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

Hironobu Yanagie, Tomoyuki Hisa, Aya Ogata, Ayaka Miyazaki, Yasumasa Nonaka, Teturo Nishihira, Isao Osada, Takayuki Sairennji, Hirotaka Sugiyama, Yoshitaka Furuya, Yosinori Kidani, Shinichi Takamoto, Hiroyuki Takahashi, Masazumi Eriguchi
Biomedicine & Pharmacotherapy 2009, 63 (8): 553-60
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.

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