TY - JOUR
T1 - Cyclooxygenase-2 dependent and independent antitumor effects induced by celecoxib in urinary bladder cancer cells
AU - Dhawan, Deepika
AU - Jeffreys, Antonella Borgatti
AU - Zheng, Rong
AU - Stewart, Jane C.
AU - Knapp, Deborah W.
PY - 2008/4/1
Y1 - 2008/4/1
N2 - Transitional cell carcinoma of the urinary bladder is the second most common genitourinary malignancy in people in the United States. Cyclooxygenase-2 (COX-2) is overexpressed in bladder cancer. COX-2 inhibitors have had antitumor activity against bladder cancer, but the mechanisms of action are unclear. Clinically relevant concentrations of COX-2 inhibitors fail to inhibit proliferation in standard in vitro assays. In pilot experiments, different culture conditions [standard monolayer, modified monolayer, soft agar, collagen, and poly(2-hydroxyethyl methacrylate)-coated plates] were assessed to determine conditions suitable for the study of COX inhibitor growth-inhibitory effects. This was followed by studies of the effects of clinically relevant concentrations of a selective COX-2 inhibitor (celecoxib) on urinary bladder cancer cell lines (HT1376, TCCSUP, and UMUC3). Celecoxib (≤5 Mmol/L) inhibited proliferation of COX-2-expressing HT1376 cells in soft agar and modified monolayer cell culture conditions in a COX-2-dependent manner. COX-2 expression, however, did not always correlate with response to celecoxib. TCCSUP cells that express COX-2 were minimally affected by celecoxib, and UMUC3 cells that lack COX-2 expression were modestly inhibited by the drug. When UMUC3 Cox-2/Tet cells overexpressing COX-2 under the control of tetracycline-inducible promoter were treated with celecoxib in modified monolayer cell culture, growth inhibition was found to be associated with changes in the expression of pRb. Not surprisingly, the proliferation of all cell lines was inhibited by excessively high concentrations of celecoxib. In conclusion, the modified culture conditions allowed detection of COX-2-dependent and COX-2-independent growth-inhibitory activity of celecoxib in urinary bladder cancer cells.
AB - Transitional cell carcinoma of the urinary bladder is the second most common genitourinary malignancy in people in the United States. Cyclooxygenase-2 (COX-2) is overexpressed in bladder cancer. COX-2 inhibitors have had antitumor activity against bladder cancer, but the mechanisms of action are unclear. Clinically relevant concentrations of COX-2 inhibitors fail to inhibit proliferation in standard in vitro assays. In pilot experiments, different culture conditions [standard monolayer, modified monolayer, soft agar, collagen, and poly(2-hydroxyethyl methacrylate)-coated plates] were assessed to determine conditions suitable for the study of COX inhibitor growth-inhibitory effects. This was followed by studies of the effects of clinically relevant concentrations of a selective COX-2 inhibitor (celecoxib) on urinary bladder cancer cell lines (HT1376, TCCSUP, and UMUC3). Celecoxib (≤5 Mmol/L) inhibited proliferation of COX-2-expressing HT1376 cells in soft agar and modified monolayer cell culture conditions in a COX-2-dependent manner. COX-2 expression, however, did not always correlate with response to celecoxib. TCCSUP cells that express COX-2 were minimally affected by celecoxib, and UMUC3 cells that lack COX-2 expression were modestly inhibited by the drug. When UMUC3 Cox-2/Tet cells overexpressing COX-2 under the control of tetracycline-inducible promoter were treated with celecoxib in modified monolayer cell culture, growth inhibition was found to be associated with changes in the expression of pRb. Not surprisingly, the proliferation of all cell lines was inhibited by excessively high concentrations of celecoxib. In conclusion, the modified culture conditions allowed detection of COX-2-dependent and COX-2-independent growth-inhibitory activity of celecoxib in urinary bladder cancer cells.
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U2 - 10.1158/1535-7163.MCT-07-0313
DO - 10.1158/1535-7163.MCT-07-0313
M3 - Article
C2 - 18413803
AN - SCOPUS:42249088089
SN - 1535-7163
VL - 7
SP - 897
EP - 904
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 4
ER -