Choose Your Country or Region

RAPAMYCIN-A BROAD SPECTRUM DRUG

by Selleckchem | Jul 22 2012

RAPAMYCIN- INHIBITS mTOR
In all around the world the treatment of cancer is a hot topic of research and as a result of extensive work in this field many of the novel therapeutic agents are undergoing clinical trials in order to sort out drugs with least side effects. In research and development efficacy is not the only thing which is under considerations but also the specificity. In cancer treatment the drugs are mostly designed as regulatory or inhibitory agents for cell cycle proteins. Rapamycin 53123-88-9 is one such inhibitor which targets mTOR protein kinase enzyme. Checking the functions of mTOR proteins cellular growth and proliferation can be controlled by affecting transcription and translation of specific genes [1]. Rapamycin mTOR inhibitor is being used since decades for the treatment of cancer. One of the effective results has been reported for cancer cure [2] and some other disorders are also noted to be treated by this drug. Four decades back this inhibitor was discovered as an anti-fungal drug [3]. Rapamycin is also used for transplantation cases where it acts as an immunosuppressing compound [4] as it also inhibits cell cycle process [5]. One of the major usages of this compound is its application for HIV treatment [6].

RAPAMYCIN PROPERTIES:
Rapamycin molecular weight is 914.2gm and its structure depicts macrocyclic triene. Polyketide synthase or PKS type I and non ribosomal peptide synthetase are synthesized by Rapamycin [7]. Rapamycin suppliers are the source if someone wants to purchase Rapamycin that is available in powder form and the brand name of this compound is Rapamycin Sirolimus. In degassed and HPLC grade methanol the Rapamycin solubility can be obtained up to 10mg/ml and this is stable for a week if stored at 4oC. Rapamycin is also soluble in multiple chemical compounds including ethanol, DMSO, chloroform, ether and acetone and N,N-dimehtylformamide. Rapamycin price is about $40 for a vial of 50mg and 1 nM is the Rapamycin IC50.

IMMUNOSUPPRESSION BY RAPAMYCIN:
Rapamycin shows a great property of immunosuppression. A gene PHLPP expression is regulated by Rapamycin [8] and it also activates Akt and elF4E pathways [9]. It promotes apoptosis in cancerous cells by inactivating mTORC1 and 4E-BP1 phosphorylation is also suppressed [10]. Rapamycin is used as a single immunosppuressant in kidney transplantation cases and showed significant results however in many cases it is also used in combination [11] and during renal allograft Rapamycin has been studied effectively when used in combination with Tacrolimus [12]. This is also used against induced infections during transplantation procedure and example includes renal transplantation [13] and kaposi’s sarcoma development [14]. Rapamycin also showed good results when used against vascular diseases allografts [15] and in Graf Versus Host Diseases or GVHD it reported as effective drug [16]. In contrast to cyclosporine Rapamycin shows better results as an immunosuppressant [17].

RAPAMYCIN AND CANCER TREATMENT:
Cancerous cells are proliferated by the help of a process that is known as angiogenesis, this process can be checked by inhibiting some of the important components involved in this process. Rapamycin reported to inhibit vascular endothelial growth factor or VEGF pathway leading to inhibition of angiogenesis [18]. In renal cancer treatment Rapamycin functions to inhibit the proliferation of cancer cells [19] and in case of breast cancer treatment this agent has also been used in combination with other drugs [20]. NSCLC and MM (multiple myeloma) are also affected by the administration of Rapamycin [21-22]. And during Rapamycin clinical trial phase I it gained success in glioblastoma multiform or GBM [23].
Rapamycin is a broad spectrum drug that is also used for many other purposes such as for stents [24] and also during laser therapy [25]. This has also been used for the angiofibromas which are considered to be caused by Tuberculosis, in this case it is used topically [26] as safety profile has been examined [27]. Tumor caused by TB are also treated by single Rapamycin or in combination with other agents [28], facial angiofibroma are also treated with it [29]. A refractory disease known as Oral Erosive Lichen Planus (OELP) was also efficiently treated with Rapamycin [30].

REFERENCES:
1. Rao, R.D.e.a., Mammalian Target of Rapamycin (mTOR) Inhibitors as Anti-Cancer Agents. Current Cancer Drug Targets, 2004.
2. Hidalgo, M.a.R., E.K., The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene, 2000.
3. 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.
4. Law, B.K., Rapamycin: an anti-cancer immunosuppressant? Crit Rev Oncol Hematol., 2005.
5. 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.
6. Donia, M.e.a., Potential use of rapamycin in HIV infection. Br J Clin Pharmacol., 2010.
7. Nicolaou, K.C.e.a., Total synthesis of rapamycin. J. Am. Chem. Soc., 1993.
8. Liu, J.e.a., mTOR-Dependent Regulation of PHLPP Expression Controls the Rapamycin Sensitivity in Cancer Cells. The Journal of Biological Chemistry, 2011.
9. Sun, S.Y.e.a., Activation of Akt and eIF4E Survival Pathways by Rapamycin-Mediated Mammalian Target of Rapamycin Inhibition. Cancer Research, 2005.
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. Stallone, G.e.a., Sirolimus for Kaposi's Sarcoma in Renal-Transplant Recipients. N Engl J Med., 2005.
14. Campistol, J.e.a., Conversion to sirolimus: a successful treatment for posttransplantation Kaposi's sarcoma 1 2. Transplantation, 2004.
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. Luan, F.L.e.a., Rapamycin is an effective inhibitor of human renal cancer metastasis. Kidney International, 2003.
20. Liu, T.e.a., Combinatorial effects of lapatinib and rapamycin in triple-negative breast cancer cells. Mol Cancer Ther., 2011.
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. 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.
26. 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.
27. 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.
28. Rauktys, A.e.a., Topical rapamycin inhibits tuberous sclerosis tumor growth in a nude mouse model. BMC Dermatology, 2008.
29. 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.
30. Soria, A.e.a., Treatment of Refractory Oral Erosive Lichen Planus with Topical Rapamycin: 7 Cases. Dermatology, 2009.

Cat.No.	Product Name	Information
S5003	Tacrolimus (FK506)	Tacrolimus (FK506) is a 23-membered macrolide lactone, it reduces peptidyl-prolyl isomerase activity in T cells by binding to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. Tacrolimus also inhibits the phosphatase activity of calcineurin. Tacrolimus induces vascular endothelial autophagy.
S1039	Rapamycin	Rapamycin is a specific mTOR inhibitor with IC50 of ~0.1 nM in HEK293 cells.Rapamycin binds to FKBP12 and specifically acts as an allosteric inhibitor of mTORC1. Rapamycin is an autophagy activator and an immunosuppressant.