Improvement of sensitivity to platinum compound with siRNA knockdown of upregulated genes in platinum complex-resistant ovarian cancer cells in vitro

Biomed Pharmacother. 2009 Sep;63(8):553-60. doi: 10.1016/j.biopha.2008.04.006. Epub 2008 May 27.


It is known that some cancers show platinum complex resistance and that others show platinum complex sensitivity among ovarian cancers. Oxaliplatin (cis-[oxalato[trans-l-1, 2-diamino-cyclohexane] platinum[II]]; l-OHP), an active anti-cancer agent consisting of platinum, inhibits RNA synthesis and results in cytostatic effects. We investigated the difference between an oxaliplatin-resistant ovarian cancer cell line, KFR, and an oxaliplatin-sensitive ovarian cancer cell line, KF-1, using DNA microarray analysis. The oxaliplatin-resistant cell line, KFR, was established by using KF-1 cells derived from human serous cystadenocarcinoma of the ovary. Acquisition of platinum resistance in human ovarian cancer cells thus appeared to be related mainly to the expression of gamma-glutamylcysteine synthetase (gamma-GCS), topo II and metallothionein (hMT) genes, and partly to that of topo I and glutathione S-transferase--pi (GST-pi) genes, in addition to a decrease in platinum accumulation. KFR cells had 8.5- and 24.7-fold higher mRNA levels of gamma-glutamylcysteine synthetase (gamma-GCS), and topo II genes than KF-1 cells, while KFR had only a slight increase in the glutathione S-transferase--pi (GST-pi) mRNA level as compared with KF-1. In comparison of the gene expressions between KFR and KF-1 ovarian cancer cell lines, tubulin-specific chaperone E (TBCE) and CBP/p300-interacting transactivator (CITED2) were overexpressed in KFR compared to KF-1. These genes are overexpressed in MKN74, an oxaliplatin-resistant gastric cancer cell line, compared to MKN28, an oxaliplatin-sensitive gastric cancer cell line. TBCE is 13-fold increased in KFR cells compared to KF-1 cells. CBP/p300-interacting transactivator is increased 2-fold in KFR cells compared to KF-1 cells. The siRNA directed to the TBCE gene and CBP/p300-interacting transactivator gene enhanced the cytotoxicity of diplatin to the platinum-resistant ovarian cancer cell line KFR. These results show that the TBCE gene and CBP/p300 gene have potential as multidrug-resistant genes. It is necessary to check the effect of siRNA to influx or exflux. It has potential to enhance the effect of anti-cancer agents to resistant cancer cells, so we will proceed to develop an inhibitor of these TBCE and CBP/p300 proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cystadenocarcinoma, Serous / enzymology
  • Cystadenocarcinoma, Serous / genetics*
  • Cystadenocarcinoma, Serous / pathology
  • DNA Topoisomerases, Type II / genetics
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic*
  • Glutamate-Cysteine Ligase / genetics
  • Glutathione S-Transferase pi / genetics
  • Humans
  • Molecular Chaperones / genetics
  • Oligonucleotide Array Sequence Analysis
  • Organoplatinum Compounds / pharmacology*
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Oxaliplatin
  • RNA Interference*
  • RNA, Small Interfering / metabolism*
  • Repressor Proteins / genetics
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Trans-Activators / genetics
  • Transfection
  • Up-Regulation


  • Antineoplastic Agents
  • CITED2 protein, human
  • Molecular Chaperones
  • Organoplatinum Compounds
  • RNA, Small Interfering
  • Repressor Proteins
  • TBCE protein, human
  • Trans-Activators
  • Oxaliplatin
  • GSTP1 protein, human
  • Glutathione S-Transferase pi
  • DNA Topoisomerases, Type II
  • Glutamate-Cysteine Ligase