Colon cancer cells with high invasive potential are susceptible to induction of apoptosis by a selective COX-2 inhibitor.
Cyclooxygenase-2 (COX-2) expression has been shown to correlate with the invasiveness of colon cancer cells. To further investigate this positive correlation and its possible therapeutic implications, a selective COX-2 inhibitor, etodolac, was tested on three variants of HT-29 colon cancer cell lines, HT-29/Inv1, HT-29/Inv2 and HT-29/Inv3, with graded increases of in vitro Matrigel invasive potential and COX-2 expression levels. HT-29 variants with higher invasive potential were found to be more sensitive to etodolac by in vitro growth inhibition assays, the estimated LD(50) being 0.5 mM for highly invasive HT-29/Inv2 and HT-29/Inv3 cells, 0.6 mM for slightly less invasive HT-29/Inv1, and 1.8 mM for the parental HT-29. Treatment of the highly invasive HT-29/Inv2 and Inv3 variants with as little as 0.1 mM etodolac in the growth medium produced signs of apoptosis, as detected by DNA fragmentation and TUNEL (terminal deoxynucleotidyl transferase dUTP-biotin nick end labeling) assay. In vivo experiments in SCID mice showed that etolodac inhibited the growth of subcutaneous tumors induced by HT-29/Inv3 cells significantly more than those by the parental HT-29 cells. These results suggest that COX-2 inhibitors have a potential role in prevention of tumor invasion in colon cancer patients.
Chen
Wei-Shone
WS
Division of Colorectal Surgery, Veterans General Hospital-Taipei and National Yang-Ming University, Taiwan. wschen@vghtpe.gov.tw
Liu
Jin-Hwang
JH
Wei
Sung-Jen
SJ
Liu
Jacqueline Ming
JM
Hong
Chi-Yuan
CY
Yang
Wen K
WK
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000473:pathology*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D004195:Disease Models, Animal; D017308:Etodolac / Q000633:toxicity*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D017308:Etodolac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases