Publications by authors named "Andrei V Gudkov"

136 Publications

Alkaloid-rich fraction of Ervatamia coronaria sensitizes colorectal cancer through modulating AMPK and mTOR signalling pathways.

J Ethnopharmacol 2021 Sep 27:114666. Epub 2021 Sep 27.

Division of Molecular Medicine, Bose Institute, Kolkata, India. Electronic address:

Ethnopharmacological Relevance: Ervatamia coronaria, a popular garden plant in India and some other parts of the world is known traditionally for its anti-inflammatory and anti-cancer properties. The molecular bases of these functions remain poorly understood.

Aim Of The Study: Efficacies of the existing therapies for colorectal cancer (CRC) are limited by their life-threatening side effects and unaffordability. Therefore, identifying a safer, efficient, and affordable therapeutic is urgent. We studied the anti-CRC activity of an alkaloid-rich fraction of E. coronaria leaf extracts (AFE) and associated underlying mechanism.

Materials And Methods: Activity guided solvant fractionation was adopted to identify the activity in AFE. Different cell lines, and tumor grown in syngeneic mice were used to understand the anti-CRC effect. Methodologies such as LCMS, MTT, RT-qPCR, immunoblot, immunohistochemistry were employed to understand the molecular basis of its activity.

Results: We showed that AFE, which carries about six major compounds, is highly toxic to colorectal cancer (CRC) cells. AFE induced cell cycle arrest at G1 phase and p21 and p27 genes, while those of CDK2, CDK-4, cyclin-D, and cyclin-E genes were downregulated in HCT116 cells. It predominantly induced apoptosis in HCT116p53+/+ cells while the HCT116p53-/- cells under the same treatment condition died by autophagy. Notably, AFE induced upregulation of AMPK phosphorylation, and inhibition of both of the mTOR complexes as indicated by inhibition of phosphorylation of S6K1, 4EBP1, and AKT. Furthermore, AFE inhibited mTOR-driven conversion of cells from reversible cell cycle arrest to senescence (geroconversion) as well as ERK activity. AFE activity was independent of ROS produced, and did not primarily target the cellular DNA or cytoskeleton. AFE also efficiently regressed CT26-derived solid tumor in Balb/c mice acting alone or in synergy with 5FU through inducing autophagy as a major mechanism of action as indicated by upregulation of Beclin 1 and phospho-AMPK, and inhibition of phosphor-S6K1 levels in the tumor tissue lysates.

Conclusion: AFE induced CRC death through activation of both apoptotic and autophagy pathways without affecting the normal cells. This study provided a logical basis for consideration of AFE in future therapy regimen to overcome the limitations associated with existing anti-CRC chemotherapy.
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http://dx.doi.org/10.1016/j.jep.2021.114666DOI Listing
September 2021

Development of infrastructure for a systemic multidisciplinary approach to study aging in retired sled dogs.

Aging (Albany NY) 2021 Sep 28;13(18):21814-21837. Epub 2021 Sep 28.

Vaika, Inc., East Aurora, NY 14052, USA.

Canines represent a valuable model for mammalian aging studies as large animals with short lifespans, allowing longitudinal analyses within a reasonable time frame. Moreover, they develop a spectrum of aging-related diseases resembling that of humans, are exposed to similar environments, and have been reasonably well studied in terms of physiology and genetics. To overcome substantial variables that complicate studies of privately-owned household dogs, we have focused on a more uniform population composed of retired Alaskan sled dogs that shared similar lifestyles, including exposure to natural stresses, and are less prone to breed-specific biases than a pure breed population. To reduce variability even further, we have collected a population of 103 retired (8-11 years-old) sled dogs from multiple North American kennels in a specialized research facility named Vaika. Vaika dogs are maintained under standardized conditions with professional veterinary care and participate in a multidisciplinary program to assess the longitudinal dynamics of aging. The established Vaika infrastructure enables periodic gathering of quantitative data reflecting physical, physiological, immunological, neurological, and cognitive decline, as well as monitoring of aging-associated genetic and epigenetic alterations occurring in somatic cells. In addition, we assess the development of age-related diseases such as arthritis and cancer. In-depth data analysis, including artificial intelligence-based approaches, will build a comprehensive, integrated model of canine aging and potentially identify aging biomarkers that will allow use of this model for future testing of antiaging therapies.
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http://dx.doi.org/10.18632/aging.203600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507265PMC
September 2021

Signaling through TLR5 mitigates lethal radiation damage by neutrophil-dependent release of MMP-9.

Cell Death Discov 2021 Sep 28;7(1):266. Epub 2021 Sep 28.

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.

Acute radiation syndrome (ARS) is a major cause of lethality following radiation disasters. A TLR5 agonist, entolimod, is among the most powerful experimental radiation countermeasures and shows efficacy in rodents and non-human primates as a prophylactic (radioprotection) and treatment (radiomitigation) modality. While the prophylactic activity of entolimod has been connected to the suppression of radiation-induced apoptosis, the mechanism by which entolimod functions as a radiomitigator remains poorly understood. Uncovering this mechanism has significant and broad-reaching implications for the clinical development and improvement of TLR5 agonists for use as an effective radiation countermeasure in scenarios of mass casualty resulting from accidental exposure to ionizing radiation. Here, we demonstrate that in contrast to radioprotection, neutrophils are essential for the radiomitigative activity of entolimod in a mouse model of lethal ARS. Neutrophils express functional TLR5 and rapidly exit the bone marrow (BM), accumulate in solid tissues, and release MMP-9 following TLR5 stimulation which is accompanied by an increase in the number of active hematopoietic pluripotent precursors (HPPs) in the BM. Importantly, recombinant MMP-9 by itself has radiomitigative activity and, in the absence of neutrophils, accelerates the recovery of the hematopoietic system. Unveiling this novel TLR5-neutrophil-MMP-9 axis of radiomitigation opens new opportunities for the development of efficacious radiation countermeasures to treat ARS following accidental radiation disasters.
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http://dx.doi.org/10.1038/s41420-021-00642-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478872PMC
September 2021

Structural dissection of sequence recognition and catalytic mechanism of human LINE-1 endonuclease.

Nucleic Acids Res 2021 Sep 23. Epub 2021 Sep 23.

Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.

Long interspersed nuclear element-1 (L1) is an autonomous non-LTR retrotransposon comprising ∼20% of the human genome. L1 self-propagation causes genomic instability and is strongly associated with aging, cancer and other diseases. The endonuclease domain of L1's ORFp2 protein (L1-EN) initiates de novo L1 integration by nicking the consensus sequence 5'-TTTTT/AA-3'. In contrast, related nucleases including structurally conserved apurinic/apyrimidinic endonuclease 1 (APE1) are non-sequence specific. To investigate mechanisms underlying sequence recognition and catalysis by L1-EN, we solved crystal structures of L1-EN complexed with DNA substrates. This showed that conformational properties of the preferred sequence drive L1-EN's sequence-specificity and catalysis. Unlike APE1, L1-EN does not bend the DNA helix, but rather causes 'compression' near the cleavage site. This provides multiple advantages for L1-EN's role in retrotransposition including facilitating use of the nicked poly-T DNA strand as a primer for reverse transcription. We also observed two alternative conformations of the scissile bond phosphate, which allowed us to model distinct conformations for a nucleophilic attack and a transition state that are likely applicable to the entire family of nucleases. This work adds to our mechanistic understanding of L1-EN and related nucleases and should facilitate development of L1-EN inhibitors as potential anticancer and antiaging therapeutics.
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http://dx.doi.org/10.1093/nar/gkab826DOI Listing
September 2021

Induction of monoamine oxidase A-mediated oxidative stress and impairment of NRF2-antioxidant defence response by polyphenol-rich fraction of Bergenia ligulata sensitizes prostate cancer cells in vitro and in vivo.

Free Radic Biol Med 2021 08 5;172:136-151. Epub 2021 Jun 5.

Division of Molecular Medicine, Bose Institute, Kolkata, India. Electronic address:

Prostate cancer (PCa) is a major cause of mortality and morbidity in men. Available therapies yield limited outcome. We explored anti-PCa activity in a polyphenol-rich fraction of Bergenia ligulata (PFBL), a plant used in Indian traditional and folk medicine for its anti-inflammatory and antineoplastic properties. PFBL constituted of about fifteen different compounds as per LCMS analysis induced apoptotic death in both androgen-dependent LNCaP and androgen-refractory PC3 and DU145 cells with little effect on NKE and WI38 cells. Further investigation revealed that PFBL mediates its function through upregulating ROS production by enhanced catalytic activity of Monoamine oxidase A (MAO-A). Notably, the differential inactivation of NRF2-antioxidant response pathway by PFBL resulted in death in PC3 versus NKE cells involving GSK-3β activity facilitated by AKT inhibition. PFBL efficiently reduced the PC3-tumor xenograft in NOD-SCID mice alone and in synergy with Paclitaxel. Tumor tissues in PFBL-treated mice showed upregulation of similar mechanism of cell death as observed in isolated PC3 cells i.e., elevation of MAO-A catalytic activity, ROS production accompanied by activation of β-TrCP-GSK-3β axis of NRF2 degradation. Blood counts, liver, and splenocyte sensitivity analyses justified the PFBL safety in the healthy mice. To our knowledge this is the first report of an activity that crippled NRF2 activation both in vitro and in vivo in response to MAO-A activation. Results of this study suggest the development of a novel treatment protocol utilizing PFBL to improve therapeutic outcome for patients with aggressive PCa which claims hundreds of thousands of lives each year.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.05.037DOI Listing
August 2021

Resistance of bone marrow stroma to genotoxic preconditioning is determined by p53.

Cell Death Dis 2021 05 26;12(6):545. Epub 2021 May 26.

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.

Transplantation of bone marrow (BM) is made possible by the differential sensitivity of its stromal and hematopoietic components to preconditioning by radiation and/or chemotherapeutic drugs. These genotoxic treatments eliminate host hematopoietic precursors by inducing p53-mediated apoptosis but keep the stromal niche sufficiently intact for the engraftment of donor hematopoietic cells. We found that p53-null mice cannot be rescued by BM transplantation (BMT) from even the lowest lethal dose of total body irradiation (TBI). We compared structural changes in BM stroma of mice differing in their p53 status to understand why donor BM failed to engraft in the irradiated p53-null mice. Irradiation did not affect the general structural integrity of BM stroma and induced massive expression of alpha-smooth muscle actin in mesenchymal cells followed by increased adiposity in p53 wild-type mice. In contrast, none of these events were found in p53-null mice, whose BM stroma underwent global structural damage following TBI. Similar differences in response to radiation were observed in in vitro-grown bone-adherent mesenchymal cells (BAMC): p53-null cells underwent mitotic catastrophe while p53 wild-type cells stayed arrested but viable. Supplementation with intact BAMC of either genotype enabled donor BM engraftment and significantly extended longevity of irradiated p53-null mice. Thus, successful preconditioning depends on the p53-mediated protection of cells critical for the functionality of BM stroma. Overall, this study reveals a dual positive role of p53 in BMT: it drives apoptotic death of hematopoietic cells and protects BM stromal cells essential for its functionality.
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http://dx.doi.org/10.1038/s41419-021-03824-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8154997PMC
May 2021

Longitudinal analysis of blood markers reveals progressive loss of resilience and predicts human lifespan limit.

Nat Commun 2021 05 25;12(1):2765. Epub 2021 May 25.

Gero PTE, Singapore, Singapore.

We investigated the dynamic properties of the organism state fluctuations along individual aging trajectories in a large longitudinal database of CBC measurements from a consumer diagnostics laboratory. To simplify the analysis, we used a log-linear mortality estimate from the CBC variables as a single quantitative measure of the aging process, henceforth referred to as dynamic organism state indicator (DOSI). We observed, that the age-dependent population DOSI distribution broadening could be explained by a progressive loss of physiological resilience measured by the DOSI auto-correlation time. Extrapolation of this trend suggested that DOSI recovery time and variance would simultaneously diverge at a critical point of 120 - 150 years of age corresponding to a complete loss of resilience. The observation was immediately confirmed by the independent analysis of correlation properties of intraday physical activity levels fluctuations collected by wearable devices. We conclude that the criticality resulting in the end of life is an intrinsic biological property of an organism that is independent of stress factors and signifies a fundamental or absolute limit of human lifespan.
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http://dx.doi.org/10.1038/s41467-021-23014-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149842PMC
May 2021

Cell-Based Methods for the Identification of Myc-Inhibitory Small Molecules.

Methods Mol Biol 2021 ;2318:337-346

Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Oncoproteins encoded by dominant oncogenes have long been considered as targets for chemotherapeutic intervention. However, oncogenic transcription factors have often been dismissed as "undruggable." Members of the Myc family of transcription factors have been identified as promising targets for cancer chemotherapy in multiple publications reporting the requirement of Myc proteins for maintenance of almost every type of tumor. Here, we describe cell-based approaches to identify c-Myc small molecule inhibitors by screening complex libraries of diverse small molecules based on Myc functionality and specificity.
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http://dx.doi.org/10.1007/978-1-0716-1476-1_19DOI Listing
August 2021

Dual Targeting of Chromatin Stability By The Curaxin CBL0137 and Histone Deacetylase Inhibitor Panobinostat Shows Significant Preclinical Efficacy in Neuroblastoma.

Clin Cancer Res 2021 Aug 16;27(15):4338-4352. Epub 2021 May 16.

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.

Purpose: We investigated whether targeting chromatin stability through a combination of the curaxin CBL0137 with the histone deacetylase (HDAC) inhibitor, panobinostat, constitutes an effective multimodal treatment for high-risk neuroblastoma.

Experimental Design: The effects of the drug combination on cancer growth were examined and in animal models of -amplified neuroblastoma. The molecular mechanisms of action were analyzed by multiple techniques including whole transcriptome profiling, immune deconvolution analysis, immunofluorescence, flow cytometry, pulsed-field gel electrophoresis, assays to assess cell growth and apoptosis, and a range of cell-based reporter systems to examine histone eviction, heterochromatin transcription, and chromatin compaction.

