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Indomethacin and telomerase activity in tumor growth retardation
C Lönnroth1, M Andersson, K Lundholm
1Department of Surgery, Sahlgrenska University Hospital, SE-413 45 Goteborg, Sweden. christina.lonnroth@surgery.gu.se
Abstract:
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.
Insights
Cyclooxygenase inhibitors, including indomethacin, slow tumor growth by inducing apoptosis and inhibiting telomere elongation. This effect on telomerase activity was observed in both mouse and human cancer cells, suggesting a novel therapeutic mechanism.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Cyclooxygenase (COX) inhibitors are known to reduce tumor growth, but the precise mechanisms remain largely unknown.
- Previous research suggests COX inhibitors impact tumor progression through various pathways, including apoptosis and angiogenesis.
Purpose of the Study:
- To investigate the underlying mechanisms by which cyclooxygenase inhibitors, specifically indomethacin, affect tumor growth and telomere elongation.
- To determine the role of cyclooxygenase activity and prostaglandin production in mediating the anti-tumor effects of NSAIDs.
Main Methods:
- Treatment of murine (MCG-101) and human (HT-29) tumor models with indomethacin and other NSAIDs (mobic, sulindac sulfone, suramin, ibuprofen).
- Assessment of tumor growth, apoptosis/necrosis, telomere elongation, and telomerase activity.
- Measurement of prostaglandin E2 (PGE2) production in tumor cells.
Main Results:
- Indomethacin significantly retarded MCG-101 tumor growth by inducing apoptosis/necrosis and inhibiting telomere elongation.
- NSAIDs inhibited telomerase activity in some models, but this was not a universal finding across all tested cell lines.
- Sulindac sulfone decreased growth and telomerase activity in MCG-101 cells without affecting PGE2 production, indicating a COX-independent mechanism.
Conclusions:
- Cyclooxygenase inhibitors can inhibit tumor growth in both murine and human cancer cells through telomerase activity inhibition, beyond previously known mechanisms like apoptosis induction.
- The anti-tumor effects of certain NSAIDs may not be solely dependent on COX-1/COX-2 activity or prostaglandin production, suggesting alternative molecular targets.
- NSAIDs represent a potential therapeutic strategy for cancer, acting through multifaceted mechanisms including telomerase inhibition.