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Published on: November 17, 2018

Statins in lymphangioleiomyomatosis. Simvastatin and atorvastatin induce differential effects on tuberous sclerosis

Elena N Atochina-Vasserman1, Dmitry A Goncharov, Alla V Volgina

  • 11 Airway Biology Initiative, Pulmonary, Allergy & Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

American Journal of Respiratory Cell and Molecular Biology
|August 17, 2013
PubMed

Insights

Simvastatin effectively inhibits tuberous sclerosis complex (TSC)2-null cell growth and promotes apoptosis, unlike atorvastatin. This suggests simvastatin as a potential adjuvant therapy for TSC and pulmonary lymphangioleiomyomatosis (LAM).

Area of Science:

  • Cell Biology
  • Pharmacology
  • Genetics

Background:

  • Mutations in TSC1/TSC2 tumor suppressor genes cause tuberous sclerosis (TS) and pulmonary lymphangioleiomyomatosis (LAM).
  • Current rapamycin therapies for TS/LAM are cytostatic, with disease recurrence upon cessation.
  • RhoA GTPase activation in LAM/TSC2-null cells suggests statins as potential adjuvant agents.

Purpose of the Study:

  • To compare the efficacy of simvastatin and atorvastatin in suppressing TSC2-null cell growth and signaling.
  • To evaluate the potential of statins as adjuvant therapy for TSC and LAM.

Main Methods:

  • In vitro cell culture of mouse TSC2-null and human LAM-derived cells.
  • Treatment with varying concentrations of simvastatin and atorvastatin.
  • Assessment of cell growth, morphology, apoptosis markers (caspase-3), and signaling pathways (Akt, Erk, mTORC1).
  • Combination therapy with rapamycin and statins.

Main Results:

  • Simvastatin, but not atorvastatin, demonstrated concentration-dependent inhibition of TSC2-null and LAM cell growth.
  • Simvastatin induced cell rounding and monolayer disruption, while atorvastatin had minimal effect.
  • Simvastatin synergized with rapamycin for growth inhibition, unlike atorvastatin.
  • Simvastatin inhibited Akt, Erk, and mTORC1 signaling and increased cleaved caspase-3, indicating apoptosis induction.

Conclusions:

  • Simvastatin exhibits significant growth-inhibitory and pro-apoptotic effects on TSC2-null cells, outperforming atorvastatin.
  • Simvastatin holds translational significance as a combinatorial therapeutic agent for inhibiting TSC2-null cell survival in TS and LAM.

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