Natural Rapalogs that Inhibit the mTOR Pathway

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In 1975 scientists discovered the mycelial bacterium Streptomyces hygroscopicus on Rapa Nui, the native name of Easter Island.  From this bacterium they created the molecule named Rapamycin, a pharmaceutical drug which requires a doctor’s prescription.  Also known as Sirolimus, it is an immunosuppressant drug used in orthodox medicine to prevent rejection following organ transplantation.

In addition to its use as an immunosuppressant drug, Rapamycin inhibits the mTOR signalling pathway and studies show it can significantly extend lifespan in mammals, even when taken in later life, with increases in life expectancy for males and females of between 9% and 14% respectively.


 

mTOR Pathway  

“mTOR” or the mechanistic target of rapamycin (mTOR), (formerly mammalian target of rapamycin before it was recognized to be highly conserved among eukaryotes) refers to an enzyme from the serine/threonine protein kinase family encoded by the mTOR gene. It is found in humans as well as worms, mice, flies and yeasts. It regulates the growth, proliferation, motility and survival of cells.

Successfully inhibiting mTOR signalling pathways has been shown to produce increased lifespan in worms, flies, yeasts and even mice if accompanied by calorie restriction and the consumption of adequate protein.

 

Image result for mtor pathway

Figure 1.  mTOR Pathway  (Source)

Since Rapamycin is poorly water soluble, which effects its bioavailability, several analogs of Rapamycin have been developed and are termed rapalogs.  Some of these rapalogs have improved pharmacokinetics and include:

  • temsirolimus
  • everolimus
  • ridaforolimus
  • 32-deoxo-rapamycin
  • zotarolimus

The use of these pharamaceutical rapalogs have been generally disappointing in human trials.  One possible explanation for the disappointing results to date is that in human cancer, rapalogs predominately inhibit mTORC1, leading to increased PI3K and AKT signaling by preventing negative feedback through S6K and GRB10.  1 

Recent studies have demonstrated that a number of natural products (or nutraceuticals) isolated from plants (e.g. fruits, vegetables, spices, nuts, legumes, herbs, etc.) also inhibit the mTOR pathway, and exhibit potent anticancer activities. These particular natural products are considered “natural rapalogs”.

The Table below lists the identified natural substances that are considered natural rapalogs or mTOR inhibitors:

Natural Rapalogs (mTOR Inhibitors)

CategorySubstanceReference
Alkaloids
Caffeine1
Amino Acids
NAC2
Herbs
Astragalus3
β-elemene (from the traditional Chinese medicinal herb Rhizoma zedoariae)4
Butein (in the stems of Rhus verniciflua)5
Capsaicin (in chili peppers)6
Celastrol (in the traditional Chinese medicine named “Thunder of God Vine”)7
Cryptotanshinone (Salvia miltiorrhiza Bunge) (Danshen)8
Rhodiola rosea9
Indoles
Indole-3-carbinol and 3,3′-diindolylmethane)10
Mushrooms
Reishi11
Peptides
Carnosine12
Polyphenols
Apigenin13
Curcumin14
Epigallocatechin gallate (EGCG, in green tea)15
Fisetin16
Isoflavones (genistein and deguelin)17
Quercetin18
Resveratrol19
Vitamins
R-Lipoic Acid20
Tocotrienol (Vitamin E)21