Activity of docetaxel in paclitaxel-resistant ovarian cancer cells

Shinya Sato, Junzo Kigawa, Yasunobu Kanamori, Hiroaki Itamochi, Tetsuro Oishi, Muneaki Shimada, Takahiro Iba, Jun Naniwa, Kazunori Uegaki, Naoki Terakawa

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Purpose: The aim of this study was to determine the behavior of docetaxel (DTX) in ovarian cancer cells resistant to paclitaxel (PTX). Methods: We used human ovarian adenocarcinoma cell lines KF, KFTx (PTX-resistant KF), SK-OV-3, and HAC-2. The sensitivity of the cells to PTX or DTX was determined by the MTT assay. Cellular accumulation of PTX and DTX was measured by high-performance liquid chromatography. mRNA of MDR-1 was detected by RT-PCR. Cell cycle distribution was determined by flow cytometry after exposure to the IC 50 of each drug. Bcl-2 phosphorylation was determined by Western blot analysis. Activity for tubulin polymerization of each drug was examined by a β-tubulin polymerization assay. Results: KFTx cells had a 5.5-fold greater resistance to PTX and a 7.3-fold greater resistance to DTX than KF cells, indicating that KFTx cells had acquired cross-resistance to DTX. SK-OV-3 cells were sensitive and HAC-2 cells were resistant to both PTX and DTX. The gene expression of MDR-1 increased after exposure to DTX in KF and KFTx cells. Residual cellular accumulation of PTX and DTX was significantly lower in KFTx cells than in KF cells. In contrast, MDR-1 expression was not detected in SK-OV-3 and HAC-2 cells. Flow cytometric analysis indicated no differences in alterations of cell cycle distribution following exposure to the two drugs. Bcl-2 phosphorylation occurred after exposure to DTX at a concentration equivalent to the clinical dose, but did not occur after exposure to PTX in KFTx cells. In HAC-2 cells, Bcl-2 phosphorylation was not detected after exposure to DTX or PTX at concentrations equivalent to the clinical doses. DTX showed greater tubulin polymerization activity than PTX in KFTx cells. β-tubulin polymerization did not correlate with the concentration of PTX or DTX, suggesting that alteration in the tubulin reaction might contribute to the resistance in HAC-2 cells. Conclusions: The present study suggests that the mechanisms involved in cytotoxicity of and resistance to PTX and DTX do not differ, but DTX has a greater cytotoxic potential in PTX-resistant cells with an efflux system.

Original languageEnglish
Pages (from-to)247-252
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume53
Issue number3
DOIs
Publication statusPublished - 2004 Mar
Externally publishedYes

Keywords

  • Bcl-2 phosphorylation
  • Docetaxel
  • MDR-1 gene
  • Paclitaxel
  • Polymerized tubulin

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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