Inhibition of human colon cancer cell growth by selective inhibition of cyclooxygenase-2.
A considerable amount of evidence collected from several different experimental systems indicates that cyclooxygenase-2 (COX-2) may play a role in colorectal tumorigenesis. Large epidemiologic studies have shown a 40-50% reduction in mortality from colorectal cancer in persons taking aspirin or other nonsteroidal antiinflammatory drugs on a regular basis. One property shared by all of these drugs is their ability to inhibit COX, a key enzyme in the conversion of arachidonic acid to prostaglandins. Two isoforms of COX have been characterized, COX-1 and COX-2. COX-2 is expressed at high levels in intestinal tumors in humans and rodents. In this study, we selected two transformed human colon cancer cell lines for studies on the role of COX-2 in intestinal tumorigenesis. We evaluated HCA-7 cells which express high levels of COX-2 protein constitutively and HCT-116 cells which lack COX-2 protein. Treatment of nude mice implanted with HCA-7 cells with a selective COX-2 inhibitor (SC-58125), reduced tumor formation by 85-90%. SC-58125 also inhibited colony formation of cultured HCA-7 cells. Conversely, SC-58125 had no effect on HCT-116 implants in nude mice or colony formation in culture. Here we provide evidence that there may be a direct link between inhibition of intestinal cancer growth and selective inhibition of the COX-2 pathway.
Sheng
H
H
Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Shao
J
J
Kirkland
S C
SC
Isakson
P
P
Coffey
R J
RJ
Morrow
J
J
Beauchamp
R D
RD
DuBois
R N
RN
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002455:Cell Division; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011453:Prostaglandins / Q000276:immunology / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D012313:RNA / Q000032:analysis / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D011720:Pyrazoles; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; D012313:RNA; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse