Ncpendmet_2007_229.indd

Therapeutic potential of statins
in thyroid proliferative disease
Maurizio Bifulco
The thyroid gland is a frequent site of abnormal epithelial cell proliferation. Proliferative diseases reductase, farnesyl transferase and geranyl- of the thyroid follicular cells that arise as either geranyl transferase have been associated with cell sporadic or nontoxic multinodular goiter prog- proliferation, and aberrant expression of these ress to neoplasia in ~5% of all cases. In addition, enzymes seems to be a characteristic of tumor the incidence of thyroid cancer has risen rapidly cells. Inappropriate activation of the Ras signaling over the past few years. In terms of histology, this pathway has a critical function in thyroid prolifera- endocrine malignancy predominantly comprises tive disease. In addition, it has been reported papillary thyroid cancer and follicular thyroid that geranylgeranylated Rho has important cancer, whereas medullary thyroid cancer and roles in cell proliferation and apoptosis beyond anaplastic thyroid cancer (ATC) occur less control of cell migration. As statins inhibit both frequently. Nonetheless, ATC is considered one farnesyla tion and geranylgeranylation (and hence of the most aggressive forms of human neoplasia Ras and/or Rho activation), it seems plausible and is refractory to conventional therapeutic that they might potentially inhibit expression of strategies. Innovative approaches are, there- the malignant phenotype of tumor cells.
fore, currently underway to investigate novel We have shown that lovastatin exerts anti- treatments for thyroid proliferative disease. For proliferative activity in rat thyroid cells (without example, statins have been reported to affect affecting cell differentiation) and induces apop- proliferation and survival of several tumor cell tosis in proliferating human thyroid cells.1,2 types (including thyroid) and display in vivo These activities occur by inhibition of protein antitumor activity when used as single agents or prenylation. In vivo experiments have confirmed in combination with other anticancer drugs.
that administration of lovastatin to rats inhibits Statins are cholesterol-lowering agents that thyroid hypertrophia and hyperplasia induced are commonly prescribed to prevent cardio- by goitrogenic agents. This result suggests that vascular and coronary heart disease. These drugs lovastatin has antigoiter activity, and so provides a inhibit 3-hydroxy-3-methylglutaryl coenzyme A rationale for innovative therapeutic strategies that (HMG-CoA) reductase, the rate-limiting enzyme exploit statins in the treatment and/or prevention of isoprenoid and cholesterol biosynthesis. of human goiter.3 In support of this hypothesis, a Inhibition of this enzyme prevents the reduction retrospective epidemiologic study in dyslipidemic of HMG-CoA to mevalonate, the precursor of patients showed that treatment with statins for cholesterol. In addition to their lipid-lowering at least 5 years was associated with a significantly properties, statins are also thought to display lower prevalence, number, and volume of thyroid immunomodulatory, anti-inflammatory, and nodules, as well as a smaller thyroid size.4 antioxidant activity, and to reduce insulin resis- Inhibition of Rho geranylgeranylation by lova- Correspondence
tance and progression of renal disease. These statin has been shown to exert growth-inhibitory effects do not seem to be directly related to inhibi- and proapoptotic effects, and to induce differentia- Pharmaceutical SciencesUniversity of Salerno tion of cholesterol biosynthesis. Mevalonate is also tion of human ATC cells resistant to conventional the precursor of prenyl groups, which are trans- therapies. Indeed, some studies have indicated ferred by farnesyl and geranylgeranyl transferases that inhibition of geranylgeranylation (but not to small guanosine triphosphate-binding proteins farnesylation) could be the main mechanism of the Ras and Rho families. Protein prenylation that regulates lovastatin-induced apoptosis.5,6 By Received 3 November 2007
Accepted 17 December 2007
is essential for anchoring these proteins to the contrast, we found that the isoprenoid pathway Published online
plasma membrane and for subsequent activa- was markedly altered in the FRTL-5 rat thyroid tion of proteins involved in cellular proliferation, cell line upon transformation with K-ras (but www.nature.com/clinicalpracticedoi:10.1038/ncpendmet0782 not H-ras). This effect occurred via induction of 242 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM farnesyl transferase activity, which resulted in the biological evidence, at least for colon cancer.10 Acknowledgments
The author’s work
preferential farnesylation and functional activa- Nonetheless, the long-term latency effects of tion of the oncogene product.7 Treatment with statin therapy remain to be evaluated as a small Associazione Educazione e Ricerca Medica Salernitana lovastatin inhibited proliferation and induced increased risk of thyroid cancer insurgence has apoptosis of the K-ras-transformed thyroid cells been reported in men, but not women, who by modulation of the cellular redox state.8 The received lovastatin or simvastatin for 5 years.
