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Chemosensitivity of BRCA1-Mutated Ovarian Cancer Cells and Established Cytotoxic Agents
  1. Caroline van Haaften, PhD*,
  2. Jaap van Eendenburg, BAS,
  3. Arnoud Boot, PhD,
  4. Willem E. Corver, PhD,
  5. Lucien Haans, MD,
  6. Tom van Wezel, PhD and
  7. J. Baptist Trimbos, MD, PhD*
  1. *Department of Gynecology,
  2. Department of Pathology, Leiden University Medical Center; and
  3. Department of Gynecology, Medical Center Haaglanden, The Hague, The Netherlands.
  1. Address correspondence and reprint requests to Caroline van Haaften, PhD, Department of Gynecology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: carocell@planet.nl.

Abstract

Objective Serous adenocarcinomas that arise in patients with inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 are initially well treatable with platinum/paclitaxel. For recurrent disease in patients with BRCA1 or BRCA2 mutations, olaparib treatment is available. To study additional therapeutic regimens, a better understanding of the cellular and molecular mechanisms of the tumors in in vitro models is important.

Methods/Materials From a high-grade serous ovarian tumor of a BRCA1 mutation carrier, we established 3 distinct cell line subclones, OVCA-TR3.1, -2, and -3. Immunohistochemical characterization, flow cytometric analyses, chemosensitivity, and somatic mutation profiling were performed.

Results The cell lines expressed AE1/AE3, Pax8, WT-1, OC125, estrogen receptor (ER), and p53, comparable to the primary tumor. Synergism could be shown in the combination treatment eremophila-1-(10)-11(13)-dien-12,8β-olide (EPD), with cisplatin, whereas combination with olaparib did not show synergism. Eremophila-1-(10)-11(13)-dien-12,8β-olide, a sesquiterpene lactone, is a novel chemotherapeutic agent. The inherited BRCA1 c.2989_2990dupAA mutation was confirmed in the cell lines. Loss of heterozygosity of BRCA1 was detected in each cell line, as well as a homozygous TP53 c.722C>A mutation. Flow cytometry showed that all cell lines had a distinct DNA index.

Conclusions Three new isogenic ovarian cancer cell lines were developed from a patient with a germ line BRCA1 mutation. Chemosensitivity profiling of the cell lines showed high tolerance for olaparib. Treatment with EPD proved synergistic with cisplatin. The effects of EPD will be further investigated for future clinical efficacy.

  • Ovarian cancer
  • BRCA1
  • EPD
  • Olaparib
  • Synergism

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Footnotes

  • The authors declare no conflicts of interest.

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