Copied CR-Request mailing list post of Conrad Roland:
---------- Forwarded message ----------
From: CONRAD ROLAND <coro@hawaii.rr.com>
To: The CR Society Main Discussion List <cr@lists.calorierestriction.org>
Date: Sun, 14 Mar 2010 04:48:47 -1000
Subject: [CR] mTOR inhibition by curcumin
Inhibition of mTOR (mammalian Target of Rapamycin) may be a promising
"adjuvant" strategy for the extension of healthspan and lifespan
(Katewa and Kapahi, 2009), just posted by Al Pater as "CR and Aging" [4].
Compare the pathways and molecules mentioned in the paper by Beevers et al.
2009 to the same or similar pathways in the Katewa & Kapahi paper !
Rapamycin is a strong immuno-suppressive drug and may not be considered, at
the present time, as a viable option, for healthy individuals, to enhance
the effects of CR by mTOR inhibition.
Two recent papers report (in vitro, but that does not make them worthless)
"that curcumin may represent a new class of mTOR inhibitor" [1].
A general discussion of mTOR and its relevance in cancer can be found
in the paper by Gibbons et al. 2009 [3].
The paper by Yu et al. 2008 [2] concludes:
" Our study reveals the profound effects of curcumin on the Akt/mTOR
signaling network in PC-3 cells and provides new mechanisms for the
anticancer effects of curcumin."
These and other recent findings establish in vitro that curcumin may be used
as a potent inhibitor of the mTOR / mTORC1 signaling pathway.
Since there is fairly convincing evidence that curcumin (obtained from
turmeric root) may have inhibitory effects on the mTOR complex 1
(mTORC1) signaling pathway and on downstream effectors.
Curcumin is presently tested in several clinical trials for various cancer
treatments and for Alzheimer's prevention and treatment. Curcumin is
"well tolerated" in quantities up to 6-8g (= 8,000 mg), even as high as 12g.
(It may result in more or less constipation...). It becomes toxic at much
higher doses.
I consume curcumin on a daily basis, as a spice in curries as Turmeric
and/ or "Indian Curry powder" - the curcumin content is fairly low at 3-5%.
In addition I started, again, to take "Curcumin" or "Turmeric root extract
with 95% curcumin" as a supplement in order to get substantially higher
doses of curcumin (at least 2-4 times 300mg or 3 x 500mg and more).
I take curcumin as food/spice and as a IMO "essential" supplement in order
to reduce systemic and/or acute inflammation - supporting the effects
of CR - and to prevent any recurrence of BCC (basal cell carcinoma) skin
cancer - with visible results (including previously low hsCRP values).
The major problem with oral supplementation of curcumin is bioavailablity -
what and how much makes it to the blood serum and into tissues and cells.
It must be consumed, in food as well as with capsules, together with some
fat - olive oil, fish oil, fatty fish, avocadoes, walnuts, other nuts, etc.
Heat treatment enhances the cellular effects of curcumin - by using it in
curries, soups, hot beverages.
Many new, absorption-enhancing forms of curcumin have been developed,
micro-encapsulation and several curcumin analogs. For our less demanding,
but *long-term* regular ingestion purposes I believe that natural
(*organic* for safety purposes, most of it is imported) turmeric/curcumin
is good enough - and a most valuable addition to a CR nutritional regimen.
It may just do in vivo what it does in vitro. The ongoing clinical trials
with oral curcumin are a good indication that it is safe and probably quite
effective IN VIVO !
Conrad
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
[1] Curcumin disrupts the Mammalian target of rapamycin-raptor complex.
Beevers CS, Chen L, Liu L, Luo Y, Webster NJ, Huang S.
Department of Biochemistry and Molecular Biology, Feist-Weiller Cancer
Center, Louisiana State University Health Sciences Center, Shreveport,
Louisiana 71130-3932, USA.
Cancer Res. 2009 Feb 1;69(3):1000-8. Epub 2009 Jan 27. PMID19176385
Curcumin (diferuloylmethane), a polyphenol natural product of the plant
Curcuma longa, is undergoing early clinical trials as a novel anticancer
agent. However, the anticancer mechanism of curcumin remains to be
elucidated.
Recently, we have shown that curcumin inhibits phosphorylation of p70 S6
kinase 1 (S6K1) and eukaryotic initiation factor 4E (eIF4E) binding protein
1 (4E-BP1), two downstream effector molecules of the mammalian target of
rapamycin complex 1 (mTORC1) in numerous cancer cell lines.
This study was designed to elucidate the underlying mechanism. We observed
that curcumin inhibited mTORC1 signaling not by inhibition of the upstream
kinases, such as insulin-like growth factor 1 receptor (IGF-IR) and
phosphoinositide-dependent kinase 1 (PDK1). Further, we found that curcumin
inhibited mTORC1 signaling independently of protein phosphatase 2A (PP2A) or
AMP-activated protein kinase AMPK-tuberous sclerosis complex (TSC). This is
evidenced by the findings that curcumin was able to inhibit phosphorylation
of S6K1 and 4E-BP1 in the cells pretreated with PP2A inhibitor (okadaic
acid) or AMPK inhibitor (compound C), or in the cells expressing
dominant-negative (dn) PP2A, shRNA to PP2A-A subunit, or dn-AMPKalpha.
