Drug sensitivity was studied for the
tubulin inhibitors taxol,
taxotere,
rhizoxin and for doxorubucin and
cisplatin, in human lung and
breast cancer cell lines, including
drug-selected cell lines, overexpressing the
membrane transporter P-glycoprotein (Pgp) or the multidrug resistance
protein (MRP). All
tubulin-inhibiting agents were more potent than
doxorubicin and
cisplatin in all cell lines. In the drug resistance-selected cell lines (
doxorubicin or
mitoxantrone resistant) there was cross-resistance between the
tubulin inhibitors and the selecting agent; however, MRP overexpressing cells were relatively less resistant to
taxanes than the Pgp overexpressing cells. Polymerization of microtubules after exposure to
taxol was observed in
drug sensitive cell lines, but not in resistant cell lines, even at high
taxol concentrations and after long exposure times. In the Pgp overexpressing cell lines, steady accumulation of 14C-taxol was defective and could be reverted by
verapamil. MRP overexpressing cells did not have a significant accumulation defect of
taxol, compared to the parental cell lines, and
verapamil did not have any effect. These data confirm that the Pgp overexpression is an important mechanism of resistance to
taxanes and
rhizoxin in human lung and
breast tumor cells. However, the presence of mechanisms other than transport defects may play an important role in non-Pgp expressing cells, and these may include an altered function of tubulins.