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RAPAMYCIN

by Selleckchem | Apr 01 2012

RAPAMYCIN AND mTOR INHIBITORS:
In the era of cancer therapy, more and more efficient and safer drugs are needed than the traditional chemotherapeutic agents. New drugs are needed to be designed in such a way that they spare normal cells but targeting the abnormal cancerous cells. Among many abnormal pathways one is mTOR pathway which is mostly present in cancer cells, thereby use of mTOR inhibitors is one the potential approach for cancer treatment [1]. One of such drug is Rapamycin mTOR inhibitor that is being used for decades as a therapeutic. Almost 40 years back Rapamycin was discovered as an antifungal antibiotic [2] and later on it started to be used as a strong immunosuppressant for transplant studies [3] and in these studies it was considered to be an inhibitor of cell cycle [4]. More recently it was used for the treatment of HIV as immunosuppressant because of its popularity [5] but the most applied uses are in cancer treatment [6].
In the synthesis of Rapamycin NRPS (nonribosomal peptide synthetase) and type-1 PKS (polyketide synthase) enzymes are involved [7], structure of Rapamycin represents a macrocyclic-triene. The mmolecular weight of Rapamycin is 914.2 and it is traded under the name Rapamycin Sirolimus and it is available to Rapamycin suppliers in lyophilized form. This is soluble in many of the solvents such as ethanol, methanol, DMSO, N,N-dimethylformamide (DMF), chloroform, ether and acetone etc. Rapamycin storage for seven days can be achieved by dissolving 10 mg/ml in methanol solution of HPLC grade and storing it in refrigerator or at 4°C. IC50 of Rapamycin is 1nM and one can purchase Rapamycin for laboratory or therapeutic uses. The Rapamycin price for 50mg is $40.

RAPAMYCIN ANDIMMUNOSUPPRESSION:
Rapamycin is known as best immunosuppressant and this is its main property. Rapamycin activates the eIF4E pathwaysand Akt pathway [8] it also regulates PHLPP gene expression [9]. It functions by inhibiting the phosphorylation of 4E-BP1 and breaking mTORC1 to stimulate apoptosis of cancer cells [10]. This agent is also used as a single drug in the kidney transplantation cases [11] and in some cases along with Tacrolimus in renal allograft patients [14]. In allograft vascular disease Rapamycin also shown remarkable results [15] and it has also been used for GVHD (Graft Versus Host Diseases) studies and worked as main immunosuppressant [16]. It is also compared with Cyclosporine and is mostly known as the superior immunosuppressant against other such agents [17].

RAPAMYCIN IN CANCERS AND BEYOND:
Rapamycin is also used against the formation of vessels in other words this is an anti-angiogenic agent because it also targets on VEGF (Vascular Endothelial Growth Factor) [18]. In case of difficult breast cancer treatment it also used in combination with other anti cancer agents [19] due to its ability to inhibit the malignant cancer cells of kidney [20]. Like many other inhibitors Rapamycin is also used against NSCLC that is non small cell lung cancer [21] and also noted as potent for MM (multiple myeloma) cancer cells [22]. In clinical trials phase I Rapamycin is also one of the remarkable drugs that is active against Glioblastomamultiforme (GBM) [23].
In addition to the cancer treatment Rapamycin is also used as stents and gained fair success [24]. Rapamycin administration in the form of tropical is one of the latest way to treat the facial angiofibromas which are mostly linked with Tuberculosis [25], for this purpose safety and efficacy also has been tested thoroughly for this work [26]. Various research groups have reported about the Rapamycin ability to treat TB tumor growths [27] along with facial angiofibromas in TB either in combination or alone [28]. A painful disease known as Oral Erosive Lichen Planus or OELP is also treated by Rapamycin [29] and it is also used in laser treatment [30].

