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: 4.03). 11/2005; 56(1):47-60. DOI: 10.1016/j.critrevonc.2004.09.009
Source: PubMed


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.
    Full-text · Article · Jan 2015 · Asian Pacific journal of cancer prevention: APJCP
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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.
    Full-text · Article · Jul 2014 · BioMed Research International
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    • "It inhibits the proliferation of various tumor cell lines in vitro. The sensitivity of MCF-7 cells to RAPA have been reported when they are used intravenously, and the mTOR rapamycin derivatives have been shown previously in human breast cancer model (Law, 2005; Martin et al., 2013; Zagouri et al., 2012). Rouf et al. (2009) also reported that the antiproliferative effects of conventional and PEGylated rapamycin liposomes were significantly more than hydroethanol solution of rapamycin. "
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    ABSTRACT: Context: Liposomes are increasingly employed to deliver chemotherapeutic agents, antisense oligonucleotides, and genes to various therapeutic targets. Objective: The present investigation evaluates the ability of fusogenic pH-sensitive liposomes of rapamycin in increasing its antiproliferative effect on human breast adenocarcinoma (MCF-7) cell line. Materials and methods: Cholesterol (Chol) and dipalmitoylphosphatidylcholine (DPPC) (DPPC:Chol, 7:3) were used to prepare conventional rapamycin liposomes by a modified ethanol injection method. Dioleoylphosphatidylethanolamine (DOPE) was used to produce fusogenic and pH-sensitive properties in liposomes simultaneously (DPPC:Chol:DOPE, 7:3:4.2). The prepared liposomes were characterized by their size, zeta potential, encapsulation efficiency percent (EE%), and chemical stability during 6 months. The antiproliferative effects of both types of rapamycin liposomes (10, 25, and 50 nmol/L) with optimized formulations were assessed on MCF-7 cells, as cancerous cells, and human umbilical vein endothelial cells (HUVEC), as healthy cells, employing the diphenyltetrazolium bromide (MTT) assay for 72 h. Results and discussion: The particle size, zeta potential, and EE% of the liposomes were 165 ± 12.3 and 178 ± 15.4 nm, -39.6 ± 1.3, and -41.2 ± 2.1 mV as well as 76.9 ± 2.6 and 76.9 ± 2.6% in conventional and fusogenic pH-sensitive liposomes, respectively. Physicochemical stability results indicated that both liposome types were relatively stable at 4 °C than 25 °C. In vitro antiproliferative evaluation showed that fusogenic pH-sensitive liposomes had better antiproliferative effects on MCF-7 cells compared to the conventional liposomes. Conversely, fusogenic pH-sensitive liposomes had less cytotoxicity on HUVEC cell line.
    Full-text · Article · Jul 2014 · Pharmaceutical Biology
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