Mechanism of actions and Adverse effects of Rapamycin

Rapamycin, also known as Sirolimus, is an immunosuppressant drug used to prevent rejection in organ transplantation; it is especially useful in kidney transplants. It prevents activation of T cells and B cells by inhibiting their response to interleukin-2. Rapamycin is also used as a coronary stent coating.

Rapamycin was originally developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties. It has since been shown to prolong the life of mice and might also be useful in the treatment of certain cancers.

Rapamycin uses widely in Medical community, but I’m sure that not many people know the Mechanism of actions of Rapamycin. Now let us tall about this.

Unlike the similarly named tacrolimus, rapamycin is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Rapamycin inhibits the response to interleukin-2 (IL-2), and thereby blocks activation of T and B cells. In contrast, tacrolimus inhibits the secretion of IL-2.

The mode of action of rapamycin is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the rapamycin-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR, rapamycin being an older name for rapamycin) pathway by directly binding the mTOR Complex1 (mTORC1).

mTOR has also been called FRAP (FKBP-rapamycin associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that rapamycin must bind FKBP12 first, and only the FKBP12-rapamycin complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of rapamycin-resistant mutants of Saccharomyces cerevisiae that identified FKBP12, Tor1, and Tor2 as the targets of rapamycin and provided robust support that the FKBP12-rapamycin complex binds to and inhibits Tor1 and Tor2.

Although Rapamycin play a very important role in Medical community, we should know there are still some adverse effects in Rapamycin. Here we can tall about it in three aspects:

1.Lung toxicity

Lung toxicity is a serious complication associated with rapamycin therapy, especially in the case of lung transplants. The mechanism of the interstitial pneumonitis caused by rapamycin and other macrolide MTOR inhibitors is unclear, and may have nothing to do with the MTOR pathway. The interstitial pneumonitis is not dose dependent, but is more common in patients with underlying lung disease.

2.Cancer risk

As with all immunosuppressive medications, in theory rapamycin may decrease the body's inherent anticancer activity and allow some cancers which would have been naturally destroyed to proliferate. Patients on immunosuppressive medications have a 10- to 100-fold increased risk of cancer compared to the general population.[citation needed] Historically, approximately 10% of solid organ recipients treated with calcineurin inhibitors develop skin tumours and lymphoma after 70 months. However, there is contradictory data regarding calcineurin inhibitors versus rapamycin via UV-induced carcinogenesis-associated processes such as DNA repair, p53 and MMP expression as a result from different biochemical mechanisms. People who currently have or have already been treated for cancer have a higher rate of tumor progression and recurrence than patients with an intact immune system[citation needed]. These general considerations counsel caution when exploring the potential of rapamycin to combat cancer. However, a plethora of studies indicate that when dosed appropriately, rapamycin can enhance the immune response to tumor targeting or otherwise promote tumor regression in clinical trials. Rapamycin seems to lower the cancer risk in some transplant patients.

3. Diabetes-like symptoms

Rapamycin inhibits a protein kinase complex known as mTORC1, and this appears to provide most of the beneficial effects of the drug (including life-lengthening in animal studies). Rapamycin also acts on a related complex known as mTORC2. Disruption of mTORC2 produces the diabetes-like symptoms of decreased glucose tolerance and insensitivity to insulin also associated with rapamycin.

Now, I hope you have make  a clear understanding about Rapamycin after reading this passage.

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