The bladder carcinoma cell line J82-NVB was selected for resistance to the new vinca alkaloid Navelbine. These cells possessed a non-MDR phenotype and were cross-resistant to vinca alkaloids and taxoids. Some morphological differences between sensitive (J82) and resistant (J82-NVB) cells were observed J82 cells had a heterogeneous population morphology with both epithelial and spindle shaped cells, while J82-NVB cells were almost all of the epithelial type. Vimentin intermediate filaments were less organized in J82-NVB than in J82 cells. Moreover, desmosomes were present in the membranes of J82NVB cells but not in J82 cells. These findings suggest that J82 cells are poorly differentiated epithelial cells while J82-NVB cells possess some characteristics of a more differentiated epithelial cell line. After a two-week treatment with all-trans retinoic acid, all the cells became spindle shaped, vimentin filaments reappeared in the cytoplasm of J82-NVB cells and desmosomes disappeared from the membranes of these cells. These changes were accompanied by a decrease from 17 to 4.6 of the resistance factor of J82-NVB cells to Navelbine. This decrease in resistance was concomitant with modifications of microtubules assembly regulation mechanisms. After Navelbine treatment, microtubule reassembly occurred in resistant but not in sensitive nor in retinoic acid treated cells. Okadaic acid, a protein phosphatase inhibitor, inhibited microtubule reassembly in resistant cells, and 2-aminopurine, a protein kinase inhibitor, induced microtubule reassembly in sensitive cells after Navelbine treatment. These findings show that microtubule reassembly after depolymerization is regulated by the kinase/phosphatase systems. A treatment with phorbol myristate acetate (PMA), a protein kinase C (PKC) agonist, induced the same morphological modifications and resistance decrease as retinoic acid treatment. A specific PKC inhibitor (Bisindolymaleimide) prevented these PMA-induced morphological modifications and resistance decrease in J82-NVB cells, showing that these effects were mediated by PKC. This study suggests that, in part by acting on some properties of the cytoskeleton, the differentiation modulator, retinoic acid, and the signal transduction modulator, phorbol myristate acetate, can decrease the resistance of J82-NVB cells to microtubule poisons.