Curcumin did not alter the TSC1/2 interaction. Knockout of TSC2 did not
affect curcumin inhibition of mTOR signaling.
Finally, we identified that curcumin was able to dissociate raptor from
mTOR, leading to inhibition of mTORC1 activity. Therefore, our data indicate
that curcumin may represent a new class of mTOR inhibitor.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
[2] Curcumin inhibits Akt/mammalian target of rapamycin signaling through
protein phosphatase-dependent mechanism.
Yu S, Shen G, Khor TO, Kim JH, Kong AN.
Department of Pharmaceutics, Ernest-Mario School of Pharmacy, Rutgers, the
State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ,USA
Mol Cancer Ther. 2008 Sep;7(9):2609-20. PMID: 18790744
Akt/mammalian target of rapamycin (mTOR) signaling plays an important role
in tumorigenesis and is dysregulated in many tumors, especially metastatic
prostate cancers.
Curcumin has been shown to effectively prevent or inhibit prostate cancer in
vivo and inhibit Akt/mTOR signaling in vitro, but the mechanism(s) remains
unclear.
Here, we show that curcumin concentration- and time-dependently inhibited
the phosphorylation of Akt, mTOR, and their downstream substrates in human
prostate cancer PC-3 cells, and this inhibitory effect acts downstream of
phosphatidylinositol 3-kinase and phosphatidylinositol-dependent kinase 1.
Overexpression of constitutively activated Akt or disruption of TSC1-TSC2
complex by small interfering RNA or gene knockout only partially restored
curcumin-mediated inhibition of mTOR and downstream signaling, indicating
that they are not the primary effectors of curcumin-mediated inhibition of
Akt/mTOR signaling. Curcumin also activated 5'-AMP-activated protein kinase
and mitogen-activated protein kinases; however, inhibition of these kinases
failed to rescue the inhibition by curcumin.
Finally, it was shown that the inhibition of Akt/mTOR signaling by curcumin
resulted from calyculin A-sensitive protein phosphatase-dependent
dephosphorylation.
Our study reveals the profound effects of curcumin on the Akt/mTOR signaling
network in PC-3 cells and provides new mechanisms for the anticancer effects
of curcumin.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
[3] Mammalian target of rapamycin: discovery of rapamycin reveals a
signaling pathway important for normal and cancer cell growth.
Gibbons JJ, Abraham RT, Yu K.
Department of Oncology Discovery, Pfizer Inc., 401 N Middletown Rd., Pearl
River, NY 10960, USA.
Semin Oncol. 2009 Dec;36 Suppl 3:S3-S17. PMID: 19963098
Since the discovery of rapamycin, considerable progress has been made in
unraveling the details of the mammalian target of rapamycin (mTOR) signaling
network, including the upstream mechanisms that modulate mTOR signaling
functions, and the roles of mTOR in the regulation of mRNA translation and
other cell growth-related responses.
mTOR is found in two different complexes within the cell, mTORC1 and mTORC2,
but only mTORC1 is sensitive to inhibition by rapamycin. mTORC1 is a master
controller of protein synthesis, integrating signals from growth factors
within the context of the energy and nutritional conditions of the cell.
Activated mTORC1 regulates protein synthesis by directly phosphorylating
4E-binding protein 1 (4E-BP1) and p70S6K (S6K), translation initiation
factors that are important to cap-dependent mRNA translation, which
increases the level of many proteins that are needed for cell cycle
progression, proliferation, angiogenesis, and survival pathways.
In normal physiology, the roles of mTOR in both glucose and lipid catabolism
underscore the importance of the mTOR pathway in the production of metabolic
energy in quantities sufficient to fuel cell growth and mitotic cell
division.
Several oncogenes and tumor-suppressor genes that activate mTORC1, often
through the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, are frequently
dysregulated in cancer. Novel analogs of rapamycin (temsirolimus,
everolimus, and deforolimus), which have improved pharmaceutical properties,
were designed for oncology indications.
Clinical trials of these analogs have already validated the importance of
mTOR inhibition as a novel treatment strategy for several malignancies.
Inhibition of mTOR now represents an attractive anti-tumor target, either
alone or in combination with strategies to target other pathways that may
overcome resistance. The far-reaching downstream consequences of mTOR
inhibition make defining the critical molecular effector mechanisms that
mediate the anti-tumor response and associated biomarkers that predict
responsiveness to mTOR inhibitors a challenge and priority for the field.
>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>
[4] Dietary restriction and aging, 2009.
Katewa SD, Kapahi P.
Aging Cell.
2010 Jan 20. [Epub ahead of print]
PMID: 20096035
