InvitedRapamune® (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression
Introduction
Rapamune® (RAPA) is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, a streptomycete that was isolated from a soil sample collected from Easter Island (Rapa Nui) 1, 2. Although RAPA is a potent antifungal agent, numerous studies revealed equally potent antitumor 3, 4 and immunosuppressive activities; the latter initially demonstrated through its ability to prevent adjuvant-induced arthritis and experimental allergic encephalomyelitis in rodent models (5). RAPA’s potent immunosuppressive activity in virtually all animal models of organ transplantation (6) supported clinical trials (7) that are now nearing completion of Phase III. Interest in RAPA as an immunosuppressive therapy in organ transplantation results, in part, from its unique mechanism of action, its side effect profile that is different from existing immunosuppressive therapies in that it has no end organ toxicity, and its ability to synergize with other immunosuppressants without overlapping toxicity. Moreover, RAPA’s widespread use as biochemical probe of cellular signal transduction pathways has provided insight into the molecular mechanism of its action as well as understanding of the physiology of cell cycle progression.
Section snippets
Cellular effects of RAPA
RAPA blocks T lymphocyte proliferation induced by stimuli employing either Ca2+-dependent or Ca2+-independent pathways (8). RAPA’s effects are not limited to IL-2- or IL-4 mediated growth of T cells, as it has been found to inhibit IL-12 (9), IL-7, and IL-15 driven proliferation of activated T cells (T. Strom, personal communication). RAPA blocks cell cycle progression in mid-to-late G1 phase (10), as demonstrated by the finding that RAPA blocks lymphocyte proliferation even when added up to 12
Interaction with immunophilins
Although the mechanism of action of RAPA is unique, it belongs to a class of macrocyclic immunosuppressive agents whose cellular activity depends upon their binding to specific cytosolic binding proteins, called immunophilins. Cyclosporin A (CsA) and FK506 (tacrolimus) are the other members of this class of compounds. CsA forms a complex with cyclophilin, whereas RAPA and FK506, due to the structural similarity in their binding domains, share a family of immunophilins called FK506 binding
Conclusion
RAPA’s key action is to inhibit the progression of the cell cycle from G1 to S phase by blocking and inhibiting several signal transduction pathways. The evidence to date shows that all these pathways are down stream of the growth factor-induced activation of mTOR. It is highly likely that phosphorylation mediated activation of one or more phosphatases or kinases by mTOR is the first step in the cascade of events that are affected by RAPA. The unique mechanism of action of RAPA is key to its
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