(Last modification:
22. November 2009)
Sirtuins:
arrangement of pages
Sirtuin Inhibitors
Note:
Most
of this page was extracted from an excellent review: Alcaín and Villalba,
2009); a few more recent references were added. See also the review by
Grubisha
et al., 2005.
Note: If the
inhibition of sirtuin activities in vitro was measured with fluorescent
substrates, the validity of the results can be questioned, as discussed with the
sirtuin activators:
more...
Introductory remarks
After all we have seen about the beneficial effects of Sirtuin activation (more...): why should somebody be
interested in the opposite effect, i.e. blocking all the good things caused by resveratrol and other activators? However, as usually, the matter is not that
simple, and sirtuin activation could have some effects that are not desirable.
To understand that, we'll have to look at some of the properties of sirtuins (this
is a selection; there are certainly more examples!).
The focus here is on human SIRT1 and SIRT2, because they appear to be the
preferred targets for activators and inhibitors, and many affect both. Have a look at the
conclusions if you do not want to go through the details:
more...
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SIRT1
Apart from all the beneficial effects, SIRT1 activation has at least one property with
a Janus head, i.e. it can be good or bad. That is the SIRT1 catalyzed deacetylation of the
tumour suppressor protein p53 (Vaziri
et al., 2001) that leads to inactivation of p53. That is good for normal
cells because it increases their survival and prolongs life span, but it is not so desirable for
tumorous cells because it has there the same effect: it might stimulate the
survival and replication of tumour cells. Actually,
SIRT1 appears to be
up-regulated in most cancer cells, e.g. in human lung cancer, prostate
cancer, leukaemia, in cancer cell lines, and in tissue samples from colon
carcinoma (reviewed in
Ashraf
et al., 2006;
Lim, 2006;
Stünkel et al., 2007;
Fraga and
Esteller, 2007;
Jung-Hynes et al., 2009). Re-activating p53, i.e. inhibiting SIRT1 instead of
stimulating it, could
trigger strong
apoptosis in tumour cells, and thus could eliminate tumours.
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SIRT2
This protein is predominantly in the cytoplasm, with highest
expression in the brain; it co-localizes with
microtubules, deacetylates tubulin (North
et al., 2003), and plays a role in the cell cycle (Inoue
et al., 2007). It is noteworthy that p53 and histones H3 and H4 are
additional substrates of SIRT2, suggesting a broader role (Heltweg
et al., 2006), and thus SIRT2 activation could potentially as
undesirable as SIRT1 activation. On the other hand, SIRT2 also deacetylates
the transcription regulator FOXO3a (Wang
et al., 2007), activating it, and in consequence promotes cell death
under severe stress. By that function SIRT2 it is a potential tumour
suppressor, and it is actually severely reduced in a large number of brain
tumour cell lines (Voelter-Mahlknecht
et al., 2005). Again, there may be good or bad effects by changing the
activity of SIRT2. See also the interesting articles by
Garske
et al., 2007, and
Jing et al.,
2007 which among other things deal with the complexity of SIRT2
functions.
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The following is a brief discussion of
some inhibitors
Note: the list
might not be up to date, and there many more references for most of the
inhibitors discussed here; only a selection is cited.
The
structures of the molecules are shown in Fig. 1
-
Splitomycin
and Derivatives
They were discovered in a screen for inhibitors of yeast Sir2 (Bedalov
et al., 2001;
Hirao et
al., 2003;
Posakony et al., 2004), but it was not very efficient
with human sirtuins. A series of more potent derivatives were
developed; some of them were quite effective, revealing a correlation
between increased SIRT1 enzyme inhibition and anticancer activity (Neugebauer
et al., 2008). HR73 is one of the effective derivatives with inhibitory activity for
SIRT1. This inhibition of SIRT1 deacetylase inhibits Tat deacetylation (Trans-Activator
of Transcription), a protein that in its deacetylated form leads to an
enormous increase in the transcription of all genes in the integrated HIV
provirus. Thus, SIRT1 deacetylase inhibitors could be a factor in treating immunodeficiency virus
infections (Pagans
et al., 2005). Later work, however, reached different conclusions: it
reported that activation of SIRT1, for example by resveratrol, inhibited
Tat-induced HIV-1 transactivation (Zhang et al.,
2009a,
2009b).
If anything, this shows that the situation is likely to be more complex than
thought before, and that the use of different model systems can lead to
conflicting results.
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Sirtinol
This drug inhibits yeast Sir2 and human SIRT2 activity in vitro,
it is probably a general inhibitor of Sirtuin deacetylase activities.
Apparently the 2-hydroxy-1-naphtol part (blue in Fig. 1) was sufficient, and
these substances represent a new class of inhibitors (Grozinger
et al., 2001). A growth-arresting effect of sirtinol has been shown with
human breast and lung cancer cells (Ota et al., 2005),
also with prostata cancer cells (Jung-Hynes
et al., 2009), and it had a protecting effect on antigen-induced airway
inflammation and hyper-responsiveness (Kim
et al., 2009). Furthermore it protected to some extent against certain
muscular dystrophies (Catoire
et al., 2008). Even more powerful
analogues were developed (Mai et al.,
2005). As noted above, SIRT1 is up-regulated in most cancer cells (see
above), and thus such inhibitors could be
useful.
Another unexpected use could be the prevention or treatment of
leishmaniasis, especially in immunodepressed patients (Vergnes
et al., 2005;
Tavares et al., 2008).
