11 replies to this topic

[Michael]

Amazed that no one has posted this yet; courtesy of Al Pater on the CR listserv:

Quote

accumulating evidence shows that SIRT1 is overexpressed in various types of malignant cells, and its inhibitors suppress the growth of tumor cells. The relationship between SIRT1 and metastasis remains to be clarified.

Here, we examined the effect of SRT1720, a SIRT1 activator, on lung metastasis of breast cancer cells. 4T1 breast cancer cells were subcutaneously implanted into syngeneic BALB/c mice and SRT1720 was administered alone or with an antitumor agent, cisplatin. As expected, cisplatin decreased the lung metastasis score, whereas SRT1720 increased metastasis irrespective of cisplatin. In the primary tumors, cisplatin suppressed the mRNA level of angiopoietin-like protein 4 (angptl4), a lung metastasis-promoting gene product of breast cancer, but SRT1720 reduced the effectiveness of cisplatin. The results obtained with animal experiments were in accordance with those in human cancer cells; SRT1720 significantly increased the amount of VEGF secreted from MDA-MB-231 cells. Moreover, a transendothelial cell migration assay showed that SRT1720 promotes the migration of MDA-MB-231 cells across an endothelial cell layer despite the presence of cisplatin.

These findings imply that SRT1720 promotes the pulmonary metastasis of breast cancer cells and SIRT1 may be an important target for suppressing metastasis to the lung.(1)

Please don't fall into the 'but it's OK if you don't already have cancer' fallacy. (And see this recent example involving telomerase and cancer specifically).

Reference

1: SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice.
Suzuki K, Hayashi R, Ichikawa T, Imanishi S, Yamada T, Inomata M, Miwa T, Matsui S, Usui I, Urakaze M, Matsuya Y, Ogawa H, Sakurai H, Saiki I, Tobe K.
Oncol Rep. 2012 Jun;27(6):1726-32. doi: 10.3892/or.2012.1750. Epub 2012 Mar 27.
PMID:22470132
http://www.spandidos...om/or/27/6/1726

[bixbyte]

This RES Study reminds me of the Movie: DUDE WHERE'S MY CAR.
They order drive thru take out Chinese and the lady on the order mike says:
"AND THEN?" ... "AND THEN?" .... "AND THEN?" ...

Edited by Michael, 16 June 2012 - 11:56 AM.

[zorba990]

And what exactly IS SRT1720?   Just because _A_ SIRT1 activator promotes cancer under certain circumstances does not follow that all activators of SIRT1 or that THE activation of SIRT1 does this.  I expect there will always be side effects from artificial molecules as the body has had little to no time to adapt to them on an evolutionary scale.   All the best stuff seems to be made in nature or in the body itself....artiificial drugs just can't compete...

[maxwatt]

Resveratrol suppresses the replication of some cancer cells in vitro, but it is much more than an SIRT1 activator.  SRT1720 was developed to specifically target SIRT1, whereas resveratrol affects expression of over 300 genes.  Whether this is good or bad, I cannot say,  I've seen it claimed resveratrol is ineffective in vitro against (some kinds of) lung cancers, but at sufficient concentrations it does kill other kinds of cancer cells.  To date, I've seen no claims of resveratrol induced cancer, not in mouse studies, nor in people -- and people have been taking large quantities for almost six years now.   The one consistent negative effect I've seen reported is joint or tendon pain, and most (but not all) of these have resolved with Vitamin D3 supplementation.

[mikeinnaples]

I am not sure what SRT1720 has to do with this forum. Shouldnt it be moved to a category more suitable?

[Logic]

Resveratrol triggers an enzyme that is present in every cancer cell to produce a compound called piceatannol, which then attacks the cancer cell.

http://dmd.aspetjour...t/37/5/932.full

http://mct.aacrjourn...nt/3/3/363.long

http://www.ncbi.nlm....les/PMC2375304/

I have no idea whether this effect is stronger than the SIRT1 activation?

[maxwatt]

Piceatannol has been shown to be a stronger activator of SIRT1 than resveratrol.  It is a normal metabolic byproduct of metabolizing resveratrol.   No cancer cells needed, though they may increase the amount of piceatannol produced.

mikeinnaples: SRT1720 was Sirtris' first attempt to synthesize a superior artificial resveratrol, as such it may be  relevant with regard to SIRT1, as far as that goes.

[Michael]

mikeinnaples, on 15 June 2012 - 12:28 PM, said:

I am not sure what SRT1720 has to do with this forum. Shouldnt it be moved to a category more suitable?

As resveratrol is a putative SIRT1 activator; as SIRT1 activation was the origin of its claim to be a CR mimetic; and as SIRT1720 is in fact a tweaked form of resveratrol -- it is evidentiary.

zorba990, on 13 June 2012 - 10:21 PM, said:

And what exactly IS SRT1720?   Just because _A_ SIRT1 activator promotes cancer under certain circumstances does not follow that all activators of SIRT1 or that THE activation of SIRT1 does this.  I expect there will always be side effects from artificial molecules as the body has had little to no time to adapt to them on an evolutionary scale.   All the best stuff seems to be made in nature or in the body itself....artiificial drugs just can't compete...

