Molecular activity of sirolimus and its possible application in tuberous sclerosis treatment

Abstract

Sirolimus is one of the intensively investigated drugs with pluripotent activities. It binds to its intracellular receptor FKBP12 (FK506-binding protein 12), a member of the family of FK506-binding proteins, and inhibits the activity of mTOR, a serine/threonine kinase involved in numerous cell processes linked to cell growth control. The drug is currently registered for the prophylaxis of organ rejection and for use in coronary stents. However, unique characteristics of sirolimus make it a good candidate for anti-cancer therapy. Indeed, phase II and III clinical studies in humans with several types of neoplasms are already under way. The review describes molecular activity of sirolimus and its analogs, characteristic for specific applications, in view of very recent advances involving tuberous sclerosis complex (TSC)-mediated signaling pathways. Current studies with sirolimus performed in tuberous sclerosis animal models are presented. Possible application of sirolimus for treating tuberous sclerosis, disease caused by mutations of TSC proteins, is discussed.

Diabetes and renal tubular cell apoptosis

“…These two proteins function within the same mTOR signaling pathway. mTOR is a serine/threonine kinase involved in numerous cell processes linked to cell growth control, like cell cycle progression, transcription and translation control as well as nutrient uptake [19] . Loss of TSC-2 function either by TSC-2 or TSC-1 deficiency leads to constitutive activation of mTOR and downstream signaling pathways due to increased levels of GTP-bound Rheb [20][21][22][23] .…”

Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review

“…While TSC is named for the sclerotic tubers in the brain 1 , individuals often develop tumors in other organs, including the skin, eyes, kidneys, heart, and lungs 4,8,[17][18][19][20][21][22][23][24][25][26][27][28][29] . While these diverse, non-specific, clinical manifestations can cause some individuals with TSC to go unrecognized or misdiagnosed for years, many show evidence of the disorder in their first 12 months of life.…”

The release kinetics of drug eluting stents containing sirolimus as coated drug: Role of release media

“…It has potent antifungal, immunosuppressant, and antitumor properties [1,2]. It has possible applications in tuberous sclerosis treatment, as a potential therapeutic agent for the treatment of choroidal neovascularization and diabetic macular edema [3][4][5]. The ability of SRL to decrease keratinocyte proliferation may help patients with psoriasis [3].…”