Effects of celecoxib on the reversal of multidrug resistance in human gastric carcinoma by downregulation of the expression and activity of P-glycoprotein.
We investigated the effects of celecoxib on the cell proliferation and the expression and activity of P-glycoprotein in the human gastric carcinoma multidrug resistance sublines SGC7901/adriamycin and SGC7901/vincristine. The cell proliferation was measured by [3H]thymidine incorporation assay and MTT test. The expression of the multidrug resistant gene (MDR1) was detected by real-time quantitative reverse transcription-polymerase chain reaction. P-glycoprotein was measured by Western blot analysis. The intracellular rhodamine 123 accumulation was analyzed by flow cytometry to evaluate the activity of P-glycoprotein. After treatment with celecoxib, the proliferation inhibitions of SGC7901 cell line and the SGC7901/adriamycin and SGC7901/vincristine sublines increased linearly in a positive dose-dependent pattern in both the [3H]thymidine incorporation assay and in the MTT test. The IC50 value of the MDR1/GAPDH ratio was 5.50 x 10(-6) mol/l in SGC7901/adriamycin and 3.89 x 10(-6) mol/l in SGC7901/vincristine. P-glycoprotein expression levels in the two multidrug resistance sublines treated with celecoxib were significantly lower than those in control groups, 0.28 vs. 0.71 in the SGC7901/adriamycin subline and 0.21 vs. 0.83 in the SGC7901/vincristine subline, respectively, P<0.05. After treatment with celecoxib, intracellular rhodamine 123 accumulation in the SGC7901/adriamycin and SGC7901/vincristine sublines increased positively in a dose-dependent pattern (P<0.05), and reached more than 50% of that in the SGC7901 cell line at the concentration of 1 x 10(-4) mol/l of celecoxib. In conclusion, celecoxib could inhibit proliferation of multidrug resistance in gastric carcinoma sublines. The reversal of multidrug resistance was caused by downregulation of the expression and activity of P-glycoprotein. The results may suggest a new way to reverse P-glycoprotein-dependent multidrug resistance in human gastric carcinoma.
Huang
Libin
L
Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, PRC.
Wang
Chunhui
C
Zheng
Wenbin
W
Liu
Rui
R
Yang
Jinlin
J
Tang
Chengwei
C
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib