Related Experiment Video
Updated: Mar 17, 2026
Isolation and Transplantation of Different Aged Murine Thymic Grafts.
Published on: May 13, 2015
Effects of molecularly targeted therapies on murine thymus: highly selective mTOR inhibitors induce reversible thymic
Suleiman Al-Hammadi1, Saeeda Almarzooqi2, Alia Albawardi2
1Department of Pediatrics, UAE University, Al-Ain, P.O. Box 17666, Abu Dhabi, United Arab Emirates.
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 O2 consumption in thymic fragments from C57BL/6 mice.
Results:
Thymocyte respiration (µM O2 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-δ 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.
Insights
Highly selective molecular target of rapamycin (mTOR) inhibitors suppress cellular respiration and induce thymic apoptosis. These effects were transient, with thymic function and structure recovering after treatment cessation.
Area of Science:
- Immunology
- Cellular Biology
- Pharmacology
Background:
- Blocking the molecular target of rapamycin (mTOR) pathway with sirolimus is known to impair cellular respiration.
- The precise impact of this impaired cellular bioenergetics on the mechanism of action of mTOR inhibitors requires further elucidation.
Purpose of the Study:
- To investigate the in vitro effects of various molecularly-targeted therapies on oxygen consumption in mouse thymic tissue.
- To determine the impact of sirolimus on thymic structure, cellularity, and function over time.
Main Methods:
- In vitro assessment of O2 consumption in thymic fragments from C57BL/6 mice exposed to targeted therapies.
- In vivo administration of sirolimus, followed by histological and biochemical analysis of thymic tissue at specific time points.
- Evaluation of thymocyte respiration, apoptosis markers (cytochrome c, caspase-3), and glutathione levels.
Main Results:
- Sirolimus and everolimus significantly reduced thymocyte respiration.
- Dual PI3K/mTOR inhibitors (BEZ235, GDC0980, GSK2126458), a PI3K-p110-δ inhibitor (idelalisib), and tacrolimus did not affect thymocyte respiration.
- Sirolimus treatment induced thymic cortex involution and apoptosis, which resolved by Day 14, with residual thymic medulla showing normal respiration and reduced caspase activity.
Conclusions:
- Highly selective mTOR inhibitors exert specific effects on the thymus, including suppressed cellular respiration and induced apoptosis.
- These observed thymic alterations are transient and reversible upon cessation of mTOR inhibitor treatment.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:43Mouse Models of Cancer Study
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...