RT Journal Article
SR Electronic
T1 Cyclooxygenase-2 Gene Induction Causes CDDP Resistance in Colon Cancer Cell Line, HCT-15
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 2723
OP 2728
VO 24
IS 5A
A1 SAIKAWA, YOSHIRO
A1 SUGIURA, TSUDOI
A1 TORIUMI, FUMIKI
A1 KUBOTA, TETSURO
A1 SUGANUMA, KAZUHIRO
A1 ISSHIKI, SOICHIRO
A1 OTANI, YOSHIHIDE
A1 KUMAI, KOICHIRO
A1 KITAJIMA, MASAKI
YR 2004
UL http://ar.iiarjournals.org/content/24/5A/2723.abstract
AB Drug resistance to cisplatin (CDDP) would represent a major obstacle for cancer therapy. The adenosine triphosphate (ATP) binding cassette (ABC) family of transport proteins, such as the 170 kDa P-glycoprotein (multidrug resistance gene-1; MDR-1) and the 190 kDa multidrug resistance-associated proteins (MRPs), are associated with multidrug resistance, including resistance to CDDP. The purpose of the present study was to investigate the relationship between cyclooxygenase-2 (COX-2) expression and the level of chemosensitivity to CDDP. We established the COX-2-overexpressed colon cancer cell line TR-5 from HCT-15 cells. We quantified the expression of m-RNA for MRP-1 and MDR-1 by a real-time PCR method, determining that the values of each gene/standardized GAPDH in HCT-15 and TR-5 were 2.3±0.4 and 6.1±0.5 in MRP-1 (p<0.02) and 9.0±4.8 and 3.6±0.5 in MDR-1, respectively. With respect to chemosensitivity, survival rates for 3 μg/ml and 10 μg/ml of CDDP were 81.5±12.2% and 26.1±11.7% (IC50=6.5 μg/ml) for HCT-15 and 96.6±1.7% and 77.4±4.9% (IC50=18.5 μg/ml) for TR-5, respectively, thus TR-5 showed higher resistance to CDDP than HCT-15 did with statistical differences. We also demonstrated a successful re-sensitization to CDDP toxicity in TR-5 by means of the COX-2 selective inhibitor JTE-522, 4-(4-cyclohexyl-2-methyl-1, 3-oxazol-5-yl)-2-fluorobenzene sulfonamide, which markedly decreased the IC50 of CDDP for TR-5 (from 17.3±2.6 μg/ml to 8.6±2.5 μg/ml). In conclusion, COX-2 overexpression induced increased MRP-1 expression in a colon cancer cell line, TR-5, resulting in chemoresistance to CDDP that was approximately triple the level of chemoresistance observed in the original HCT-15 cells line, as measured by calculation of the IC50. We also confirmed the efficacy of pretreatment of TR-5 cells with the COX-2 selective inhibitor JTE-522 in restoring chemosensitivity of these cells to CDDP, suggesting a strategy for overcoming drug resistance to CDDP. Copyright© 2004 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved