Renal and liver tumors in Tsc2(+/-) mice, a model of tuberous sclerosis complex, do not respond to treatment with atorvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.

Abstract

Inactivating mutations of the tumor suppressor gene TSC2 are associated with tumorigenesis in tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis. Statins, as 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, have the potential to limit the growth of these tumors by limiting the isoprenylation of activated GTPases in Tsc2-null cells. We tested atorvastatin as a therapy for (a) ethylnitrosourea (ENU)-enhanced renal cystadenoma and (b) spontaneous liver hemangioma in 129Sv/Jae Tsc2(+/-) mice. ENU-treated Tsc2(+/-) mice were given atorvastatin chow (0.1%, w/w) for 1 or 3 months before sacrifice at 6 months; 129Sv/Jae Tsc2(+/-) mice were given atorvastatin chow (0.1%, w/w) for 6 months before sacrifice at 12 months. All treatment groups were compared with mice of identical genotype and strain background that were fed control chow. Pathologic analyses revealed a predominance of renal cystadenoma in ENU-treated and liver hemangioma in non-ENU-treated 129Sv/Jae Tsc2(+/-) mice. In both cohorts, serum cholesterol levels and levels of phosphorylated S6 and GTP-RhoA in healthy tissue were significantly (>50%) reduced in atorvastatin-treated mice as compared with controls. Following atorvastatin treatment, no significant reduction in tumor size, morphology, or phosphorylated S6 levels was observed for either ENU-associated renal cystadenoma or spontaneous liver hemangioma as compared with the untreated groups. In conclusion, although the marked reduction in cholesterol levels indicates that atorvastatin was effective as an 3-hydroxy-3-methylglutaryl CoA reductase inhibitor, it did not inhibit the growth of tumors that develop in these Tsc2(+/-) models, suggesting that it is unlikely to have benefit as a single-agent therapy for TSC-associated tumors.

• Authors: Geraldine A Finlay, Amy J Malhowski, Kristen Polizzi, Izabela Malinowska-Kolodziej, David J Kwiatkowski
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 8 Issue 7 Pg. 1799-807 (Jul 2009) ISSN: 1538-8514 [Electronic] United States
• PMID: 19584242 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Pyrroles
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• Cholesterol
• Atorvastatin

Topics

• Animals
• Atorvastatin
• Cholesterol (metabolism)
• Cystadenoma (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Female
• Hemangioma (drug therapy, metabolism, pathology)
• Heptanoic Acids (therapeutic use)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Immunoenzyme Techniques
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pyrroles (therapeutic use)
• Survival Rate
• Tuberous Sclerosis (pathology)
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (physiology)