Immunopharmacology of Rapamycin

Abraham, Robert T.; Wiederrecht, Gregory

doi:10.1146/annurev.immunol.14.1.483

Cited by 596 publications

(469 citation statements)

References 120 publications

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“…Thus, mTOR and its downstream effectors have emerged as novel targets for cancer therapeutics (Huang and Houghton, 2003). Inhibition of mTOR by the immunosuppressant rapamycin results in reduced cell size and cell proliferation (Abraham and Wiederrecht, 1996). Rapamycin has limited water solubility and stability in solution, and a variety of analogs such as CCI-779and RAD001are currently being studied in the clinic for the treatment of a variety of tumor types (Hidalgo and Rowinsky, 2000;Huang and Houghton, 2003).…”

Section: Introductionmentioning

confidence: 99%

Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism

et al. 2006

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Rapamycin and several analogs, such as CCI-779 and RAD001, are currently undergoing clinical evaluation as anticancer agents. In this study, we show that inhibition of mammalian target of rapamycin (mTOR) signaling by rapamycin leads to an increase of Akt phosphorylation in Rh30 and RD human rhabdomyosarcoma cell lines and xenografts, and insulin-like growth factor (IGF)-II-treated C2C12 mouse myoblasts and IGF-IIoverexpressing Chinese hamster ovary cells. RNA interference-mediated knockdown of S6K1 also results in an increase of Akt phosphorylation. These data suggest that mTOR/S6K1 inhibition either by rapamycin or small interfering RNA (siRNA) triggers a negative feedback loop, resulting in the activation of Akt signaling. We next sought to investigate the mechanism of this negative feedback regulation from mTOR to Akt. Suppression of insulin receptor substrate (IRS)-1 and tuberous sclerosis complex-1 by siRNAs failed to abrogate rapamycininduced upregulation of Akt phosphorylation in both Rh30 and RD cells. However, pretreatment with h7C10 antibody directed against insulin-like growth factor-1 receptor (IGF-1R) led to a blockade of rapamycin-induced Akt activation. Combined mTOR and IGF-1R inhibition with rapamycin and h7C10 antibody, respectively, resulted in additive inhibition of cell growth and survival. These data suggest that rapamycin mediates Akt activation through an IGF-1R-dependent mechanism. Thus, combining an mTOR inhibitor and an IGF-1R antibody/inhibitor may be an appropriate strategy to enhance mTOR-targeted anticancer therapy.

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Section: Introductionmentioning

confidence: 99%

Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism

et al. 2006

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“…Glucocorticoids, cyclosporin A and FK506 inhibit cytokine synthesis by T cells by preventing the action of nuclear transcription factors [3,4]. In contrast, rapamycin (RAP) inhibits the ability of lymphocytes to proliferate in response to IL-2 by preventing the down-regulation of cell cycle inhibitors such as Kip-1 and thus blocks the transition from G1 into S phase [5]. Mycophenolic acid and methotrexate exert antiproliferative effects by interfering metabolically with DNA synthesis [6,7] and cyclophosphamide inhibits T cell proliferation by introducing DNA damage [8].…”

Section: Introductionmentioning

confidence: 99%

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Strauß

Osen

Debatin

2002

Clinical and Experimental Immunology

146

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SUMMARYImmunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graftversus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigenspecific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.

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“…Sirolimus inhibits the clonal expansion of activated lymphocytes by interacting with the mammalian target of rapamycin (mTOR), inhibiting progression from the G1 to the S phase of the cell cycle [20]. Since the proteins bound by sirolimus are not unique to T cells, it is possible that sirolimus exerts this antiproliferative effect on other cell types.…”

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confidence: 99%

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

et al. 2006

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Aims/hypothesis The Edmonton Protocol for islet transplantation has provided hope for type 1 diabetic patients. However, this protocol requires lifelong immunosuppression, specifically sirolimus, a cellular antiproliferate. The effect of sirolimus on human pancreatic ductal cells (HDCs) is not known. This may be important since HDCs are believed to be islet precursors. Since neonatal porcine islets (NPIs), which contain many ductal precursor cells, could be a potential clinical source of islets, we also tested the effects of sirolimus on this tissue. Methods HDCs (n=4), NPIs (n=9) and human islets (n=5) were cultured with and without sirolimus (20 ng/ml) for 6 days. Results HDCs and NPIs cultured with sirolimus showed a 50 and 28% decrease, respectively, in cell number relative to control (p<0.05). Control cultures expanded 1.65-and 2.44-fold relative to time 0. Decreases in cell number of sirolimus-treated HDCs were not due to apoptosis as measured by TUNEL staining. No functional effects on human islets or NPIs were observed following static incubation with high glucose. Treatment of syngeneically transplanted and naïve BALC/c mice with sirolimus resulted in altered OGTT profiles with prolonged elevation of hyperglycaemia and weight gain. There was no difference in graft and organ insulin content between treatment groups. Conclusions/interpretation Our results indicate that sirolimus decreases ductal cell numbers in culture and alters glucose-stimulated insulin secretion in vivo. The administration of sirolimus to islet transplant recipients is likely to impair graft function as a result of decreasing ductal neogenesis and induction of insulin resistance.

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Immunopharmacology of Rapamycin

Cited by 596 publications

References 120 publications

Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism

Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

The impact of the mTOR inhibitor sirolimus on the proliferation and function of pancreatic islets and ductal cells

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