Elsevier

Clinical Biochemistry

Volume 31, Issue 5, July 1998, Pages 335-340
Clinical Biochemistry

Invited
Rapamune® (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression

https://doi.org/10.1016/S0009-9120(98)00045-9Get rights and content

Abstract

Objective: Rapamune is a novel immunosuppressive agent in Phase III clinical trial in renal transplantation. Its unique mechanism of action has created great interest in its use as a biochemical probe of signal transduction pathways that has provided insight into its molecular mechanism of action. This article reviews the current state of our understanding of the mechanism of action of rapamune.

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

References (69)

  • M.C. Lorenz et al.

    TOR mutations confer rapamycin resistance by preventing interaction with FKBP12-rapamycin

    J Biol Chem

    (1995)
  • J. Chung et al.

    Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 Kd S6 protein kinases

    Cell

    (1992)
  • E.J. Brown et al.

    A signaling pathway to translational control

    Cell

    (1996)
  • R.P. de Groot et al.

    Positive regulation of the cAMP-Responsive Activator CREM by the p70 S6 Kinasean alternative route to mitogen-induced gene expression

    Cell

    (1994)
  • J.H. Lai et al.

    CD28 signalling causes a sustained down-regulation of 1 kappa B alpha which can be prevented by the immunosuppressant rapamycin

    J Biol Chem

    (1994)
  • C.J. Sherr

    G1 Phase progressioncycling on Cue

    Cell

    (1994)
  • M. Adachi et al.

    Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine-rich region within IL-2 receptor beta c chain

    Blood

    (1996)
  • T. Miyazaki et al.

    Three distinct IL-2 signaling pathways mediated by bcl-2, c-myc, and lck cooperate in hematopoietic cell proliferation

    Cell

    (1995)
  • C. Vezina et al.

    Rapamycin (AY-22,989), a new antifungal antibiotic. I. toxonomy of the producing streptomycete and isolation of the active principle

    J Antibiot

    (1975)
  • S.N. Sehgal et al.

    Rapamycin (AY-22,989) a new antifungal antibiotic. II. Fermentation, isolation and characterization

    J Antibiot

    (1975)
  • C.P. Eng et al.

    Activity of rapamycin (AY-22,989) against transplanted tumors

    J Antibiot

    (1984)
  • R.R. Martel et al.

    Inhibition of the immune response by rapamycin, a new antifungal antibiotic

    Can J Physiol Pharmacol

    (1977)
  • S.N. Sehgal et al.

    Rapamycina novel Immunosuppressive macrolide

    Medicinal Research Reviews

    (1994)
  • B.D. Kahan et al.

    Multi-center Phase II Trails of Sirolimus (SRL) in Renal Transplantationsix-month results

    Abstracts of XVI International Congress of the Transplantation Society

    (1996)
  • S.N. Sehgal et al.

    An in vitro immunological profile of rapamycin

    Annal NY Acadm Sci

    (1993)
  • M.M. Bertagnolli et al.

    Evidence that rapamycin inhibits interleukin-12-induced proliferation of activated T lymphocytes

    Transplantation

    (1994)
  • N. Terada et al.

    Rapamycin blocks cell cycle progression of activated T cells prior to events characteristic of the middle to late G1 phase of the cycle

    J Cell Physiol

    (1993)
  • F.J. Dumont et al.

    Distinct mechanisms of suppression of murine T-cell activation by the related macrolides FK-506 and rapamycin

    J Immunology

    (1990)
  • K.M. Aaguaard-Tillery et al.

    Inhibition of human B lymphocyte cell cycle progression and differentiation by rapamycin

    Cell Immunol

    (1994)
  • H.S. Kim et al.

    Effects of cyclosporine and rapamycin on immunoglobulin production by preactivated human B cells

    Clin Exp Immunol

    (1994)
  • M. Ferraresso et al.

    Rapamycin inhibits production of cytotoxic but not noncytotoxic antibodies and preferentially activates T helper 2 cells that mediate long-term survival of heart allografts in rats

    J Immunol

    (1994)
  • G. Schmidbauer et al.

    Abrogation by rapamycin of accelerated rejection in sensitized rats by inhibition of alloantibody responses and selective suppression of intragraft mononuclear and endothelial cell activation, cytokine production, and cell adhesion

    Transplantation

    (1994)
  • K.L. Molnar-Kimber et al.

    Evidence that the anti-tumor and immunosuppressive effects of rapamycin are mediated via similar mechanisms

    Cold Spring Harbor Symposium

    (1994)
  • W. Cao et al.

    Effect of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis

    Transplantation

    (1995)
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