Emergence of cisplatin-resistant cells from the OVCAR-3 ovarian carcinoma cell line with p53 mutations, altered tumorigenicity, and increased apoptotic sensitivity to p53 gene replacement

K. Mujoo, L. Zhang, J. Klostergaard, N. J. Donato

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Resistance to chemotherapy commonly compromises the treatment of many advanced cancers. Evidence suggests a correlation between chemoresistance and more aggressive tumor growth, possibly through accumulation of additional genetic defects in drug-treated or resistant cells. To study this process in a human ovarian canter model, we examined OVCAR-3 cells for acute sensitivity to cisplatin (cDDP) and subsequent emergence of drug-resistant clones following chronic cDDP exposure. Clonal cells (OVCAR-3/C-1) that displayed 20-fold reduced sensitivity to cisplatin but retained equivalent sensitivity to paclitaxel, as compared with the parental population, were isolated. The cDDP-resistant clone had growth kinetics similar to those of parental population, but when transplanted into the peritoneal cavity of nude mice, they acquired the ability to grow with the development of both ascites and solid tumor masses; such growth was not detectable after transplantation of the drug-sensitive parental cell line. C-1 cells had a p53 gene mutation (codon 266) that was not detected in the parental OVCAR-3 cell line, and infection of C-1 cells with p53-adenovirus (rAd-p53) caused greater apoptosis and gene transduction than that observed in the similarly infected parental population, rAd-p53 induced high levels of p21WAF1, p27Kip1, activated caspase 3 and apoptosis in C-1 cells, without causing major changes in bax or bcl-X(L) levels. Together, the results suggest that alterations in tumor growth and gene mutations characterize cDDP-resistance in OVCAR-3 cells, and viral replacement of one of these defective genes (p53) may provide an effective treatment for elimination of drug-resistant cells.

Original languageEnglish (US)
Pages (from-to)105-114
Number of pages10
JournalInternational Journal of Gynecological Cancer
Volume10
Issue number2
DOIs
StatePublished - 2000

Keywords

  • Apoptosis
  • Cell cycle
  • Drug resistance
  • Ovarian cancer
  • p53

ASJC Scopus subject areas

  • Oncology
  • Obstetrics and Gynecology

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