Results: The combination of CBL0137 and panobinostat enhanced nucleosome destabilization, induced an IFN response, inhibited DNA damage repair, and synergistically suppressed cancer cell growth. Similar synergistic effects were observed when combining CBL0137 with other HDAC inhibitors. The CBL0137/panobinostat combination significantly delayed cancer progression in xenograft models of poor outcome high-risk neuroblastoma. Complete tumor regression was achieved in the transgenic Th-MYCN neuroblastoma model which was accompanied by induction of a type I IFN and immune response. Tumor transplantation experiments further confirmed that the presence of a competent adaptive immune system component allowed the exploitation of the full potential of the drug combination.

Conclusions: The combination of CBL0137 and panobinostat is effective and well-tolerated in preclinical models of aggressive high-risk neuroblastoma, warranting further preclinical and clinical investigation in other pediatric cancers. On the basis of its potential to boost IFN and immune responses in cancer models, the drug combination holds promising potential for addition to immunotherapies.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380471PMC
August 2021

Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG.

Cell Rep 2021 Apr;35(2):108994

Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia; School of Women's and Children's Health, University of New South Wales, Sydney, NSW, Australia; Kid's Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia. Electronic address:

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extends animal survival. The FACT subunit SPT16 is found to directly interact with H3.3K27M, and treatment with CBL0137 restores both histone H3 acetylation and trimethylation. Combined treatment of CBL0137 with the histone deacetylase inhibitor panobinostat leads to inhibition of the Rb/E2F1 pathway and induction of apoptosis. The combination of CBL0137 and panobinostat significantly prolongs the survival of mice bearing DIPG orthografts, suggesting a potential treatment strategy for DIPG.
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http://dx.doi.org/10.1016/j.celrep.2021.108994DOI Listing
April 2021

A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications.

Commun Biol 2021 04 12;4(1):466. Epub 2021 Apr 12.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

The Toll-like receptor 5 (TLR5) agonist entolimod, a derivative of Salmonella flagellin, has therapeutic potential for several indications including radioprotection and cancer immunotherapy. However, in Phase 1 human studies, entolimod induced a rapid neutralizing immune response, presumably due to immune memory from prior exposure to flagellated enterobacteria. To enable multi-dose applications, we used structure-guided reengineering to develop a next-generation, substantially deimmunized entolimod variant, GP532. GP532 induces TLR5-dependent NF-κB activation like entolimod but is smaller and has mutations eliminating an inflammasome-activating domain and key B- and T-cell epitopes. GP532 is resistant to human entolimod-neutralizing antibodies and shows reduced de novo immunogenicity. GP532 also has improved bioavailability, a stronger effect on key cytokine biomarkers, and a longer-lasting effect on NF-κB. Like entolimod, GP532 demonstrated potent prophylactic and therapeutic efficacy in mouse models of radiation-induced death and tissue damage. These results establish GP532 as an optimized TLR5 agonist suitable for multi-dose therapies and for patients with high titers of preexisting flagellin-neutralizing antibodies.
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http://dx.doi.org/10.1038/s42003-021-01978-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041767PMC
April 2021

Stimulation of an anti-tumor immune response with "chromatin-damaging" therapy.

Cancer Immunol Immunother 2021 Jul 13;70(7):2073-2086. Epub 2021 Jan 13.

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Sts, Buffalo, NY, 14263, USA.

Curaxins are small molecules that bind genomic DNA and interfere with DNA-histone interactions leading to the loss of histones and decondensation of chromatin. We named this phenomenon 'chromatin damage'. Curaxins demonstrated anti-cancer activity in multiple pre-clinical tumor models. Here, we present data which reveals, for the first time, a role for the immune system in the anti-cancer effects of curaxins. Using the lead curaxin, CBL0137, we observed elevated expression of several group of genes in CBL0137-treated tumor cells including interferon sensitive genes, MHC molecules, some embryo-specific antigens suggesting that CBL0137 increases tumor cell immunogenicity and improves recognition of tumor cells by the immune system. In support of this, we found that the anti-tumor activity of CBL0137 was reduced in immune deficient SCID mice when compared to immune competent mice. Anti-tumor activity of CBL0137 was abrogated in CD8 T cell depleted mice but only partially lost when natural killer or CD4 T cells were depleted. Further support for a key role for the immune system in the anti-tumor activity of CBL0137 is evidenced by an increased antigen-specific effector CD8 T cell and NK cell response, and an increased ratio of effector T cells to Tregs in the tumor and spleen. CBL0137 also elevated the number of CXCR3-expressing CTLs in the tumor and the level of interferon-γ-inducible protein 10 (IP-10) in serum, suggesting IP-10/CXCR3 controls CBL0137-elicited recruitment of effector CTLs to tumors. Our collective data underscores a previously unrecognized role for both innate and adaptive immunity in the anti-tumor activity of curaxins.
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http://dx.doi.org/10.1007/s00262-020-02846-8DOI Listing
July 2021

Immune checkpoint protein VSIG4 as a biomarker of aging in murine adipose tissue.

