Comprehensive lung injury pathology induced by mTOR inhibitors.
ABSTRACT Interstitial lung disease is a rare side effect of temsirolimus treatment in renal cancer patients. Pulmonary fibrosis is characterised by the accumulation of extracellular matrix collagen, fibroblast proliferation and migration, and loss of alveolar gas exchange units. Previous studies of pulmonary fibrosis have mainly focused on the fibroproliferative process in the lungs. However, the molecular mechanism by which sirolimus promotes lung fibrosis remains elusive. Here, we propose an overall cascade hypothesis of interstitial lung diseases that represents a common, partly underlying synergism among them as well as the lung pathogenesis side effects of mammalian target of rapamycin inhibitors.
- SourceAvailable from: Jose ANTONIO Rodriguez Portal[Show abstract] [Hide abstract]
ABSTRACT: Introduction: Inhibitors of the mammalian target of rapamycin (mTOR) are widely utilized in cancer and transplantation, with increased use of these agents expected in future years. Although generally well tolerated, drug-induced pneumonitis (DIP) has been described as a class effect associated with these compounds, especially at higher doses. This toxicity is observed in about a third of cancer patients, although only around 10% will have symptoms necessitating treatment. Clinical DIP can be effectively managed by early recognition and prompt intervention, including dose reduction and/or treatment cessation. However, little is known about the pathophysiology of this entity and its best management. Areas covered: This article will review current understanding of the mechanism of DIP, as well as the clinical impact and management of this toxicity in cancer patients treated with mTOR inhibitors. It also provides direction for future research. Expert opinion: Although guidelines on the management of mTOR inhibitor-associated DIP in cancer patients have been published, these do not always concur or cover all management aspects. Education of patients and healthcare professionals is a key component in managing mTOR inhibitor therapy; assessing the history of pulmonary conditions before the initiation of such a therapy is also essential. Updated diagnostic criteria for pneumonitis might improve our knowledge in the future.Expert Opinion on Drug Safety 02/2014; · 2.74 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Tracheal stenosis due to either benign or malignant disease is a situation that the pulmonary physicians and thoracic surgeons have to cope in their everyday clinical practice. In the case where tracheal stenosis is caused due to malignancy mini-interventional interventions with laser, apc, cryoprobe, balloon dilation or with combination of more than one equipment and technique can be used. On the other hand, in the case of a benign disease such as; tracheomalacia the clinician can immediately upon diagnosis proceed to the stent placement. In both situations however; it has been observed that the stents induce formation of granuloma tissue in both or one end of the stent. Therefore a frequent evaluation of the patient is necessary, taking also into account the nature of the primary disease. Evaluation methodologies identifying different types and extent of the trachea stenosis have been previously published. However; we still do not have an effective adjuvant therapy to prevent granuloma tissue formation or prolong already treated granuloma lesions. There have been proposed many mechanisms which induce the abnormal growth of the local tissue, such as; local pressure, local stress, inflammation and vascular endothelial growth factor overexpression. Immunomodulatory agents inhibiting the mTOR pathway are capable of inhibiting the inflammatory cascade locally. In the current mini-review we will try to present the current knowledge of drug eluting stents inhibiting the mTOR pathway and propose a future application of these stents as a local anti-proliferative treatment.Journal of molecular and genetic medicine: an international journal of biomedical research 08/2013; 7:65.
- [Show abstract] [Hide abstract]
ABSTRACT: mTOR, which can form mTOR Complex 1 (mTORC1) or mTOR Complex 2 (mTORC2) depending on its binding partners, is frequently deregulated in the pulmonary neoplastic conditions and interstitial lung diseases of the patients treated with rapalogs. In this study, we investigated the relationship between mTOR signaling and epithelial mesenchymal transition (EMT) by dissecting mTOR pathways. Components of mTOR signaling pathway were silenced by shRNA in a panel of non-small cell lung cancer cell lines and protein expression of epithelial and mesenchymal markers were evaluated by immunoblotting and immunocytochemistry. mRNA level of the E-cadherin repressor complexes were evaluated by qRT-PCR. IGF-1 treatment decreased expression of the E-cadherin and rapamycin increased its expression, suggesting hyperactivation of mTOR signaling relates to the loss of E-cadherin. Genetic ablation of rapamycin-insensitive companion of mTOR (Rictor), a component of mTORC2, did not influence E-cadherin expression, whereas genetic ablation of regulatory-associated protein of mTOR (Raptor), a component of mTORC1, led to a decrease in E-cadherin expression at the mRNA level. Increased phosphorylation of AKT at Ser473 and GSK-3beta at Ser9 were observed in the Raptor-silenced NSCLC cells. Of the E-cadherin repressor complexes tested, Snail, Zeb2, and Twist1 mRNAs were elevated in raptor-silenced A549 cells, and Zeb2 and Twist1 mRNAs were elevated in Raptor-silenced H2009 cells. These findings were recapitulated by treatment with the GSK-3beta inhibitor, LiCl. Raptor knockdown A549 cells showed increased expression of N-cadherin and vimentin with mesenchymal phenotypic changes. In conclusion, selective inhibition of mTORC1 leads to hyperactivation of the AKT/GSK-3beta pathway, inducing E-cadherin repressor complexes and EMT. These findings imply the existence of a feedback inhibition loop of mTORC1 onto mTORC2 that plays a role in the homeostasis of E-cadherin expression and EMT, requiring caution in the clinical use of rapalog and selective mTORC1 inhibitors.Respiratory research 02/2014; 15(1):26. · 3.38 Impact Factor