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RAPAMYCIN-A MULTI PURPOSE DRUG

by Selleckchem | Apr 27 2012

RAPAMYCIN- AN mTOR INHIBITOR
Cancer and its treatment has been an active area of research and a lot of new drugs are in clinical trials in order to find an efficacious drug against cancer having least side effects. In addition to efficacy, specificity is also an issue that is being considered in research. Most of the drugs being researched are cell cycle regulatory protein inhibitors. Rapamycin is also one of them which are an mTOR protein kinase inhibitor. Inhibiting mTOR proteins may modify cell growth, proliferation, migration and activities related to transcription and translation thus preventing cancer cell proliferation [1]. Rapamycin mTOR inhibitor had been used since decades for treatment against cancer. Although it’s most efficient use has been seen for cancer [2], it is used for the treatment of other diseases too. It has been four decades since this inhibitor has been discovered as anti-fungal agent [3] . Rapamycin has also been used as an immunosuppressing agent in case of transplantation [4] by blocking the process of cell cycle [5]. As Rapamycin has been seen to act as an immunosuppressant, it has also been employed for the treatment of HIV [6].

PROPERTIES OF RAPAMYCIN
Rapamycin structure contains a macrocyclic triene in it with a molecular weight of 914.2 gm. Rapamycin synthesis involves PKS (Polyketide synthase) type I and NRPS (non-ribosomal peptide synthetase) [7] Rapamycin Sirolimus is the brand name of the drug under which it is supplied in lyophilized form by Rapamycin suppliers. Rapamycin solubility upto 10mg/ml in HPLC grade degassed methanol can make it stable for a week if kept at 4oC. The drug is also soluble in many other organic compounds e.g., ethanol, chloroform, DMSO, acetone, ether, (DMF) N,N-dimethylformamide etc. Rapamycin IC50 is about 1 nM and researchers or physicians can buy Rapamycin 50 mg in about $40.

RAPAMYCI AS AN IMMUNOSUPPRESSION
Rapamycin shows a remarkable immunosuppressing activity. It is involved in the regulation of expression of the gene PHLPP [8] as well as activating elF4E and Akt pathways [9]. It suppresses the 4E-BP1 phosphorylation and dissociates the mTORC1 to cause apoptosis in cancer cells [10]. In case of transplantation procedure the drug has shown good results whether used singly or in combination for the purpose of immunosuppressing e.g., in kidney transplant it was used as single agent [11] and in renal allograft the drug has been studied successfully as combinatorial therapy with Tacrolimus [12].Rapamycin has also been used in transplantation procedure in order to fight the induced infections e.g., in renal transplantation [13], the development of kaposi’s sarcoma [14]. In case of vascular diseases in allografts [15] and GVHD (Graft Versus Host Diseases) the drug showed remarkable results [16]. When compared to Cyclosporine considering immunosuppresssion it has always been superior [17].

RAPAMYCIN IN CANCER
Angiogenesis, one of the properties of the cancerous cells, can be inhibited if some of the factors involving in the process are inhibited. This drug has been seen to inhibit VEGF (Vascular endothelial growth factor) pathway and thus inhibits angiogenesis [18]. Rapamycin has been a success in metastasizing cells in renal cancer [19] therefore was given in a combinatorial therapy in breast cancer having comparatively difficult treatment i.e., triple negative [20]. Rapamycin also showed efficacy in case of NSCLC (Non-small cell lung cancer) and [21] MM (multiple myeloma cells) [22]. Rapamycin gained successful results in GBM (Glioblastoma multifome) in clinical trial phase I [23].
Rapamycin is a multipurpose drug and has many other too. It has also been successfully used as stents [24] and in laser therapy [25]. Rapamycin has been used topically for the treatment of angiofibromas on face considered to be due to Tuberculosis [26] after getting its safety tests studied extensively [27]. In case of TB it has been studied to work singly or in the form of combination with other drugs for tumor growth [28] and for facial angiofibroma [29]. Study of Rapamycin in case of OELP (Oral Erosive Lichen Planus) that is a refractory disease also showed successful results [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.