REFERENCES:
1. Rao, R.D.e.a., Mammalian Target of Rapamycin (mTOR) Inhibitors as Anti-Cancer Agents. Current Cancer Drug Targets, 2004.
2. Vézina, C.e.a., Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot, 1975.
3. Law, B.K., Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol., 2005.
4. Sehgal, S.N.e.a., Rapamune® (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clinical Biochemistry, 1998.
5. Donia, M.e.a., Potential use of rapamycin in HIV infection. Br J Clin Pharmacol., 2010.
6. Hidalgo, M.a.R., E.K., The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene, 2000.
7. Nicolaou, K.C.e.a., Total synthesis of rapamycin. J. Am. Chem. Soc., 1993.
8. Sun, S.Y.e.a., Activation of Akt and eIF4E Survival Pathways by Rapamycin-Mediated Mammalian Target of Rapamycin Inhibition. Cancer Research, 2005.
9. Liu, J.e.a., mTOR-Dependent Regulation of PHLPP Expression Controls the Rapamycin Sensitivity in Cancer Cells. The Journal of Biological Chemistry, 2011.
10. Yellen, P.e.a., High-dose rapamycin induces apoptosis in human cancer cells by dissociating mTOR complex1 and suppressing phosphorylation of 4E-BP1. Cell Cycle, 2011.
11. Webster, A.e.a., Target of Rapamycin Inhibitors (Sirolimus and Everolimus) for Primary Immunosuppression of Kidney Transplant Recipients: A Systematic Review and Meta-Analysis of Randomized Trials. Transplantation, 2006.
12. Qi, S.e.a., Effect of Tacrolimus (Fk506) and Sirolimus (Rapamycin) Mono- and Combination Therapy in Prolongation of Renal Allograft Survival in the Monkey. Transplantation, 2000.
13. Campistol, J.e.a., Conversion to sirolimus: a successful treatment for posttransplantation Kaposi's sarcoma 1 2. Transplantation, 2004.
14. Stallone, G.e.a., Sirolimus for Kaposi's Sarcoma in Renal-Transplant Recipients. N Engl J Med., 2005.
15. Ikonen, T.e.a., Sirolimus (Rapamycin) Halts and Reverses Progression of Allograft Vascular Disease in Non-Human Primates. Transplantation, 2000.
16. Benito, A.e.a., Sirolimus (Rapamycin) for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease. Transplantation, 2001.
17. Groth, C.e.a., Transplantation. SIROLIMUS (RAPAMYCIN)-BASED THERAPY IN HUMAN RENAL TRANSPLANTATION: Similar Efficacy and Different Toxicity Compared with Cyclosporine., 1999.
18. Guba, M.e.a., Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nature Medicine, 2002.
19. Liu, T.e.a., Combinatorial effects of lapatinib and rapamycin in triple-negative breast cancer cells. Mol Cancer Ther., 2011.
20. Luan, F.L.e.a., Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney International, 2003.
21. Seufferlein, T.a.R., E., Rapamycin Inhibits Constitutive p70s6k Phosphorylation, Cell Proliferation, and Colony Formation in Small Cell Lung Cancer Cells. Cancer Research, 1996.
22. Raje, N.e.a., Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood, 2004.
23. Cloughesy, T.F.e.a., Antitumor Activity of Rapamycin in a Phase I Trial for Patients with Recurrent PTEN-Deficient Glioblastoma. PLoS Medicine, 2008.
24. Lemos, P.A.e.a., Unrestricted Utilization of Sirolimus-Eluting Stents Compared With Conventional Bare Stent Implantation in the “Real World”. Circulation, 2004.
25. Mutizwa, M.M.e.a., Treatment of facial angiofibromas with topical application of oral rapamycin solution (1 mg mL−1) in two patients with tuberous sclerosis. British Journal of Dermatology, 2011.
26. Salido, R.e.a., Sustained clinical effectiveness and favorable safety profile of topical sirolimus for tuberous sclerosis - associated facial angiofibroma. Journal of the European Academy of Dermatology and Venereology, 2011.
27. Rauktys, A.e.a., Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model. BMC Dermatology, 2008.
28. Kaneda, M.W.e.a., A topical combination of rapamycin and tacrolimus for the treatment of angiofibroma due to tuberous sclerosis complex (TSC): a pilot study of nine Japanese patients with TSC of different disease severity. British Journal of Dermatology, 2011.
29. Soria, A.e.a., Treatment of Refractory Oral Erosive Lichen Planus with Topical Rapamycin: 7 Cases. Dermatology, 2009.
30. Jia, W.e.a., Long-term blood vessel removal with combined laser and topical rapamycin antiangiogenic therapy: Implications for effective port wine stain treatment. Lasers in Surgery and Medicine, 2010.