Known pharmacological agents that target these substrates and enzymes to increase NAD+ levels are marked on the figure in black, or indicated with gray arrows. Figure 5.2. These mice are highly resistant to weight gain in response to a HFD relative to controls.
STACs are allosteric modulators of SIRT1 that bind to a site on the protein other than the active site to induce a conformational change that increases the activity of the enzyme. Also, mice lacking the NAD+-consuming enzyme CD38 have increased cellular NAD+ and SIRT1 activity in several metabolically active tissues (Barbosa et al., 2007). Based on the earlier studies of sirtuin 1 and its activation by resveratrol, a number of small molecule SIRT1 activators have been synthesized and are currently being tested.63 Sirtuin-activating compounds (STACs) exert their effect by allosteric activation of this deacetylase. Interestingly, U937 and MOLT-4 leukemia cell lines are the most sensitive to resveratrol, and treatment is associated with increased BAX expression [253]. In a murine BMT model, genetic and pharmacologic Sirt1 inhibition attenuated GVHD while preserving the graft-versus-leukemia effect [270]. Michael S. Goligorsky, in Kidney Transplantation, Bioengineering and Regeneration, 2017, The more traditional therapeutics acting on EPCs and endothelial cells belong to categories of ACE inhibitors, aldosterone inhibitors and statins, as has been exhaustively described in the past.46.
Treatment of lymphoma cell lines and a lymphoma cell line xenograft in mice with cambinol (a SIRT1 inhibitor) causes apoptosis [53]. An increase in the cellular NAD+/NADH ratio will increase sirtuin activity. We use cookies to help provide and enhance our service and tailor content and ads. Concordantly, Parp knockout mice show increased SIRT1 activity, mitochondrial metabolism, and biomass [269]. Epigenetic modifications, unlike genetic changes, are usually reversible. SRT2104 has shown benefit in psoriasis [261] and metabolic syndrome [262]. Furthermore, a significant inhibition of growth and induction of apoptosis were demonstrated in malignant lymphoid cell lines when these compounds were used in adjunct with panobinostat [275].
Increased epigenetic alterations of histone deacetylase-3 (HDAC3) are one of the main epigenetic signatures found in patients with T2D and concomitant proinflammation, poor glycemic control, and insulin resistance. (D) Crystal structure of Sirt6 in complex with UBCS039 (cyan) and the product fragment ADP-ribose (yellow; PDB entry 5MF6).
Although no difference in body weight, caloric intake or physical activity was observed, SRT2104-supplemented mice exhibit a lower percentage of fat mass, decreased fasting blood glucose and insulin levels, and increased skeletal muscle endurance. Sirtuin-activating compounds (STACs) including plant-derived metabolites and the well-known resveratrol, represent the first and most potent sirtuin activator and have been shown to extend life span in various organisms (Hubbard and Sinclair, 2014; Pearson et al., 2008). RSV supplementation shifts the gene expression pattern observed in mice on a HFD toward a profile associated with a standard diet. Activator development for the other isoforms, which lack Sirt1s SBD, has lagged behind, but promising compounds are now emerging. Epigenetic drugs or nucleoside-like compounds such as DNA methylation inhibitors, e.g., histone acetyltransferases (HATs) and histone deacetylases (HDACs), have been evaluated and approved for the treatment of certain cancers [96].
Spermidine supplementation confers lifespan extension in both invertebrate model organisms and mice [98]. Copyright 2022 Elsevier B.V. or its licensors or contributors. As this chapter has discussed, many sirtuins have been shown to promote chemotherapy resistance. These compounds include biguanides such as metformin, which targets the AMPK and insulin signaling pathways; resveratrol, which partially affects sirtuin activity; and rapamycin, which interacts with mTOR signaling. In mice, RSV treatment stimulates mitochondrial function, activates AMPK and increases NAD+ levels. Application of an mTOR inhibitor, rapamycin, has been shown to act as a rejuvenating therapy, even when applied late in life.66, Our previous studies have implicated a selenorganic peroxynitrite scavenger, ebselen, in in vitro and in vivo rejuvenation of EPC39 and have been reviewed elsewhere.12,67, Sbastien Moniot, Clemens Steegborn, in Introductory Review on Sirtuins in Biology, Aging, and Disease, 2018, Sirtuins show beneficial effects on lifespan and healthspan. Microarray analysis revealed that SRT2104 likely has anti-inflammatory properties in skeletal muscle tissue, evidenced by a decrease in expression of NF-B target genes. Additionally, treatment with SRT1720 synergizes with an inhibitor of the K3K79 methyltransferase, DOT1L, in mixed lineage leukemia (MLL)-rearranged leukemia cells [258]. A first meta-analysis of six studies regarding resveratrol supplementation showed statistically significant positive effects on systolic BP, hemoglobin A1c, creatinine, but not on fasting glucose, homeostatic model assessment of insulin resistance, diastolic BP, or lipid profiles [90]. (A) STACs resveratrol and SRT1720; (B) NAD+ precursors nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN); (C) Potential nicotinamide phosphoribosyltransferase (NAMPT) activator P7C3 and CD38 inhibitor apigenin. It will also be critical to assess how PARP inhibitors affect the activity of the other sirtuins.
