Statins in lymphangioleiomyomatosis. Simvastatin and atorvastatin induce differential effects on tuberous sclerosis complex 2-null cell growth and signaling.

[lymphangioleiomyomatosis]

Mutations of the tumor suppressor genes tuberous sclerosis complex (TSC )1 and TSC 2 cause pulmonary lymphangioleiomyomatosis (LAM ) and tuberous sclerosis (TS ). Current rapamycin-based therapies for TS and LAM have a predominantly cytostatic effect , and disease progression resumes with therapy cessation . Evidence of RhoA GTPase activation in LAM -derived and human TSC 2 -null cells suggests that 3 -hydroxy-3 -methylglutaryl-coenzyme A reductase inhibitor statins can be used as potential adjuvant agents . The goal of this study was to determine which statin (simvastatin or atorvastatin ) is more effective in suppressing TSC 2 -null cell growth and signaling . Simvastatin , but not atorvastatin , showed a concentration-dependent (0 .5 -10 Î¼M ) inhibitory effect on mouse TSC 2 -null and human LAM -derived cell growth . Treatment with 10 Î¼M simvastatin induced dramatic disruption of TSC 2 -null cell monolayer and cell rounding ; in contrast , few changes were observed in cells treated with the same concentration of atorvastatin . Combined treatment of rapamycin with simvastatin but not with atorvastatin showed a synergistic growth -inhibitory effect on TSC 2 -null cells . Simvastatin , but not atorvastatin , inhibited the activity of prosurvival serine-threonine kinase Akt and induced marked up-regulation of cleaved caspase-3 , a marker of cell apoptosis . Simvastatin , but not atorvastatin , also induced concentration-dependent inhibition of p 42 /p 44 Erk and mTORC 1 . Thus , our data show growth -inhibitory and proapoptotic effects of simvastatin on TSC 2 -null cells compared with atorvastatin . These findings have translational significance for combinatorial therapeutic strategies of simvastatin to inhibit TSC 2 -null cell survival in TS and LAM .

Diseases
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Diseases presenting "synergistic growth-inhibitory effect" symptom

lymphangioleiomyomatosis

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