Rapa Nui (Easter Island) is situated in the southeastern Pacific Ocean, 163 km2, population 6.600 residents. Easter Island is famous for its 887 extant monumental statues, called moai, created by the early Rapa Nui people. Is a volcanic high island, dominated by hawaiite and basalt, the climate is classified as a tropical rainforest climate (Af) that borders on a humid subtropical climate.

A streptomycete was isolated from an Easter Island soil sample and found to inhibit Candida albicans, Microsporum gypseum and Trichophyton granulosum. The antibiotic-producing microorganism was characterized and identified as Streptomyces hygroscopicus. The antifungal principle was extracted with organic solvent from the mycelium, isolated in crystalline form and named rapamycin.

Stresptomyces hygroscopicus  (Actenomyces hygroscopicus synonimus) is a bacterial species in the genus Streptomyces. It was first described by Hans Laurits Jensen in 1931. He was born in Graese, he came under the influence of Professor Weis in the Department of Plant Physiology at the Agricultural University in Lyngby, Denmark. His growing interest in soil microbiology. Main terms to his work have been supplied by actinomycetes, coryneform bacteria, and both free-living and symbiotic nitrogen fixing bacteria.

Scientific classification

• Kingdom: Bacteria
• Phylum: Actinobacteria
• Class: Actinobacteria
• Order: Actinomycetales
• Family: Streptomycetaceae
• Genus: Streptomyces
• Species: hygroscopicus
• Subspecies: hygroscopicus angustmyceticus, S. hygroscopicus decoyicus, S. hygroscopicus glebosus, S.hygroscopicus hygroscopicus, S. hygroscopicus ossamyceticus

 

Sirolimus, also known as rapamycin, is a macrolide, is used in medicine to prevent organ transplant rejection and to treat lymphangioleiomyomatosis.

• Was isolated for the first time in 1972 by Suren Sehgal and colleagues from samples of Streptomyces hygroscopicus found on Easter Island. Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent inmunosuppresive and antiproliferative properties due to its ability to inhibit mTOR
• In the 1980s, found to have anticancer activity although the exact mechanism of action remained unknown until many years later.
• Rapamycin was also it was approved by the US Food and Drug Administration in September 1999 and is marketed under the trade name.

mTOR  inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR). One of the most promising antiaging mechanisms was discovered by accident. In 2001 biologist Valter Longo of the University of Souther Calirfornia went away for a weekend and forgot to feed yeast cells that he was using in an experiment. He was surprised to discover that starving them completely for a time made them live longer than usual. The reason, he learned, lay in a cascade of molecular actions usually referred to by the enzyme at its center, which is called mTOR.

This pathway was originally discovered years earlier thanks to a drug called rapamycin, which was found in soil bacteria. The drug, scientists learned, affected a mayor pathway regulation growth and division in the cell, like the circuit breaker in a tiny factory. Researchers named the path mTOR because it is a “mechanistic target of rapamycin”. When mTOR is activated, the “factory” (that is, the cell)

• producing new proteins,
• growing
• and ultimately dividing.

When mTOR is bloked, suchs as by rapamycin cell growth and replication slow down or stop. This is why rapamycin has been effective as an immunosuppressor to protect transplanted organs and more recently as a cancer therapy; these conditions involve runaway cell division.

Silorimus inhibits IL-2 and other cytokines receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells. The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tracrolimus. The sirolimus-FKBP12 complex inhibits the mTOR. Target Of Rapamycin,  pathway by directly binding to mTOR Complex 1 (mTORC1). mTOR  has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP.

Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump. It has elinimation half-life of 57-63 hours. The byosynthesis of the rapamycin core is accomplished by a type 1 polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three myltienzymes, Rap A, Rap B, Rap C, which contain a total of 14 modules. Then, the linear polyketide is modified by the NRPS, Rap P, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, pherapamycin.

When dosed appropriately, sirolimus can enhance the immune response to tumor targeting or otherwise promote tumor regression in clinical trials. Sirolimus seems to lower the cancer risk in some transplant patients. It was shown to inhibit the progression of dermal Kaposi´s sarcoma in patients with renal transplants. Other mTOR   inhibitors, such as temsirolimus or eversolimus, are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.

A combination therapy of doxorubicin and sirolimus has been shown to drive AKT-positive lymphomas into remission in mice. Sirolimus blocks AKT signaling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; eIF4E-expressing lymphomas are not sensitive to sirolimus.

mTOR  inhibitors are a class of drugs that inhibit the mechanistic target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that belongs to the family of phosphatidylinositol-3 kinase (PI3K) related kinases (PIKKs), Mtor  regulates cellular metabolism, growth, and proliferation by forming and signaling through two protein complexes:  mTOR1  and mTOR2.  The most established mTOR inhibitors are so-called rapalogs, which have shown tumor responses in clinical trials against various tumor types.

Many human tumors occur because of dysregulation of mTOR signaling, and can conferhigher susceptibility to inhibitors of mTOR. Deregulations of multiple elements of the mTOR pathway, like P13K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1, and eIF4E overexpression have been related to many types of cancers. Therefore, mTOR is an interesting therapeutic target for treating multiple cancers, both the mTOR inhibitors themselves or in combination with inhibitors of other pathways.

 

Relation links:

• Rapamycin

http://www.nature.com/nri/journal/v15/n10/box/nri3901_BX1.html

• mTOR

https://www.youtube.com/watch?v=hbWUkArdptA

 

Bibliography:

• Wikipedia
• Jensen, HL (1931) “Contributions to our knowledge of actinomycetales” Biodiversity Heritage Library.
• Vézina,C; Kudelski,A; Sehgal, S N (1975) “Rapamycin (AY-22,989), a new antigungal antibiotic. I. Taxonomuy of the producing streptomycete and isolation of the active principle”. The Journal of Antibiotics 28(10): 721-726.
• Valter Long, Fabricio,P; Pozza, F; Plethcer,S; Gendrom, C.M; Longo, VD (2001) “Regulation of Logevity and Stross Resistence by Sch9 in Yeast”.
• Chan S (2004) “Targeting the mmammalian target of rapamycin (mTOR): a new approach to treating cancer”. Br J Cancer 91(8)1420-4.
• Wendel HG, De Stanchina E, Fridman JS, et al (2004) “Survival signaling by Akt and Eif4e in oncogenesis and cancer therapy”. Nature 428 (6980):332-7.Science Daily.
• Novak, Kristine (2004) “Therapeutics: Means to an end” Nature Reviews Cancer 4:332.
• Mayo Clinic Researches (2009) “Formulate Treatment Combination Lethal To Pancreatic Cancer Cells” Science, 292 (5515): 288-290. Doi:10//26/science.
• Meric-Gernstam, F; Gonzalez-Angulo, A.M. (2009) “Targeting the Mtor Signaling Network for Cancer Therapy”. Journal of Clinical Oncology. 27 (13):2278-87.
• Populo, Helena; Lopez, José Manuel; Soarez, Paula (2012) “The mTOR Signaling Patway in Human Cancer”. International Journal of Molecular Sciences.13 (12): 1886-918.
• Bill Gifford (September  2016) “Will defeat aging”. Scientific American 58-60.