Next, the coadministration of a HDAC inhibitor with a sirtuin inhibitor results in synergy of their cytotoxicity in primary AML and CLL samples and the following cell lines: U937 (AML), 697 (pre-B-cell leukemia), and Jurkat (acute T-cell leukemia). A number of clinical trials involving resveratrol showed benefits in glucose metabolism and cardiovascular disease risk factors [263,264], but many others have shown little to no benefits [265]. Despite substantial recent progress (reviewed in Hubbard and Sinclair, 2014), many key questions remain in this area. Evidence suggests that the inhibition of HDAC3 protects -cells from cytokine-induced apoptosis, improves insulin production and insulin sensitivity, and reduces the expression of proinflammatory cytokines such as IL-1b [104]. 6.2). In addition, resveratrol delays the onset of neurodegeneration and improves learning and memory in aged mice (Graff et al., 2013; Zhao et al., 2013). Allosteric modulators bind to a site on a protein other than the substrate binding site and induce a conformational change that increases the binding affinity of the protein for the target substrate(s). In preclinical animal studies, both STACs and NBMs have shown effects on cardioprotection, neuroprotection, metabolic improvements, the delay of age-related diseases, and increases in life span. Figure 6.1. PARP inhibitors increase NAD+ levels, which in theory could activate sirtuins. An emerging branch of rejuvenation pharmacology seeks to interfere with one of three major pathways of cell aging: sirtuins, target of rapamycin (mTOR), and insulin-like growth factor, all involved in EPC senescence and dysfunction. An interesting question is how much of the carcinogenic effect of these exposures is conferred by the theoretical reduced sirtuin activity. Resveratrol also shows benefit in improving insulin sensitivity in nonhuman primates [259]. However, RSV treatment does not extend longevity in mice fed a standard diet (Miller et al., 2011; Pearson et al., 2008). Consistent with the observed binding mode, the compounds activate Sirt6 only against acetylated substrate and instead show competition against substrate carrying the longer myristoyl modification that requires these Sirt6 regions for binding, indicating the exciting possibility to develop acyl-specific Sirt6 modulators. The sirtuin inhibitors tenovin-1 and tenovin-6 show activity in models of a number of hematologic malignancies, including ALL [37], DLBCL [257], and cutaneous T cell lymphoma [45]. Phenotypes resulting from increased NAD+ levels must be rigorously elucidated in model organisms before use of these non-allosteric approaches can be attempted in humans.
NAD+ is also salvaged from precursors by the conversion of nicotinamide (NAM) to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT). RSV is a potent SIRT1 agonist with implicated antitumor capability. It will be interesting to see how these affect sirtuin signaling in hematologic malignancies.
Despite the apparent beneficial effects of RSV and other STACs in multiple systems, in human patients with nonalcoholic fatty liver disease, RSV treatment appeared to exert toxic effects on hepatocytes, and did not ameliorate liver steatosis or insulin resistance (Chachay et al., 2014). Drug design approaches and high-throughput screening have since identified thousands of both naturally occurring and synthesized STACs.4 STACs of a variety of chemotypes, including oxazolo[4,5-b]pyridine, thiazolopyridine, and bridged urea have been developed with improved activation potency, physiochemical properties, and therapeutic potential.5,6 Another unrelated class of 1,4-dihydropyridine-based compounds bearing a benzyl group at the N1 position are reported to activate SIRT1, SIRT2, and SIRT3.7 Molecules such as SRT1720 and SRT2104 (from the third generation) have improved bioavailability and up to 1000 times the potency of resveratrol, and have been extensively tested in animals8,9 (Fig. Crystal structures of Sirt6/activator complexes revealed that the pyrrolo[1,2-a]quinoxalines bind to the acyl channel exit (Fig. A second class of sirtuin activators are the NBMs. In the context of CD38-deficient mice, protection against weight gain was lost when animals were treated with a sirtuin inhibitor, implicating sirtuin activation in this effect.
