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Rapamycin: An anti-cancer immunosuppressant?

Department of Pharmacology and Therapeutics, University of Florida, P.O. Box 100267, R5-136, ARB, 1600 SW Archer Road, Gainesville, FL 32610, USA.
Critical Reviews in Oncology/Hematology (Impact Factor: 4.05). 11/2005; 56(1):47-60. DOI: 10.1016/j.critrevonc.2004.09.009
Source: PubMed

ABSTRACT Rapamycin and its derivatives are promising therapeutic agents with both immunosuppressant and anti-tumor properties. These rapamycin actions are mediated through the specific inhibition of the mTOR protein kinase. mTOR serves as part of an evolutionarily conserved signaling pathway that controls the cell cycle in response to changing nutrient levels. The mTOR signaling network contains a number of tumor suppressor genes including PTEN, LKB1, TSC1, and TSC2, and a number of proto-oncogenes including PI3K, Akt, and eIF4E, and mTOR signaling is constitutively activated in many tumor types. These observations point to mTOR as an ideal target for anti-cancer agents and suggest that rapamycin is such an agent. In fact, early preclinical and clinical studies indicate that rapamycin derivatives have efficacy as anti-tumor agents both alone, and when combined with other modes of therapy. Rapamycin appears to inhibit tumor growth by halting tumor cell proliferation, inducing tumor cell apoptosis, and suppressing tumor angiogenesis. Rapamycin immunosuppressant actions result from the inhibition of T and B cell proliferation through the same mechanisms that rapamycin blocks cancer cell proliferation. Therefore, one might think that rapamycin-induced immunosuppression would be detrimental to the use of rapamycin as an anti-cancer agent. To the contrary, rapamycin decreases the frequency of tumor formation that occurs in organ transplant experiments when combined with the widely used immunosuppressant cyclosporine compared with the tumor incidence observed when cyclosporine is used alone. The available evidence indicates that with respect to tumor growth, rapamycin anti-cancer activities are dominant over rapamycin immunosuppressant effects.

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    • "Moreover, as in posttransplant immunosuppression protocols, rapamycin is presently used as one of the constituents in a multidrug treatment to prevent graft rejection (Rizzieri et al., 2008). Law (2005) proposed that rapamycin has a potent antitumor action against certain tumor cell types. Current studies have shown that rapamycin demonstrated very effective anti-tumor effects in a large variety of cancers such as lung cancer (Boffa et al., 2004), gastrointestinal cancer (Wiedmann and Caca, 2005), renal cell carcinoma (Rathmell, Wright and Rini, 2005) and others. "
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    ABSTRACT: Background: Rapamycin is an effective anti-angiogenic drug. However, the mode of its action remains unclear. Therefore, in this study, we aimed to elucidate the antitumor mechanism of rapamycin, hypothetically via apoptotic promotion, using MCF-7 breast cancer cells. Materials and Methods: MCF-7 cells were plated at a density of 15105 cells/well in 6-well plates. After 24h, cells were treated with a series of concentrations of rapamycin while only adding DMEM medium with PEG for the control regiment and grown at 37oC, 5% CO2 and 95% air for 72h. Trypan blue was used to determine the cell viability and proliferation. Untreated and rapamycin-treated MCF-7 cells were also examined for morphological changes with an inverted-phase contrast microscope. Alteration in cell morphology was ascertained, along with a stage in the cell cycle and proliferation. In addition, cytotoxicity testing was performed using normal mouse breast mammary pads. Results: Our results clearly showed that rapamycin exhibited inhibitory activity on MCF-7 cell lines. The IC50 value of rapamycin on the MCF-7 cells was determined as 0.4μg/ml (p<0.05). Direct observation by inverted microscopy demonstrated that the MCF-7 cells treated with rapamycin showed characteristic features of apoptosis including cell shrinkage, vascularization and autophagy. Cells underwent early apoptosis up to 24% after 72h. Analysis of the cell cycle showed an increase in the G0G1 phase cell population and a corresponding decrease in the S and G2M phase populations, from 81.5% to 91.3% and 17.3% to 7.9%, respectively. Conclusions: This study demonstrated that rapamycin may potentially act as an anti-cancer agent via the inhibition of growth with some morphological changes of the MCF-7 cancer cells, arrest cell cycle progression at G0/G1 phase and induction of apoptosis in late stage of apoptosis. Further studies are needed to further characterize the mode of action of rapamycin as an anti-cancer agent.
    Asian Pacific journal of cancer prevention: APJCP 01/2015; 15(24):10659-10663. DOI:10.7314/APJCP.2014.15.24.10659 · 2.51 Impact Factor
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    • "An interesting case to discuss in this section of a commercially successful, but controversial, example of a compound produced from an Actinobacteria isolated from another well-known Chilean environment is that of rapamycin (also known as sirolimus), isolated by Brazilian researchers from a strain of Streptomyces hygroscopicus endemic of Eastern Island, or Rapa Nui [40]. Rapamycin was originally used as an antibiotic, but later on it was discovered to show potent immunosuppressive and antiproliferative properties [41] [42] and even claimed to extend life span [43]. Sadly, nothing of this development benefited the Chilean economy, as agreements like the United Nations Rio Declaration on Environment and Development were yet to be established. "
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    ABSTRACT: The Atacama Desert in Chile is well known for being the driest and oldest desert on Earth. For these same reasons, it is also considered a good analog model of the planet Mars. Only a few decades ago, it was thought that this was a sterile place, but in the past years fascinating adaptations have been reported in the members of the three domains of life: low water availability, high UV radiation, high salinity, and other environmental stresses. However, the biotechnological applications derived from the basic understanding and characterization of these species, with the notable exception of copper bioleaching, are still in its infancy, thus offering an immense potential for future development.
    BioMed Research International 07/2014; 2014(Article ID 909312):1-7. DOI:10.1155/2014/909312 · 2.71 Impact Factor
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    • "Immunosuppression is another concern. The immunosuppressive effect of rapamycin derives from the inhibition of T-and B-cell proliferation, through mechanisms similar to those that block cancer cell proliferation (Law, 2005). In a clinical context, a more potent suppression of mTOR signalling by the ATP-competitive TKIs also raises concerns regarding the consequent higher level of immunosuppression. "
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    ABSTRACT: The mammalian target of rapamycin (mTOR) plays an important role in the regulation of protein translation, cell growth and metabolism. The mTOR protein forms two distinct multi-subunit complexes: mTORC1 and mTORC2. The mTORC1 complex is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals; and essential signaling pathways, such as PI3K and MAPK, in order to control cell growth, proliferation and survival. mTORC1 also activates S6K1 and 4EBP1, which are involved in mRNA translation. The mTORC2 complex is resistant to rapamycin inhibitory activity and is generally insensitive to nutrient- and energy- dependent signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of the mTOR signaling pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) is common in cancer, and alterations in components of the mTOR pathway have a major role in tumour progression. Therefore, mTOR is an appealing therapeutic target in many tumours. Here we summarize the upstream regulators and downstream effectors of the mTORC1 and mTORC2 pathways, the role of mTOR in cancer, and the potential therapeutic values and issues related to the novel agents targeting the mTOR-signaling pathway.
    British Journal of Pharmacology 04/2014; 171(16). DOI:10.1111/bph.12749 · 4.99 Impact Factor
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