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ORIGINAL RESEARCH ARTICLE

Indomethacin Inhibits Cell Growth of Medullary Thyroid Carcinoma by Reducing Cell Cycle Progression into S Phase

Chisato Tomoda^*,, Farhad Moatamed, Faramarz Naeim, Jerome M. Hershman^* and Masahiro Sugawara^*,1

^* Division of Endocrinology and Diabetes, Greater Los Angeles Veterans Affair Medical Center and Department of Medicine, David Geffen School of Medicine at University of California in Los Angeles, Los Angeles, California 90073; Division of Otolaryngology, Head and Neck Surgery, Department of Medicine Sensory and Motor Organ, Tottori University Faculty of Medicine, Tottori 683-8503, Japan; and Department of Pathology, Greater Los Angeles Veterans Affair Medical Center and Department of Medicine, David Geffen School of Medicine at University of California in Los Angeles, Los Angeles, California 90073

To whom requests for reprints should be addressed at ¹ GLA VA Medical Center (111M), 11301 Wilshire Blvd., Los Angeles, CA 90073. E-mail: msugawar{at}ucla.edu

Indomethacin, a non-steroidal anti-inflammatory drug (NSAID), has been reported to inhibit the growth of medullary thyroid carcinoma (MTC) cells in vitro. However, the mechanism of inhibition of MTC cell growth by indomethacin and its potency have yet to be revealed. We examined the effect of indomethacin on three different MTC cell lines (TT cells, DRO 81–1 cells and HRO 85–1 cells) and two non-MTC cells. The mechanism of indomethacin action in MTC cells was investigated by analyzing intracellular prostaglandin level, apoptosis, and cell cycle in TT cells. Indomethacin inhibited cell growth of all three MTC cell lines but not normal thyroid cells or anaplastic thyroid carcinoma cells. Indomethacin at 10 µM or greater showed a dose response inhibition of cell growth. Indomethacin at 25 µM, a putative therapeutic serum indomethacin level, showed potency similar to 100 to 200 nM sunitinib, a receptor tyrosine kinase inhibitor. To examine whether prostaglandin depletion might determine the inhibition of MTC cell growth, we created different prostaglandin E2 (PGE2) levels in TT cells using three different NSAIDs. A profound PGE2 depletion by indomethacin-ester, a potent cyclooxygenase (COX) II inhibitor, showed the least inhibition of cell growth. Indomethacin did not increase apoptosis of TT cells. Indomethacin, but not naproxen or indomethacin-ester, reduced cell cycle progression into S phase; this was unrelated to the degree of PGE2 depletion. The expression of phosphorylated retinoblastoma (pRb) protein that shifts cells from G₁ to S phase was reduced after exposure to indomethacin. In conclusion, indomethacin has specific anti-tumor effect on MTC cells, probably by reducing cell cycle progression into S phase rather than by prostaglandin depletion. Since no drug therapy is currently available for MTC, indomethacin may be one of the therapeutic candidates.

Key Words: medullary thyroid cancer • indomethacin • sunitinib • cell cycle • prostaglandin