NAD+ is a cofactor for activation of several sirtuins. Thus further evaluation of STACs activity in a cancer-specific manner is required. HDACs also play a major role in pancreatic beta cell differentiation, preservation, and proliferation, as well as improving insulin resistance and inhibiting adipogenesis [102]. This study also reported that RSV treatment induces autophagy through SIRT1/S6K pathways and inhibits the incidence of precursor lesions of prostate cancer through the Akt/mTOR signaling pathway [277]. However, SRT1720 has also been reported to promote breast cancer metastasis [274], suggesting that the effects of STACs may function in the opposite manner. In response to moderate RSV doses, SIRT1 activates AMPK in the skeletal muscle, which results in an increase in NAD+ levels through an unknown mechanism to generate a positive feedback loop to maintain mitochondrial function in energetically active tissues. Three generations of STACs include, in addition to resveratrol, quercetin and butein (first generation), SRT 1720, 1460, and 2183 (second generation), and STAC-5, -9, and -10 (third generation), all extending lifespan and/or health-span in preclinical settings. A sustained activation of SIRT6 as a result of UBCS039 treatment also resulted in autophagy-related cell death [287]. CD38, as discussed above, is the major human NADase that increases with age, resulting in decreased NAD+ levels [252].
However, clinical trials to date have been less promising than the preclinical studies. A considerable amount of data has accumulated on treating humans with potential STACs with inconclusive results [9093]. (C) Crystal structure of Sirt1 in complex with FdL peptide (beige) and three resveratrol molecules (cyan) around its fluorophore (PDB entry 4BTR). Activation of Sirt6-dependent deacetylation can be achieved with fatty acids, and competition experiments implicated the enzymes long acyl-binding channel as a binding site.35 This activating effect required several hundred M fatty acid concentrations, however, and only more recently, pyrrolo[1,2-a]quinoxaline-derived compounds were discovered as first potent Sirt6 activators.36 These compounds increase Sirt6-dependent deacetylation of peptide substrates, histone proteins, and complete nucleosomes. The use of CR mimetics would be much easier to incorporate into clinical practice than lifelong CR [4]. Synthetic activators such as SRT1720 and SRT2104 improve the metabolic profile and extend life span and health span of mice under a high-fat and normal diet (Mitchell et al., 2014; Minor et al., 2011). Acetyl peptide (beige) and NAD+ (yellow) were modeled to indicate their binding sites. Pharmacological mechanisms of sirtuin modulation. This suggests a potential therapeutic strategy in treating leukemia with a combination of sirtuin and HDAC inhibitors [52]. As mentioned previously, it will first be critical to reconcile the oncogenic and tumor-suppressive roles of sirtuins in hematologic malignancies, but it is tempting to speculate that certain sirtuin activators could potentially prevent the development of hematologic malignancies. Means of sirtuin activation. Wang and colleagues have previously shown that in vivo SIRT1+/; p53+/ mice xenograft models with different malignancy types (i.e. Resveratrol (RSV) is a natural polyphenol compound containing two phenyl rings separated by a methylene bridge. Similarly, primary leukemia cells, leukemia cell lines, healthy leukocytes, and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, and EX527) in combination with HDAC inhibitors (valproic acid, sodium butyrate, and vorinostat). SIRT1 activators and inhibitors have been through the first clinical trials with evidence of safety and some efficacy. To date, several epigenetic modifiers are in the market or currently under clinical trial, including HDAC inhibitors (HDACi), HAT inhibitors (HATi), protein arginine methyltransferase inhibitors (PRMTis), DNA methyltransferase inhibitors (DNMTis), histone demethylating inhibitors (HDMis), and sirtuin-activating compounds (STACs) [97]. Thus, human clinical studies using NAD+ precursors are currently ongoing. Sirt3 knockout donor T cells cause reduced GVHD severity [271].