A side line for sirtuins in plants:
The experiments of Grozinger et al. (2001)
also investigated the effects of sirtinol on the development of
Arabidopsis thaliana seedlings. This appeared interesting because plants
do contain proteins related to sirtuins (Pandey
et al., 2002), and it was an attractive possibility that they had
similar functions. The results with seedlings of Arabidopsis indeed revealed
some auxin-like effects of sirtinol, suggesting a possibility that sirtuins
may be involved in some aspect of auxin action/control. However, later
studies showed that the sirtinol action in plants most likely had nothing to
do with sirtuins: careful investigations showed that the sirtinol was
degraded in plants to
2-hydroxy-1-naphthaldehyde and 2-hydroxy-1-naphthoic acid, which are
auxin-analogues and induce auxin-controlled developments (Dai
et al., 2005).
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AGK2
The application of this SIRT2 inhibitor showed, at least in
an cellular and in a Drosophila model, amelioration of the formation of
alpha-synuclein fibrils that are characteristic for neurodegenerative
diseases, e.g. Parkinson's disease (Outeiro
et al., 2007). AGK2 has also been used as sirtuin inhibitor in more
recent experiments (Giammona
et al., 2009).
-
Tenovin
Lain et al.
(2008) screened 30,000 small molecules for p53-activating activity, and
found two compounds that turned out to be SIRT1 inhibitors. They decreased
tumour growth in vitro at micromolar concentrations, and delayed tumour
growth in vivo as single agents, with tenovin-6 a bit more effective. See
also the comments by
Brooks
and Gu (2008).
-
Gambinol
Heltweg et al. (2006) identified and characterized this interesting
compound which shares a ß-napthol pharmacore with Sirtinol, Splitomycin,
HR73, and Salermide (also in Fig. 1, and described in the next para). It inhibited human
SIRT1 and SIRT2 deacetylase activity, and was most active with
Burkitt lymphoma
cell lines. Recent work described modifications leading to higher potency
and modified selectivity (Medda
et al., 2009).
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Salermide
This drug was described only recently (Lara
et al., 2009). It was an efficient inhibitor of SIRT1 and SIRT2 in vitro,
in much lower concentrations than sirtinol, and it was well tolerated by
mice in concentrations up to 0.1 mM. Salermide induced apoptosis in cancer,
but not in normal cells. Interestingly, the effect was independent of p53. Instead,
it was a consequence of SIRT1-mediated deacetylation of K16H4 (= Lysine 16 in Histone 4),
which apparently led to a re-activation of proapoptotic genes repressed exclusively in cancer cells.
Fig. 1.
Structures of some Sirtuin inhibitors.
Blue: the 2-hydroxy-1-naphtol part common
to several inhibitors.
Adapted from Alcain and Villalba, 2009, with modifications.
'This short overview does not cover all described inhibitors, for example the
Thiobarbiturates and some others (see Alcain and Villalba, 2009, refererence
given below) for the details.
Conclusion:
I admit that I was a bit shocked after looking at these
publications because I was not aware of the aspect that SIRT activators might
have a positive effect on cancer or tumourous growth. Most of the literature on
resveratrol deals with its benefits.
The paper by
Jang et al.
(1997) on the cancer chemopreventive activity of resveratrol was certainly one of the major triggers. This was followed by a flurry of optimistic
publications, including a few years later the identification of sirtuins as
major targets of resveratrol. At first sight, it seems that the publications
reporting on the possible benefits rarely mention or know about the possible
side effects, or possibly do not take that seriously.
Regardless of that, my advice would be: if you are thinking
about taking resveratrol regularly, it would be good to talk to your Doctor
about that (taking for granted that he is up to date with the recent literature).
I think this would be highly advisable if one has a family history of cancer/tumours
in the family. Or if you happen to be not so young anymore: who can be
sure that one does not have some degenerated cells in his body?
See
also a comment in the page on Sirtuins (more...)
a look at possible concerns with the human use of resveratrol (more...)
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Reference
-
Alcain, F. J., Villalba, J. M., 2009b. Sirtuin
inhibitors. Expert Opinion on Therapeutic Patents 19, 283-294.
BACKGROUND: The sirtuin family of deacetylase enzymes comprises seven
proteins (SIRT1-7) that are dependent on NAD+ for their activity.
Three proteins are located in the nucleus, three in the mitochondria and
only one is predominantly cytoplasmic. Caloric restriction and oxidative
stress generally up-regulate their expression. SIRT1, the orthologue of
yeast Sir2, is the mammalian sirtuin that has been most extensively studied
to date. Among other targets, SIRT1 down-regulates the activity of the
nuclear transcription factor p53, being this related with an increase in
lifespan and cell survival associated to stress resistance.
OBJECTIVE: Because sirtuin modulation could have beneficial effects
on several human diseases, there is a growing interest in the discovery and
development of small molecules that modify its activity. This review will be
focused on sirtuin inhibitors.
CONCLUSIONS: Several specific inhibitors of SIRT1 have been described.
These compounds could be mainly useful for the treatment of cancers by
increasing p53 activity that stops the formation of tumours and induces
apoptosis. A p53-independent massive induction of apoptosis has been also
described for one inhibitor. In addition, a potent and selective SIRT2
inhibitor that ameliorates the alpha-synuclein fibril formation in Parkinson
disease has been proposed to treat this kind of neurodegenerative disease.
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File History:
-
22.11.2009: Update on a
few links, and sirtinol action in plants: more...
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20.11.2009: Update on a
few more references
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03.11.2009: Design of
page
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