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Lovastatin, a 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Inhibitor, Induces Apoptosis and Differentiation in Human Anaplastic Thyroid Carcinoma Cells

Graduate Institute of Physiology, College of Medicine, National Taiwan University (C.Y.W., W.B.Z., Y.F.T.); and Department of Anatomy and Cell Biology (L.S.M.) and Division of Endocrinology (C.Y.W., T.C.C.), Department of Internal Medicine, Far-Eastern Memorial Hospital and National Taiwan University Hospital, College of Medicine, National Taiwan University, 10063, Taipei, Taiwan

Address all correspondence and requests for reprints to: Dr. Tien-Chun Chang, Division of Endocrinology, Department of Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei, Taiwan. E-mail: tcchang1{at}ms10.hinet.net.

Although only 1% of differentiated thyroid cancers transform into anaplastic thyroid cancer, this disease is always fatal. Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells; these effects are unrelated to lipid reduction. Recently, we found that TNF induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression; however, TNF is cytotoxic for normal human tissue. The aim of this study was to determine whether lovastatin, an HMG-CoA reductase inhibitor, could induce apoptosis and differentiation in anaplastic thyroid cancer cells. Anaplastic thyroid cancer cells were treated with lovastatin, then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation, phosphatidylserine externalization/flow cytometry, and electron microscopy. Thyroglobulin levels in the culture medium were also measured. Our results showed that at a higher dose (50 µM), lovastatin induced apoptosis of anaplastic thyroid cancer cells, whereas at a lower dose (25 µM), it promoted 3-dimensional cytomorphological differentiation. It also induced increased secretion of thyroglobulin by anaplastic cancer cells. Our results show that lovastatin not only induces apoptosis, but also promotes redifferentiation in anaplastic thyroid cancer cells, and suggest that it and other HMG-CoA reductase inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer.

Abbreviations: CD buffer, Cacodylate buffer; 3-D, three-dimensional; FOH, farnesol; GGOH, geranylgeraniol; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; PI, propidium iodide; PPAR, peroxisome proliferator-activated receptor-; SEM, scanning electron microscopy; TEM, transmission electron microscopy.

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