ability to form colonies in soft agar. These observations suggest that despite high levels of P-glycoprotein in MDR cells, a sufficient amount of taxol remains intracellular to accelerate the cell cycle machinery and activate the MAPK pathway. These alterations accumulate in resistant cells and contribute to a more transformed phenotype. Thus, in addition to the development of MDR, exposure of tumor cells to antimitotic agents produces further cellular changes that may contribute to the failure of chemotherapy.