Phloroglucinol Derivatives Guttiferone G, Aristoforin, and Hyperforin: Inhibitors of Human Sirtuins SIRT1 and SIRT2

Gey, Claudia; Kyrylenko, Sergiy; Hennig, Lothar; Nguyen, Lien‐Hoa D.; Büttner, Anita; Pham, Hung D.; Giannis, Athanassios

doi:10.1002/anie.200605207

Cited by 95 publications

(60 citation statements)

References 36 publications

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“…Furthermore, hyperforin might stimulate another pathway of apoptosis such as caspase-independent programmed cell death (also associated with pS externalization) which has been shown to play a role in CLL cells (41). Finally, we cannot exclude that the inhibitory properties of hyperforin on sirtuins, which are HDAC capable of preventing apoptosis (42), may be implicated.…”

Section: Discussionmentioning

confidence: 94%

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

Billard

2011

Int J Oncol

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Abstract. We previously reported that hyperforin, a phloroglucinol purified from Hypericum perforatum, induces the mitochondrial pathway of caspase-dependent apoptosis in chronic lymphocytic leukemia (CLL) cells ex vivo, and that this effect is associated with upregulation of Noxa, a BH3-only protein of the Bcl-2 family. Here, we investigated the role of this upregulation in the pro-apoptotic activity of hyperforin in the cells of CLL patients and MEC-1 cell line. We found that the increase in Noxa expression is a time-and concentrationdependent effect of hyperforin occurring without change in Noxa mRNA levels. A post-translational regulation is suggested by the capacity of hyperforin to inhibit proteasome activity in CLL cells. Noxa silencing by siRNA reduces partially hyperforin-elicited apoptosis. Furthermore, treatment with hyperforin, which has no effect on the expression of the prosurvival protein Mcl-1, induces the interaction of Noxa with Mcl-1 and the dissociation of Mcl-1/ Bak complex, revealing that upregulated Noxa displaces the proapoptotic protein Bak from Mcl-1. This effect is accompanied with Bak activation, known to allow the release of apoptogenic factors from mitochondria. Our data indicate that Noxa upregulation is one of the mechanisms by which hyperforin triggers CLL cell apoptosis. They also favor that new agents capable of mimicking specifically the BH3-only protein Noxa should be developed for apoptosis-based therapeutic strategy in CLL.

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Section: Discussionmentioning

confidence: 94%

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

Billard

2011

Int J Oncol

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“…122 Some phloroglucinol derivatives were also identified as sirtuin inhibitors with its most potent representative aristoforin (25), a synthetic hyperforin derivative. 123 It displayed an IC 50 -value of 7 mM against SIRT1 and 21 mM for SIRT2. Antiproliferative activity on HUVEC and LEC cells was shown by aristoforin at a low micromolar range, but a possible link to sirtuin inhibition, for example hyperacetylation of sirtuin protein substrates via western blot, was not established.…”

Section: Structural Diverse Sirtuin Inhibitorsmentioning

confidence: 99%

NAD⁺-dependent histone deacetylases (sirtuins) as novel therapeutic targets

et al. 2009

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Histone deacetylases (HDACs) are enzymes that cleave off acetyl groups from acetyl-lysine residues in histones and various nonhistone proteins. Four different classes of HDACs have been identified in humans so far. Although classes I, II, and IV are zinc-dependent amidohydrolases, class III HDACs depend on nicotinamide adenine dinucleotide (NAD(+)) for their catalytic activity. According to their homology to Sir2p, a yeast histone deacetylase, the class III is also termed sirtuins. Seven members have been described in humans so far. As sirtuins are involved in many physiological and pathological processes, their activity has been associated with the pathogenesis of cancer, HIV, metabolic, or neurological diseases. Herein, we present an overview over sirtuins including their biology, targets, inhibitors, and activators and their potential as new therapeutic agents.

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“…Nicotinamide (NAM), commonly used as a sirtuin inhibitor, can physiologically inhibit the catalytic activity of sirtuins by binding to a conserved region of the sirtuin catalytic site [45]. Guttiferone G and amurensin G are potent SIRT1 inhibitors and are the most commonly used natural SIRT1 inhibitors [46,47]. High-throughput screening and rational design studies have found a large number of potent sirtuin inhibitors.…”

Section: Essential Characteristics Of Sirt1mentioning

confidence: 99%

SIRT1 and Neural Cell Fate Determination

Cai

et al. 2015

Mol Neurobiol

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During the development of the central nervous system (CNS), neurons and glia are derived from multipotent neural stem cells (NSCs) undergoing self-renewal. NSC commitment and differentiation are tightly controlled by intrinsic and external regulatory mechanisms in space- and time-related fashions. SIRT1, a silent information regulator 2 (Sir2) ortholog, is expressed in several areas of the brain and has been reported to be involved in the self-renewal, multipotency, and fate determination of NSCs. Recent studies have highlighted the role of the deacetylase activity of SIRT1 in the determination of the final fate of NSCs. This review summarizes the roles of SIRT1 in the expansion and differentiation of NSCs, specification of neuronal subtypes and glial cells, and reprogramming of functional neurons from embryonic stem cells and fibroblasts. This review also discusses potential signaling pathways through which SIRT1 can exhibit versatile functions in NSCs to regulate the cell fate decisions of neurons and glia.

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Phloroglucinol Derivatives Guttiferone G, Aristoforin, and Hyperforin: Inhibitors of Human Sirtuins SIRT1 and SIRT2

Cited by 95 publications

References 36 publications

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

NAD⁺-dependent histone deacetylases (sirtuins) as novel therapeutic targets

SIRT1 and Neural Cell Fate Determination

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Phloroglucinol Derivatives Guttiferone G, Aristoforin, and Hyperforin: Inhibitors of Human Sirtuins SIRT1 and SIRT2

Cited by 95 publications

References 36 publications

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

Hyperforin induces apoptosis of chronic lymphocytic leukemia cells through upregulation of the BH3-only protein Noxa

NAD+-dependent histone deacetylases (sirtuins) as novel therapeutic targets

SIRT1 and Neural Cell Fate Determination

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NAD⁺-dependent histone deacetylases (sirtuins) as novel therapeutic targets