Effects of molecularly targeted therapies on murine thymus: highly selective mTOR inhibitors induce reversible thymic involution

Background: Blocking mTOR (molecular target of rapamycin) by sirolimus has been shown to suppress cellular respiration. The bearing of this impaired cellular bioenergetics on the mode-of-action of mTOR inhibitors has yet to be illustrated. Methods: This study investigated in vitro effects of several molecularly-targeted therapies on O-2 consumption in thymic fragments from C57BL/6 mice. Results: Thymocyte respiration (mu M O-2 min(-1) mg(-1)) was reduced by sirolimus and everolimus (p <= 0.007). In contrast, the dual PI3K (phosphatidylinositol-3-kinase)/mTOR inhibitors BEZ235, GDC0980 and GSK2126458, the highly-selective PI3 K-p110-delta inhibitor idelalisib and the calcineurin inhibitor tacrolimus had no effects on thymocyte respiration. Sirolimus was administered intraperitoneally on Days 0-3 and the thymus was then examined on Days 4 and 14. Cortex involution associated with increased cytochrome c and caspase-3 positive cells (apoptosis) were observed on Day 4; these changes were resolved on Day 14 (10 days after sirolimus treatment). On Day 4, the residual thymus (mostly medulla) had normal cellular respiration, decreased caspase activity and increased glutathione. Intraperitoneal administration of sorafenib (a multikinase inhibitor) or idelalisib had no effects on thymus size. Conclusion: Thus, the highly-selective mTOR inhibitors imposed specific effects on the thymus, manifested by suppression of cellular respiration and induction of apoptosis.