Aging Cell 2020 10 28;19(10):e13219. Epub 2020 Aug 28.

Everon Biosciences Inc, Buffalo, NY, USA.

Adipose tissue is recognized as a major source of systemic inflammation with age, driving age-related tissue dysfunction and pathogenesis. Macrophages (Mφ) are central to these changes yet adipose tissue Mφ (ATMs) from aged mice remain poorly characterized. To identify biomarkers underlying changes in aged adipose tissue, we performed an unbiased RNA-seq analysis of ATMs from young (8-week-old) and healthy aged (80-week-old) mice. One of the genes identified, V-set immunoglobulin-domain-containing 4 (VSIG4/CRIg), encodes a Mφ-associated complement receptor and B7 family-related immune checkpoint protein. Here, we demonstrate that Vsig4 expression is highly upregulated with age in perigonadal white adipose tissue (gWAT) in two mouse strains (inbred C57BL/6J and outbred NIH Swiss) independent of gender. The accumulation of VSIG4 was mainly attributed to a fourfold increase in the proportion of VSIG4 ATMs (13%-52%). In a longitudinal study, VSIG4 expression in gWAT showed a strong correlation with age within a cohort of male and female mice and correlated strongly with physiological frailty index (PFI, a multi-parameter assessment of health) in male mice. Our results indicate that VSIG4 is a novel biomarker of aged murine ATMs. VSIG4 expression was also found to be elevated in other aging tissues (e.g., thymus) and was strongly induced in tumor-adjacent stroma in cases of spontaneous and xenograft lung cancer models. VSIG4 expression was recently associated with cancer and several inflammatory diseases with diagnostic and prognostic potential in both mice and humans. Further investigation is required to determine whether VSIG4-positive Mφ contribute to immunosenescence and/or systemic age-related deficits.
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http://dx.doi.org/10.1111/acel.13219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576241PMC
October 2020

Superior cancer preventive efficacy of low versus high dose of mTOR inhibitor in a mouse model of prostate cancer.

Oncotarget 2020 Apr 14;11(15):1373-1387. Epub 2020 Apr 14.

Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

The mechanistic target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation and survival in response to the availability of energy sources and growth factors. Cancer development and progression is often associated with constitutive activation of the mTOR pathway, thus justifying mTOR inhibition as a promising approach to cancer treatment and prevention. However, development of previous rapamycin analogues has been complicated by their induction of adverse side effects and variable efficacy. Since mTOR pathway regulation involves multiple feedback mechanisms that may be differentially activated depending on the degree of mTOR inhibition, we investigated whether rapamycin dosing could be adjusted to achieve chemopreventive efficacy without side effects. Thus, we tested the efficacy of two doses of a novel, highly bioavailable nanoformulation of rapamycin, Rapatar, in a mouse prostate cancer model (male mice with prostate epithelium-specific -knockout). We found that the highest efficacy was achieved by the lowest dose of Rapatar used in the study. While both doses tested were equally effective in suppressing proliferation of prostate epithelial cells, higher dose resulted in activation of feedback circuits that reduced the drug's tumor preventive efficacy. These results demonstrate that low doses of highly bioavailable mTOR inhibitor, Rapatar, may provide safe and effective cancer prevention.
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http://dx.doi.org/10.18632/oncotarget.27550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170500PMC
April 2020

First-in-human study of anticancer immunotherapy drug candidate mobilan: safety, pharmacokinetics and pharmacodynamics in prostate cancer patients.

Oncotarget 2020 Apr 7;11(14):1273-1288. Epub 2020 Apr 7.

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Toll-like receptor 5 (TLR5) controls endogenous immune responses to pathogens and is a promising target for pharmacological stimulation of anti-tumor immunity. Mobilan is an innovative gene therapy agent consisting of a non-replicating bicistronic adenovirus directing constitutive expression of human Toll-like receptor 5 (TLR5) and the secreted flagellin-based TLR5 agonist, 502s. In mice, Mobilan injection into prostate tumors resulted in autocrine TLR5 signaling, immune system activation, and suppression of tumor growth and metastasis. Here we report a first-in-human placebo-controlled clinical study of Mobilan aimed at evaluating safety, tolerability, pharmacokinetics and pharmacodynamics of a single intra-prostate injection of Mobilan in early stage prostate cancer patients. Mobilan was safe and well-tolerated at all tested doses; thus, the maximum tolerated dose was not identified. Injection of Mobilan induced signs of self-resolving inflammation not present in placebo-injected patients, including transient elevation of PSA and cytokine (G-CSF, IL-6) levels, and increased lymphoid infiltration in prostate tissue. The highest dose of Mobilan (10 viral particles) produced the best combination of safety and pharmacodynamic effects. Therefore, Mobilan is well-tolerated and induces the expected pharmacodynamic response in humans. These results support further clinical development of Mobilan as a novel immunotherapy for prostate cancer.
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http://dx.doi.org/10.18632/oncotarget.27549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147088PMC
April 2020

TLR5 agonist entolimod reduces the adverse toxicity of TNF while preserving its antitumor effects.