This study also reported that SRT1460 and SRT3025 were effective in inhibiting the growth and survival of pancreatic cancer. Figure 6.2. Moreover, such studies might suggest ways to modulate sirtuin signaling to enhance treatment efficacy. SIRT1 deficiency induced an abnormal accumulation of cells in the early phases of mitosis-impaired DNA damage repair, and chromosome instability which could subsequently cause cancer [60]. In addition, calorie restriction diet, which possibly induces SIRT1, acts via mTOR signaling and nicotine amide dinucleotide (NAD)-dependent pathways,64 both representing novel venues of rejuvenation therapy. Therefore, they represent an important target for therapeutic intervention. Common NAD+-boosting molecules (NBMs) and sirtuin-activating compounds (STACs). Among them, resveratrol, the most popular and evaluated STAC, exhibited mixed efficiency including anti-oxidant, anti-inflammatory, and anti-tumor properties [94]. Ryan A. Denu, in Sirtuin Biology in Cancer and Metabolic Disease, 2021. Besides, RSV has been shown to alleviate EMT processes in lung and ovarian cancer in vitro and in vivo [279,280]. SRT2104 protects against experimentally induced muscle atrophy in wild-type mice, and muscle-specific Sirt1 knockdown in vivo accelerates muscle loss. Based on earlier studies of sirtuin 1 activation by resveratrol, a number of small-molecule SIRT1 activators have been synthesized and are being currently tested.87 Sirtuin-activating compounds (STACs) exert their effect by allosteric activation of this deacetylase. There are two different types of STACs: natural and synthetic. 5.2A).32,33 The flexibility of the linker between SBD and catalytic core and of a salt bridge between Glu230 and Arg446 that can form in this closed Sirt1 conformation were indeed essential for Sirt1 activation also with regular substrates.30 Thus, resveratrol and synthetic STACs are assumed to activate Sirt1 against artificial as well as natural substrates through binding to the SBD and formation of the closed conformation, resulting in direct activator/substrate contacts that increase substrate affinity and rationalize the relevance of the substrate sequence for activation (see above). Although resveratrol and these compounds represent several differing chemotypes, biochemical and structural studies suggest that they all employ a common activation mechanism.29,30 Sirt1/STAC complex structures revealed a Sirt1-specific STAC binding domain (SBD) N-terminal from the catalytic core, which provides a rather hydrophobic and flat depression as a STAC docking site, leaving the second activator surface solvent accessible (Fig. Interestingly, the resveratrol effect on Sirt5 also depends on the acyl modification, since resveratrol activated Sirt5-dependent FdL deacetylation but inhibited Sirt5-dependent FdL desuccinylation.32.
SIRT1 STACs, SRT2183, and SRT501 have demonstrated significant inhibition of growth and induction of apoptosis in malignant lymphoid cell lines. For example, Sirt1 activity protects against the negative effects of a high-fat diet, and Sirt6 extends the lifespan in male mice and suppresses aging phenotypes and cancer growth.26 Sirtuin-activating small molecules are thus considered attractive therapeutics for metabolic disorders and aging-related diseases.1,26, Sirtuin-activating compounds (STACs) were initially described for Sirt1. Furthermore, another study also reported an enhanced effect when SRT1720 was used in combination with dexamethasone or bortezomib [269,283]. A variety of stilbene derivatives with modifications at the 4 position of the B ring of resveratrol were synthesized that have lower toxicity and higher potency with respect to SIRT1 activation and lifespan extension in budding yeast, showing for the first time that it is possible to improve upon naturally occurring STACs.3. The activation of SIRT6 by MDL-800 inhibits cell proliferation and induces cell cycle arrest in HCC. Resveratrol and newly developed analogues should have a place in the prevention of endothelial cell senescence and the restoration of metabolic abnormalities. 6.1). SRT1720 has been shown to reduce cancer cell viability and sensitize cancer cells to chemotherapy drugs. Synthetic STACS have also been demonstrated to exert beneficial cardiovascular effects on healthy cigarettes smokers (Venkatasubramanian et al., 2013). In this study, antioxidants such as NAC or Trolox were reported to completely counteract UBCS039-induced autophagy, indicating that increased ROS had a key role in upstream events that commit the cells to autophagy.
