Indomethacin and telomerase activity in tumor growth retardation.
It is well-recognized that cycloogygenase inhibitors attenuate tumor growth in tumor models, although underlying mechanisms are unclear. In the present study we report that indomethacin retards MCG-101 tumor growth on mice by induction of apoptosis/necrosis and inhibits telomere elongation. The inhibition of telomerase activity by NSAIDs (indomethacin, mobic, sulindac sulfone, suramin) was, however, not a universal finding, since a mouse melanoma (K1735-M2) did not respond. By contrast, a human cell line of colon carcinoma origin (HT-29), responded by both retarded growth and telomerase activity despite a low intrinsic production of prostaglandins, mainly PGE2. Therefore, it is not likely that indomethacin inhibition of tumor growth and telomere elongation is directly related to Cox-1/Cox-2 activities in tumor cells. Also, NSAIDs at 25 microM (sulindac sulfone) decreased growth and telomerase activity in MCG-101 cells, without any effects on PGE2 production, while ibuprofen reduced PGE2 production but had no effect on growth or telomerase activity. Our results demonstrate that cyclooxygenase inhibitors can retard tumor growth both in murine tumors and in human tumor cells by inhibition of telomerase activity in addition to previously recognized mechanisms as induction of apoptosis, inhibition of cell proliferation, influence on the expression of growth factors around growing tumors and attenuation of neoangiogenesis.
Lönnroth
C
C
Department of Surgery, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden. christina.lonnroth@surgery.gu.se
Andersson
M
M
Lundholm
K
K
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D015232:Dinoprostone / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D016133:Polymerase Chain Reaction; D012313:RNA; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D017931:DNA Primers; D004268:DNA-Binding Proteins; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; D015232:Dinoprostone; D007213:Indomethacin