PLoS One 2020 6;15(2):e0227940. Epub 2020 Feb 6.

Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, United States America.

Tumor necrosis factor alpha (TNF) is capable of inducing regression of solid tumors. However, TNF released in response to Toll-like receptor 4 (TLR4) activation by bacterial lipopolysaccharide (LPS) is the key mediator of cytokine storm and septic shock that can cause severe tissue damage limiting anticancer applications of this cytokine. In our previous studies, we demonstrated that activation of another Toll-like receptor, TLR5, could protect from tissue damage caused by a variety of stresses including radiation, chemotherapy, Fas-activating antibody and ischemia-reperfusion. In this study, we tested whether entolimod could counteract TNF-induced toxicity in mouse models. We found that entolimod pretreatment effectively protects livers and lungs from LPS- and TNF-induced toxicity and prevents mortality caused by combining either of these agents with the sensitizer, D-galactosamine. While LPS and TNF induced significant activation of apoptotic caspase 3/7, lipid tissue peroxidation and serum ALT accumulation in mice without entolimod treatment, these indicators of toxicity were reduced by entolimod pretreatment to the levels of untreated control mice. Entolimod was effective when injected 0.5-48 hours prior to, but not when injected simultaneously or after LPS or TNF. Using chimeric mice with hematopoiesis differing in its TLR5 status from the rest of tissues, we showed that this protective activity was dependent on TLR5 expression by non-hematopoietic cells. Gene expression analysis identified multiple genes upregulated by entolimod in the liver and cultured hepatocytes as possible mediators of its protective activity. Entolimod did not interfere with the antitumor activity of TNF in mouse hepatocellular and colorectal tumor models. These results support further development of TLR5 agonists to increase tissue resistance to cytotoxic cytokines, reduce the risk of septic shock and enable safe systemic application of TNF as an anticancer therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227940PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004342PMC
April 2020

OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis.

Leukemia 2020 07 2;34(7):1828-1839. Epub 2020 Jan 2.

Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Effective treatment of some types of cancer can be achieved by modulating cell lineage-specific rather than tumor-specific targets. We conducted a systematic search for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings followed by hit-to-lead optimization identified OT-82, a small molecule with strong efficacy against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt's lymphoma in vitro and in mouse xenograft models. OT-82 was also more toxic towards patients-derived leukemic cells versus healthy bone marrow-derived hematopoietic precursors. OT-82 was shown to induce cell death by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD synthesis. In mice, optimization of OT-82 dosing and dietary niacin further expanded the compound's therapeutic index. In toxicological studies conducted in mice and nonhuman primates, OT-82 showed no cardiac, neurological or retinal toxicities observed with other NAMPT inhibitors and had no effect on mouse aging or longevity. Hematopoietic and lymphoid organs were identified as the primary targets for dose limiting toxicity of OT-82 in both species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 as a promising candidate for the treatment of hematological malignancies.
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http://dx.doi.org/10.1038/s41375-019-0692-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326709PMC
July 2020

Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia.

Leukemia 2020 06 17;34(6):1524-1539. Epub 2019 Dec 17.

Children's Cancer Institute, Lowy Cancer Research Centre, UNSW, Sydney, NSW, Australia.

The prognosis for children diagnosed with high-risk acute lymphoblastic leukemia (ALL) remains suboptimal, and more potent and less toxic treatments are urgently needed. We investigated the efficacy of a novel nicotinamide phosphoribosyltransferase inhibitor, OT-82, against a panel of patient-derived xenografts (PDXs) established from high-risk and poor outcome pediatric ALL cases. OT-82 was well-tolerated and demonstrated impressive single agent in vivo efficacy, achieving significant leukemia growth delay in 95% (20/21) and disease regression in 86% (18/21) of PDXs. In addition, OT-82 enhanced the efficacy of the established drugs cytarabine and dasatinib and, as a single agent, showed similar efficacy as an induction-type regimen combining three drugs used to treat pediatric ALL. OT-82 exerted its antileukemic action by depleting NAD and ATP, inhibiting the NAD-requiring DNA damage repair enzyme PARP-1, increasing mitochondrial ROS levels and inducing DNA damage, culminating in apoptosis induction. OT-82 sensitivity was associated with the occurrence of mutations in major DNA damage response genes, while OT-82 resistance was characterized by high expression levels of CD38. In conclusion, our study provides evidence that OT-82, as a single agent, and in combination with established drugs, is a promising new therapeutic strategy for a broad spectrum of high-risk pediatric ALL for which improved therapies are urgently needed.
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http://dx.doi.org/10.1038/s41375-019-0683-6DOI Listing
June 2020

Latest advances in aging research and drug discovery.

