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piperine and mTOR


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I'm posting this after reading the article, linked by Burak in another thread, where it is suggested that piperine activates AMPK. From there I envisaged a longevity-boosting effect since AMPK downregulates mTOR.


As it turns out, piperine has been observed to boost mTOR rather than decreasing it in some context, like in peritoneal resident macrophages. In this case boosting mTOR equals to boosting immunity since upregulation of macrophages potentiates the anti-bacterial activity in that substrate. Piperine improves the cellular absorption of leucine, whose signal is necessary to mTOR activation.



Oncotarget. 2015 Oct 20; 6(32): 32468–32483.
Published online 2015 Oct 2. doi:  10.18632/oncotarget.5957
PMCID: PMC4741706
Piperine metabolically regulates peritoneal resident macrophages to potentiate their functions against bacterial infection


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This is another article where, in a neurodegenerative context (Parkinson Disease), piperine has been observed to inhibit mTOR hence triggering mitochondrial autophagy, by suppressing the factors triggering the activity of akt (suppressing the rotenone-induced inhibition of PP2A). In a few words, piperine is a neuro protective factor against PD, allowing autophagy of damaged mitochondria.


Now, I remain speechless. Are we dealing with a miraculous compound, which is able to upregulate mTOR where it boosts immunity and to downregulate it where it boosts autophagy? Opposite mechanisms in different context with an equally positive effect? 




Oncotarget. 2016 Sep 20; 7(38): 60823–60843.
Published online 2016 Aug 27. doi:  10.18632/oncotarget.11661
PMCID: PMC5308619
Piperine induces autophagy by enhancing protein phosphotase 2A activity in a rotenone-induced Parkinson's disease model
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In this article piperine is related to suppression of proliferation in osteosarcoma cells thru different mechanisms, among which akt inhibition. Piperine tends to be an anti-tumorigen in bone tumours. akt inhibition inhibits mTOR in normal cells but I dont know in cancer cells.


Int Immunopharmacol. 2015 Jan;24(1):50-8. doi: 10.1016/j.intimp.2014.11.012. Epub 2014 Nov 20.
Piperine inhibits proliferation of human osteosarcoma cells via G2/M phasearrest and metastasis by suppressing MMP-2/-9 expression.
Zhang J1Zhu X2Li H1Li B1Sun L1Xie T1Zhu T1Zhou H1Ye Z3.

The piperidine alkaloid piperine, a major ingredient in black pepper, inhibits the growth and metastasis of cancer cells both in vivo and in vitro, although its mechanism of action is unclear. Furthermore, its anticancer activity against osteosarcoma cells has not been reported. In this study, we show that piperine inhibited the growth of HOS and U2OS cells in dose- and time-dependent manners but had a weaker effect on the growth of normal hFOB cellsPiperine inhibited osteosarcoma cell proliferation by causing G2/M phase cell cycle arrest associated with decreased expression of cyclin B1 and increased phosphorylation of Cyclin-dependent kinase-1(CDK1) and checkpoint kinase 2 (Chk2). In addition, piperine treatment inhibited phosphorylation of Akt and activated phosphorylation of c-Jun N-terminal kinase (c-JNK) and p38 mitogen-activated protein kinase (MAPK) in HOS and U2OS cellsPiperine induced colony formation in these two cell types. We proved that piperine could suppress the metastasis of osteosarcoma cells using scratch migration assays and Transwell chamber tests. Moreover, gelatin zymography showed that piperine inhibited the activity of matrix metalloproteinase (MMP)-2/-9 and increased the expression of tissue inhibitor of metalloproteinase (TIMP)-1/-2. Taken together, our results indicate that piperine inhibits proliferation, by inducing G2/M cell cycle arrest, and the migration and invasion of HOS and U2OS cellsvia increased expression of TIMP-1/-2 and down-regulation of MMP-2/-9. These findings support further study of piperine as a promising therapeutic agent in the treatment of osteosarcoma.

Copyright © 2014 Elsevier B.V. All rights reserved.


Cell cycle arrest; Matrix metalloproteinase; MetastasisOsteosarcomaPiperine

PMID:   25479727   DOI:   10.1016/j.intimp.2014.11.012
Edited by mccoy
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Similarly to above, piperine is shown to have an anti-tumorigen effect on breast cancer cells as well, by inhibition of akt.


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Cancer Lett. 2015 Feb 1;357(1):129-40. doi: 10.1016/j.canlet.2014.11.017. Epub 2014 Nov 13.
Piperine inhibits the growth and motility of triple-negative breast cancercells.

Piperine, an alkaloid from black pepper, is reported to have anticancer activities. In this study, we investigated the effect of piperine on the growth and motility of triple-negative breast cancer (TNBC) cellsPiperine inhibited the in vitro growth of TNBC cells, as well as hormone-dependent breast cancer cells, without affecting normal mammary epithelial cell growth. Exposure to piperine decreased the percentage of TNBC cells in the G2 phase of the cell cycle. In addition, G1- and G2-associated protein expression was decreased and p21(Waf1/Cip1) expression was increased in piperine-treated TNBC cellsPiperine also inhibited survival-promoting Akt activation in TNBC cells and caused caspase-dependent apoptosis via the mitochondrial pathway. Interestingly, combined treatment with piperine and γ radiation was more cytotoxic for TNBC cells than γ radiation alone. The in vitro migration of piperine-treated TNBC cells was impaired and expression of matrix metalloproteinase-2 and -9 mRNA was decreased, suggesting an antimetastatic effect by piperine. Finally, intratumoral administration of piperine inhibited the growth of TNBC xenografts in immune-deficient mice. Taken together, these findings suggest that piperine may be useful in the treatment of TNBC.

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.


Apoptosis; Breast cancer; Metastasis; Piperine; Xenograft

PMID:   25444919   DOI:   10.1016/j.canlet.2014.11.017
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Thank you mccoy. Adding these to the other benefits of piperine such as autophagy, energy metabolism, nutrient absorption and polyhenol (resveratrol, curcumin) bioavailibilty, it seems to me that black pepper is a must consume spice in a longevity diet. No wonder I like it so much. On the other side, with the combination of red chili peppers it causes me to sweat too much during meal which leads to occasional acne here and there but no big deal.

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Burak, some cuisines like North African really use a lot of black pepper. At times I too eat a lot of it and after knowing these benefits I'll commit to eat even more. I'll let my body intelligence decide when it's too much, usually after indulging in a certain phytochemical if some threshold has been reached the body just refuses it. I remember it happened to me with consistent ingestion of large amounts of freshly picked tomatoes (tomatine) and with hot chilis (capsaicin)

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