Furthermore, resveratrol provides positive effects for systolic blood pressure, hemoglobin A1c, and creatinine in patients affected by type 2 diabetes (Hausenblas et al., 2015). Nicotinamide riboside (NR) is converted to NMN by nicotinamide riboside kinase (NMRK), and nicotinic acid (NA) to nicotinic acid mononucleotide (NaMN) by nicotinic acid phosphoribosyltransferase (NAPRT).
1,4-Dihydropyridine (DHP)-based compounds, e.g., which can activate Sirt1 against regular substrates, showed activating effects on Sirt2 and Sirt3 in the FdL assay, but such effects remain to be confirmed with physiological substrates.34 The isoform besides Sirt1 for which potent activation against physiological substrates is well established is Sirt6. SRT1720 induced apoptosis through caspase 8/9/3 activation and ATM-CHK2 signaling pathways which will subsequently inhibit the NF-B signaling pathway, which otherwise maintains cell growth and survival [283]. NAD+ bioavailability is reduced in disease states and aging.65 A precursor of NAD+, nicotinamide, is paving ways as a therapy to correct NAD+ deficiency. Among various candidates for CR mimetics, sirtuin-activating compounds (STACs) and spermidine may confer cardiovascular protection through epigenomic modification in humans, at least in part. Interestingly, daratumumab, an anti-CD38 antibody, is FDA-approved for the treatment of multiple myeloma. Although it is clear that resveratrol can activate Sirt1 invitro, bioavailability of resveratrol invivo remains unresolved [94]. These compounds are presently undergoing clinical trials. SRT1720 induced apoptosis in multiple cancer cells including breast and myeloma [283,284] through the increase in SIRT1 deacetylase activity. This section will summarize preclinical and clinical studies of sirtuin modulators and discuss some of the most impactful future avenues of investigation. Jana Nano, Taulant Muka, in Epigenetics in Human Disease (Second Edition), 2018. Inhibition of NAD+-consuming enzymes, PARPs or CD38, also enlarges the cellular NAD+ pool. . The first and most well-known is resveratrol, a compound naturally found in grapes. However, this combination could have significant toxicity, as it would presumably prevent healthy cells from responding to damage and stresses induced by chemotherapy. 5.2B).30 However, in the presence of FdL substrate, resveratrol was found to interact with the SBD but to rotate with this domain on top of the active site (Fig.
This shift occurs in parallel with improved overall health, insulin sensitivity, increased mitochondrial content, and maintenance of motor function (Barger et al., 2008a,b; Pearson et al., 2008). To date, several epigenetic modifiers are in the market or currently under clinical trial, including HDAC inhibitors (HDACi), HAT inhibitors (HATi), protein arginine methyltransferase inhibitors (PRMTis), DNA methyltransferase inhibitors (DNMTis), histone demethylating inhibitors (HDMis), and. NaMN is converted to nicotinic acid adenine dinucleotide (NAAD) by NMNATs, and then NAAD to NAD+ by NAD-synthase. Reduced NAD+ levels induced by advanced age, caloric excess, or a sedentary lifestyle would impair activity of sirtuins and other NAD+-dependent cellular processes. These compounds are undergoing clinical trials. These synthetic STACs are potent SIRT1 activators with 800- to 1000-fold efficacy compared to RSV [259,267]. These questions are worth pursuing in phase 1 clinical trials. Clinical trials aimed at increasing the intake of this polyamine seems feasible for the purpose of suppressing cardiovascular aging in humans.
Another recent SIRT6 activator that has been discovered is MDL-800 [288].
Firstly regarding activators, the study of resveratrol sensitivity of cancer cell lines found a marked degree of variability based on cell type. For example, which RSV effects occur through SIRT1, and which are due to effects on other targets? NAD+ levels can be increased by providing NAD+ precursors via activation of NAD biosynthetic enzymes, or via inhibition of NAD hydrolase CD38. There is also evidence of SIRT3 involvement in preventing GVHD. Pharmacological sirtuin activation. These STACs activate SIRTs allosterically [235]. Yeuan Ting Lee, Chern Ein Oon, in Sirtuin Biology in Cancer and Metabolic Disease, 2021.