Molecular activity of sirolimus and its possible application in tuberous sclerosis treatment.
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.
Jozwiak
Jaroslaw
J
Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, Warsaw, Poland. jjozwiak@atdv.com.pl
Jozwiak
Sergiusz
S
Oldak
Monika
M
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D023903:Coronary Restenosis / Q000517:prevention & control; D004351:Drug Resistance; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000188:drug therapy*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
D000903:Antibiotics, Antineoplastic; D007166:Immunosuppressive Agents; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D022061:Tacrolimus Binding Protein 1A; D020123:Sirolimus