Acquisition of taxol resistance via P-glycoprotein- and non-P-glycoprotein-mediated mechanisms in human ovarian carcinoma cells.
Taxol-resistant clones from a human ovarian carcinoma cell line (2008) were selected by an initial exposure to 0.05 microM (2008/13) or 0.5 microM (2008/17) taxol. Thereafter, a series of clones with increasing taxol resistance were derived from the 2008/17 and 2008/13 cells by stepwise sequential exposure to increasing concentrations of taxol. The 2008/17 clones displayed a classical P-glycoprotein-mediated drug-resistance phenotype. In contrast, the 2008/13 clones followed the classical P-glycoprotein-mediated resistance phenotype until a 245-fold taxol-resistant clone (2008/13/2) was obtained, which was followed by a further increase in the degree of resistance but significant down-regulation of P-glycoprotein expression in the 252-fold taxol-resistant 2008/13/4 cells. This clone (2008/13/4) also accumulated significantly higher intracellular levels of taxol than those expressing the P-glycoprotein. No correlation between the expression of the multidrug resistance-associated protein and taxol resistance was observed. Verapamil increased the sensitivity of all drug-resistant clones to taxol, and this was probably related to the ability of verapamil to increase the intracellular concentration of taxol (except in the case of 2008/13/4 cells). The 2008/17 clones were highly cross-resistant to Adriamycin, etoposide, and vincristine. They also displayed a low level of cross-resistance to camptothecin but were not cross-resistant to cisplatin. The taxol-resistant 2008/13 clones displayed a similar pattern of cross-resistance for all drugs (except Adriamycin). The 2008/13 clones were only 2-to 4-fold cross-resistant Adriamycin. The levels of alpha-tubulin and beta-tubulin were similar in the parental 2008 and taxol-resistant 2008/13/4 cells. Furthermore, the in vitro binding of [3H]taxol to semipurified microtubule preparations derived from the parental 2008 and the taxol-resistant 2008/13/2 and 2008/13/4 cells was similar. These results show that in human ovarian carcinoma cells resistance to taxol can be acquired via as yet undescribed mechanisms.
Parekh
H
H
Department of Pathology, Temple University School of Medicine, Philadelphia, PA 19140, USA. hparck00@thunder.ocis.temple.edu
Wiesen
K
K
Simpkins
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D017239:Paclitaxel