Aging (Albany NY) 2019 11 21;11(22):9971-9981. Epub 2019 Nov 21.

Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6 annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7 annual ARDD exhibition will transpire 2-4 of September, 2020, in Basel.
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http://dx.doi.org/10.18632/aging.102487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914421PMC
November 2019

Prevention of Colorectal Carcinogenesis by DNA-Binding Small-Molecule Curaxin CBL0137 Involves Suppression of Wnt Signaling.

Cancer Prev Res (Phila) 2020 01 25;13(1):53-64. Epub 2019 Oct 25.

N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russian Federation.

Chemoprevention is considered a valid approach to reduce the incidence of colorectal cancer, one of the most common malignancies worldwide. Here, we investigated the tumor-preventive activity of curaxin CBL0137. This compound represents a new class of nonmutagenic DNA-binding small molecules that alter chromatin stability and inhibit the function of the histone chaperone FACT. Among downstream effects of CBL0137 treatment are activation of p53 and type I interferons and inhibition of NFκB, HSF1, and MYC. In addition, our data show that in both human and mouse colorectal cancer cells , CBL0137 inhibits the APC/WNT/β-catenin signaling pathway, which plays a key role in colon carcinogenesis. Using quantitative RT-PCR and microarray hybridization, we have demonstrated decreased expression of multiple components and downstream targets of the WNT pathway in colon cancer cells treated with CBL0137. At the same time, CBL0137 induced expression of WNT antagonists. Inhibition of WNT signaling activity by CBL0137 was also confirmed by luciferase reporter assay. Tumor-preventive activity of CBL0137 was tested in a murine model of colorectal carcinogenesis induced by 1,2-dimethylhydrazine (DMH), which is known to involve WNT pathway dysregulation. After DMH subcutaneous treatment, mice were administered CBL0137 in drinking water. Efficacy of CBL0137 in suppressing development of colorectal cancer in this model was evidenced by reduced incidence of adenocarcinomas and adenomas in both males and females and decrease in tumor multiplicity. These data support the prospective use of CBL0137 in chemoprevention of colorectal cancer as well as of other malignances associated with activated WNT signaling.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0198DOI Listing
January 2020

LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation.

Cell Metab 2019 04 7;29(4):871-885.e5. Epub 2019 Mar 7.

Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address:

Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.
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http://dx.doi.org/10.1016/j.cmet.2019.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449196PMC
April 2019

Cells exhibiting strong promoter activation in vivo display features of senescence.

Proc Natl Acad Sci U S A 2019 02 25;116(7):2603-2611. Epub 2019 Jan 25.

Curriculum in Genetics and Molecular Biology, University of North Carolina School of Medicine, Chapel Hill, NC 27599;

The activation of cellular senescence throughout the lifespan promotes tumor suppression, whereas the persistence of senescent cells contributes to aspects of aging. This theory has been limited, however, by an inability to identify and isolate individual senescent cells within an intact organism. Toward that end, we generated a murine reporter strain by "knocking-in" a fluorochrome, tandem-dimer Tomato (tdTom), into exon 1α of the locus. We used this allele ( ) for the enumeration, isolation, and characterization of individual -expressing cells (tdTom). The half-life of the knocked-in transcript was shorter than that of the endogenous mRNA, and therefore reporter expression better correlated with promoter activation than transcript abundance. The frequency of tdTom cells increased with serial passage in cultured murine embryo fibroblasts from mice. In adult mice, tdTom cells could be readily detected at low frequency in many tissues, and the frequency of these cells increased with aging. Using an in vivo model of peritoneal inflammation, we compared the phenotype of cells with or without activation of and found that tdTom macrophages exhibited some features of senescence, including reduced proliferation, senescence-associated β-galactosidase (SA-β-gal) activation, and increased mRNA expression of a subset of transcripts encoding factors involved in SA-secretory phenotype (SASP). These results indicate that cells harboring activation of the promoter accumulate with aging and inflammation in vivo, and display characteristics of senescence.
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http://dx.doi.org/10.1073/pnas.1818313116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377452PMC
February 2019

A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction.

Oncogene 2019 05 22;38(20):3824-3842. Epub 2019 Jan 22.

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology Monash Institute of Pharmaceutical Sciences, Monash University, Clayton, VIC, Australia.

Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.
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http://dx.doi.org/10.1038/s41388-018-0666-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756102PMC
May 2019

Quantitative characterization of biological age and frailty based on locomotor activity records.