I think you're getting dangerously close to vitalism here. IAC, the fact that SIRT1 is overactivated in many cancers (prostate cancer, acute myeloid leukemia, colon cancer, and in some reports, hepatocellular cardinoma); "SIRT1 Promotes Tumorigenesis and Resistance to Chemotherapy in Hepatocellular Carcinoma and its Expression Predicts Poor Prognosis" in cancer patients (PMID: 22146883); that overexpressing SIRT1 inhibits cancer cell apoptosis, while  silencing it using RNA interference sensitizes cancer cells to several chemotherapy agents;  that pharmacological and genetic repression of SIRT1 slows the growth of such cancers in vitro; and that this report finds that activation of SIRT1 by what is claimed to be a highly molecularly precise SIRT1 activator increases metastasis and overrides the effectiveness of cisplatin in fighting it -- all suggests that it's SIRT1 activation per se that's the problem, and thus caution in the use of putative SIRT1 activators.

I do agree with Maxwatt, however, that there is little evidence that resveratrol increases cancer risk in normal mice: it just seems to be of no effect at all. Ths may be because it's a "dirty" drug, or because (as many contend) it really doesn't activate SIRT1 in the first place.

Logic, on 15 June 2012 - 01:52 PM, said:

Resveratrol triggers an enzyme that is present in every cancer cell to produce a compound called piceatannol, which then attacks the cancer cell.

http://dmd.aspetjour...t/37/5/932.full

http://mct.aacrjourn...nt/3/3/363.long

http://www.ncbi.nlm....les/PMC2375304/

I have no idea whether this effect is stronger than the SIRT1 activation?

You and I also have no idea whether these effects actually happens in vivo .

[bixbyte]

Michael, on 16 June 2012 - 12:26 PM, said:

I do agree with Maxwatt, however, that there is little evidence that resveratrol increases cancer risk in normal mice: it just seems to be of no effect at all. Ths may be because it's a "dirty" drug,? or because (as many contend) it really doesn't activate SIRT1 in the first place.

AND THEN ... AND THEN ... AND THEN ...
Dude where is my car?
Appears we are on track here.
RES IS BAD?

Edited by bixbyte, 16 June 2012 - 02:54 PM.

[zorba990]

Michael, on 16 June 2012 - 12:26 PM, said:

mikeinnaples, on 15 June 2012 - 12:28 PM, said:

I am not sure what SRT1720 has to do with this forum. Shouldnt it be moved to a category more suitable?

As resveratrol is a putative SIRT1 activator; as SIRT1 activation was the origin of its claim to be a CR mimetic; and as SIRT1720 is in fact a tweaked form of resveratrol -- it is evidentiary.

zorba990, on 13 June 2012 - 10:21 PM, said:

And what exactly IS SRT1720?   Just because _A_ SIRT1 activator promotes cancer under certain circumstances does not follow that all activators of SIRT1 or that THE activation of SIRT1 does this.  I expect there will always be side effects from artificial molecules as the body has had little to no time to adapt to them on an evolutionary scale.   All the best stuff seems to be made in nature or in the body itself....artiificial drugs just can't compete...

I think you're getting dangerously close to vitalism here. IAC, the fact that SIRT1 is overactivated in many cancers (prostate cancer, acute myeloid leukemia, colon cancer, and in some reports, hepatocellular cardinoma); "SIRT1 Promotes Tumorigenesis and Resistance to Chemotherapy in Hepatocellular Carcinoma and its Expression Predicts Poor Prognosis" in cancer patients (PMID: 22146883); that overexpressing SIRT1 inhibits cancer cell apoptosis, while  silencing it using RNA interference sensitizes cancer cells to several chemotherapy agents;  that pharmacological and genetic repression of SIRT1 slows the growth of such cancers in vitro; and that this report finds that activation of SIRT1 by what is claimed to be a highly molecularly precise SIRT1 activator increases metastasis and overrides the effectiveness of cisplatin in fighting it -- all suggests that it's SIRT1 activation per se that's the problem, and thus caution in the use of putative SIRT1 activators.

I do agree with Maxwatt, however, that there is little evidence that resveratrol increases cancer risk in normal mice: it just seems to be of no effect at all. Ths may be because it's a "dirty" drug, or because (as many contend) it really doesn't activate SIRT1 in the first place.

Logic, on 15 June 2012 - 01:52 PM, said:

Resveratrol triggers an enzyme that is present in every cancer cell to produce a compound called piceatannol, which then attacks the cancer cell.

http://dmd.aspetjour...t/37/5/932.full

http://mct.aacrjourn...nt/3/3/363.long

http://www.ncbi.nlm....les/PMC2375304/

I have no idea whether this effect is stronger than the SIRT1 activation?

