Biochemical mechanism of cross-resistance to paclitaxel in a mitomycin c-resistant human bladder cancer cell line

Richard J. Bleicher, Hong Xia, Howard A. Zaren, Shivendra V. Singh

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The present study describes the biochemical mechanism(s) of cross- resistance to paclitaxel in a human bladder cancer cell line (J82/MMC-2), which is >9-fold more resistant to mitomycin C (MMC) than parental cells (J82/WT). The IC50 values for paclitaxel in J82/WT and J82/MMC-2 cell lines were 0.7 ± 0.03 and 2.8 ± 0.7 μM, respectively (P < 0.05). Thus, the J82/MMC-2 cell line exhibited 4-fold cross-resistance to paclitaxel compared with J82/WT. Intracellular accumulation of [3H]paclitaxel was comparable in J82/WT and J82/MMC-2 cell lines. There were no qualitative or quantitative differences between the J82/WT and J82/MMC-2 cell lines in terms of their α- tubulin and β-tubulin contents. Paclitaxel-induced apoptosis could not be detected in either cell line over a wide range of drug concentrations. These results indicate that cross-resistance to paclitaxel in the J82/MMC-2 cell line is not linked to reduced drug accumulation, increased drug efflux, alterations in tubulin content or reduced paclitaxel-induced apoptosis. Paclitaxel-induced DNA strand breakage, however, determined by alkaline elution, was markedly lower in the J82/MMC-2 cell line than in J82/WT. These results suggest that paclitaxel cross-resistance in J82/MMC-2 may be attributed to reduced paclitaxel-induced DNA strand breakage. The precise mechanism of reduced paclitaxel-induced DNA strand breakage in J82/MMC-2 cell line relative to J82/WT cells, however, remains to be elucidated. (C) 2000 Elsevier Science Ireland Ltd.

Original languageEnglish (US)
Pages (from-to)129-135
Number of pages7
JournalCancer Letters
Volume150
Issue number2
DOIs
StatePublished - Mar 31 2000

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Mitomycin
Paclitaxel
Urinary Bladder Neoplasms
Cell Line
Tubulin
DNA
Pharmaceutical Preparations
Apoptosis
Inhibitory Concentration 50

Keywords

  • Bladder cancer
  • DNA damage
  • Drug resistance
  • Mitomycin C
  • Paclitaxel
  • Taxol

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Biochemical mechanism of cross-resistance to paclitaxel in a mitomycin c-resistant human bladder cancer cell line. / Bleicher, Richard J.; Xia, Hong; Zaren, Howard A.; Singh, Shivendra V.

In: Cancer Letters, Vol. 150, No. 2, 31.03.2000, p. 129-135.

Research output: Contribution to journalArticle

Bleicher, Richard J. ; Xia, Hong ; Zaren, Howard A. ; Singh, Shivendra V. / Biochemical mechanism of cross-resistance to paclitaxel in a mitomycin c-resistant human bladder cancer cell line. In: Cancer Letters. 2000 ; Vol. 150, No. 2. pp. 129-135.
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abstract = "The present study describes the biochemical mechanism(s) of cross- resistance to paclitaxel in a human bladder cancer cell line (J82/MMC-2), which is >9-fold more resistant to mitomycin C (MMC) than parental cells (J82/WT). The IC50 values for paclitaxel in J82/WT and J82/MMC-2 cell lines were 0.7 ± 0.03 and 2.8 ± 0.7 μM, respectively (P < 0.05). Thus, the J82/MMC-2 cell line exhibited 4-fold cross-resistance to paclitaxel compared with J82/WT. Intracellular accumulation of [3H]paclitaxel was comparable in J82/WT and J82/MMC-2 cell lines. There were no qualitative or quantitative differences between the J82/WT and J82/MMC-2 cell lines in terms of their α- tubulin and β-tubulin contents. Paclitaxel-induced apoptosis could not be detected in either cell line over a wide range of drug concentrations. These results indicate that cross-resistance to paclitaxel in the J82/MMC-2 cell line is not linked to reduced drug accumulation, increased drug efflux, alterations in tubulin content or reduced paclitaxel-induced apoptosis. Paclitaxel-induced DNA strand breakage, however, determined by alkaline elution, was markedly lower in the J82/MMC-2 cell line than in J82/WT. These results suggest that paclitaxel cross-resistance in J82/MMC-2 may be attributed to reduced paclitaxel-induced DNA strand breakage. The precise mechanism of reduced paclitaxel-induced DNA strand breakage in J82/MMC-2 cell line relative to J82/WT cells, however, remains to be elucidated. (C) 2000 Elsevier Science Ireland Ltd.",
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