Competing interests
preferential inhibition of a specific Ras isoform In conclusion, both antiproliferative and The author declared no competing interests.
might, therefore, represent an alternative mecha- proapoptotic effects of statins have been described nism of lovastatin action and so provide a useful in several experimental models. Statins show selective chemotherapeutic tool for tumors therapeutic potential in thyroid proliferative disease and might represent a novel approach to The findings discussed above should prompt treat dedifferentiated thyroid cancer, although further basic and clinical studies on the thera- questions remain about the clinical significance peutic potential of statins in thyroid cancer, of the antiproliferative activity of statins in the particularly in order to clarify whether the thyroid gland. Identification of the statin with anti angiogenic and anti-inflammatory effects maximal efficacy and specificity will directly are relevant to anticancer therapy. Additional influence the clinical application of statin therapy studies are also needed to determine whether in the management of cancer. In addition, experi- the antitumoral activities of statins are mediated mental and clinical trials must determine whether solely by their effects on protein prenylation or the promising protective effects of statins are if they also relate to the lipid-lowering activity. applicable both to patients with and without We are currently studying the molecular mecha- hypercholesterolemia. Finally, inclusion of statins nism of lovastatin action in detail to determine in combined therapies for the more aggressive whether the main cellular target is Ras, Rho or thyroid cancers must also be evaluated.
another prenylated protein, such as the novel References
et al. (1999) Inhibition of farnesylation blocks 2',3'-cyclic nucleo tide 3'-phosphodiesterase. We growth but not differentiation in FRTL-5 thyroid cells.
Biochimie 81: 287–290
have previously shown in FRTL-5 cells that lova- et al. (1999) Prenyltransferase inhibitors statin induces cytoskeletal disorganization and induce apoptosis in proliferating thyroid cells through a disconnection of microtubules from the plasma p53-independent, CrmA-sensitive, and caspase-3-like
protease-dependant mechanism. Endocrinology 140:
membrane.8 Evaluation of the cellular function of 2',3'-cyclic nucleotide 3'-phosphodiesterase C et al. (2006) HMG-CoA reductase inhibitors might, therefore, provide additional insight as inhibit rat propylthiouracil-induced goiter by
modulating the ras-MAPK pathway. J Mol Med 84:
to how lovastatin could act as an anticancer agent via microtubule disassembly. Finally, et al. (2008) Reduced thyroid volume and nodularity in dyslipidaemic patients on statin gene therapy approaches for the treatment of treatment. Clin Endocrinol (Oxf) 68: 16–21
ATC have also been investigated. In this regard, et al. (2003) Lovastatin, a 3-hydroxy-3- we have demonstrated that lovastatin increases methylglutaryl coenzyme A reductase inhibitor, induces apoptosis and differentiation in human adenoviral replication and enhances the in vitro anaplastic thyroid carcinoma cells. J Clin Endocrinol and in vivo effects of the oncolytic adenovirus Metab 88: 3021–3026
dl1520 (Onyx-015, Onyx Pharmaceuticals, WB et al. (2005) Lovastatin suppresses invasiveness of anaplastic thyroid cancer cells by Emeryville, CA) in ATC cells. This observa- inhibiting Rho geranylgeranylation and RhoA/ROCK tion suggests that lovastatin could be a useful signaling. Endocr Relat Cancer 12: 615–629
et al. (1998) v-K-ras leads to preferential farnesylation of p21(ras) in FRTL-5 cells: multiple Although usually well tolerated, statins have interference with the isoprenoid pathway. Proc Natl been associated with adverse effects such as Acad Sci USA 95: 13646–13651
myotoxicity and potential interactions with 8 Bifulco M (2005) Role of the isoprenoid pathway in ras transforming activity, cytoskeleton organization, cell other drugs; however, lovastatin has been used proliferation and apoptosis. Life Sci 77: 1740–1749
extensively with negligible adverse effects and et al. (2007) Lovastatin enhances the replication of the oncolytic adenovirus dl1520 and has a well-defined clinical pharmacokinetic its antineoplastic activity against anaplastic thyroid profile. In a meta-analysis of randomized trials carcinoma cells. Endocrinology 148: 5186–5194
there was no evidence that statin therapy was 10 Friedman GD et al. (2007) Screening statins for possible carcinogenic risk: up to 9 years of follow-up associated with increased short-term cancer of 361 859 recipients. Pharmacoepidemiol Drug Saf risk, and chemoprevention was supported by the NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 243

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