You and I also have no idea whether these effects actually happens in vivo .

http://www.biolsci.org/v05p0147.htm

Anecdotal evidence of tumor suppression by resveratrol is certainly there.  The relationship between P53 and SIRT1 and how precisely this is affected by resveratrol may need to be further clarified -- I'd say its more likely that SIRT1 shows as activated in some cancers because P53 is depressed and as a reaction to that SIRT1 is over expressed.   But there doesn't appear to be sufficient evidence to say that resveratrol adds fuel to the fire.

[bixbyte]

zorba990, on 16 June 2012 - 06:23 PM, said:

Michael, on 16 June 2012 - 12:26 PM, said:

mikeinnaples, on 15 June 2012 - 12:28 PM, said:

I am not sure what SRT1720 has to do with this forum. Shouldnt it be moved to a category more suitable?

As resveratrol is a putative SIRT1 activator; as SIRT1 activation was the origin of its claim to be a CR mimetic; and as SIRT1720 is in fact a tweaked form of resveratrol -- it is evidentiary.

zorba990, on 13 June 2012 - 10:21 PM, said:

And what exactly IS SRT1720?   Just because _A_ SIRT1 activator promotes cancer under certain circumstances does not follow that all activators of SIRT1 or that THE activation of SIRT1 does this.  I expect there will always be side effects from artificial molecules as the body has had little to no time to adapt to them on an evolutionary scale.   All the best stuff seems to be made in nature or in the body itself....artiificial drugs just can't compete...

I think you're getting dangerously close to vitalism here. IAC, the fact that SIRT1 is overactivated in many cancers (prostate cancer, acute myeloid leukemia, colon cancer, and in some reports, hepatocellular cardinoma); "SIRT1 Promotes Tumorigenesis and Resistance to Chemotherapy in Hepatocellular Carcinoma and its Expression Predicts Poor Prognosis" in cancer patients (PMID: 22146883); that overexpressing SIRT1 inhibits cancer cell apoptosis, while  silencing it using RNA interference sensitizes cancer cells to several chemotherapy agents;  that pharmacological and genetic repression of SIRT1 slows the growth of such cancers in vitro; and that this report finds that activation of SIRT1 by what is claimed to be a highly molecularly precise SIRT1 activator increases metastasis and overrides the effectiveness of cisplatin in fighting it -- all suggests that it's SIRT1 activation per se that's the problem, and thus caution in the use of putative SIRT1 activators.

I do agree with Maxwatt, however, that there is little evidence that resveratrol increases cancer risk in normal mice: it just seems to be of no effect at all. Ths may be because it's a "dirty" drug, or because (as many contend) it really doesn't activate SIRT1 in the first place.

Logic, on 15 June 2012 - 01:52 PM, said:

Resveratrol triggers an enzyme that is present in every cancer cell to produce a compound called piceatannol, which then attacks the cancer cell.

http://dmd.aspetjour...t/37/5/932.full

http://mct.aacrjourn...nt/3/3/363.long

http://www.ncbi.nlm....les/PMC2375304/

I have no idea whether this effect is stronger than the SIRT1 activation?

You and I also have no idea whether these effects actually happens in vivo .

http://www.biolsci.org/v05p0147.htm

Anecdotal evidence of tumor suppression by resveratrol is certainly there.  The relationship between P53 and SIRT1 and how precisely this is affected by resveratrol may need to be further clarified -- I'd say its more likely that SIRT1 shows as activated in some cancers because P53 is depressed and as a reaction to that SIRT1 is over expressed.   But there doesn't appear to be sufficient evidence to say that resveratrol adds fuel to the fire.

________

FROM THE STUDY I QUOTE:

"Interestingly, most tumors developed in the Sirt1+/-;p53+/- mice lost the remaining wild-type allele of p53 yet retained a functional wild-type Sirt1 allele. Accordingly, administration of resveratrol to these mice significantly reduced tumor formation [11]."

____________


So Resveratrol can cause cancer tumors in haploinsufficient Mice.
Am I allowed to say RES causes cancer in abnormal breed genetic mice?

Edited by bixbyte, 16 June 2012 - 07:21 PM.

[mikeinnaples]

Michael, on 16 June 2012 - 12:26 PM, said:

mikeinnaples, on 15 June 2012 - 12:28 PM, said:

I am not sure what SRT1720 has to do with this forum. Shouldnt it be moved to a category more suitable?

As resveratrol is a putative SIRT1 activator; as SIRT1 activation was the origin of its claim to be a CR mimetic; and as SIRT1720 is in fact a tweaked form of resveratrol -- it is evidentiary.

Hate to do it, but I have to jump on the:

...and then, and then, and then, and then

bandwagon with that response.


Doesn't CR activate Sirt 1 AND then ......?