Aging (Albany NY) 2018 10;10(10):2973-2990

Gero LLC, Moscow 1015064, Russia.

We performed a systematic evaluation of the relationships between locomotor activity and signatures of frailty, morbidity, and mortality risks using physical activity records from the 2003-2006 National Health and Nutrition Examination Survey (NHANES) and UK BioBank (UKB). We proposed a statistical description of the locomotor activity tracks and transformed the provided time series into vectors representing physiological states for each participant. The Principal Component Analysis of the transformed data revealed a winding trajectory with distinct segments corresponding to subsequent human development stages. The extended linear phase starts from 35-40 years old and is associated with the exponential increase of mortality risks according to the Gompertz mortality law. We characterized the distance traveled along the aging trajectory as a natural measure of biological age and demonstrated its significant association with frailty and hazardous lifestyles, along with the remaining lifespan and healthspan of an individual. The biological age explained most of the variance of the log-hazard ratio that was obtained by fitting directly to mortality and the incidence of chronic diseases. Our findings highlight the intimate relationship between the supervised and unsupervised signatures of the biological age and frailty, a consequence of the low intrinsic dimensionality of the aging dynamics.
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http://dx.doi.org/10.18632/aging.101603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224248PMC
October 2018

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma.

J Clin Invest 2018 10 10;128(10):4682-4696. Epub 2018 Sep 10.

Department of Cell Stress Biology.

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.
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http://dx.doi.org/10.1172/JCI70712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159960PMC
October 2018

TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells.

Elife 2018 02 5;7. Epub 2018 Feb 5.

Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, United States.

Cellular responses to the loss of genomic stability are well-established, while how mammalian cells respond to chromatin destabilization is largely unknown. We previously found that DNA demethylation on p53-deficient background leads to transcription of repetitive heterochromatin elements, followed by an interferon response, a phenomenon we named TRAIN (Transcription of Repeats Activates INterferon). Here, we report that curaxin, an anticancer small molecule, destabilizing nucleosomes via disruption of histone/DNA interactions, also induces TRAIN. Furthermore, curaxin inhibits oncogene-induced transformation and tumor growth in mice in an interferon-dependent manner, suggesting that anticancer activity of curaxin, previously attributed to p53-activation and NF-kappaB-inhibition, may also involve induction of interferon response to epigenetic derepression of the cellular 'repeatome'. Moreover, we observed that another type of drugs decondensing chromatin, HDAC inhibitor, also induces TRAIN. Thus, we proposed that TRAIN may be one of the mechanisms ensuring epigenetic integrity of mammalian cells via elimination of cells with desilenced chromatin.
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http://dx.doi.org/10.7554/eLife.30842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815852PMC
February 2018

Novel mouse models of hepatic artery infusion.

J Surg Res 2017 11 21;219:25-32. Epub 2017 Jun 21.

Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, New York; Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York. Electronic address:

Background: The liver has unique anatomy in that most blood flow to normal hepatocytes is derived from the portal venous system, whereas liver tumors obtain their nutrient blood supply exclusively from the hepatic artery. The focused arterial delivery of anticancer agents to liver tumors has been performed for decades; however, preclinical models to standardize drug regimens and examine novel agents have been lacking. The purpose of this study was to establish preclinical hepatic artery infusion (HAI) models in a mouse and to evaluate the safety and delivery capability of the models.

Material And Methods: C57BL/6 and BALB/c mice were used to develop models of HAI via the hepatic artery (HA), superior pancreaticoduodenal artery (SPDA), or lienogastric artery (LGA). Success rates, distribution of perfusion, and associated morbidity and mortality were analyzed between groups.

Results: All three models were feasible and reproducible in mice, and there was no statistical difference on body weight change between models. The HA model had a 13.3% mortality from acute liver failure, and the SPDA model demonstrated duodenal and pancreatic toxicity. SPDA and LGA routes had the highest success rates (96.7% and 91.4%, respectively) with low mortality, better drug delivery, and preserved physiologic liver function compared with the HA model.

Conclusions: The optimal route of HAI was mouse breed specific; SPDA access in BALB/c mice, and the LGA access in C57BL/6 mice. The described techniques serve as a reproducible platform for the identification and characterization of therapeutics for diverse metastatic liver tumors.
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http://dx.doi.org/10.1016/j.jss.2017.05.083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986560PMC
November 2017

p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli.

Aging (Albany NY) 2017 08;9(8):1867-1884

Everon Biosciences, Inc., Buffalo, NY 14203, USA.

Constitutive expression, along with senescence-associated β-galactosidase (SAβG), are commonly accepted biomarkers of senescent cells (SCs). Recent reports attributed improvement of the healthspan of aged mice following -positive cell killing to the eradication of accumulated SCs. However, detection of /SAβG-positive macrophages in the adipose tissue of old mice and in the peritoneal cavity of young animals following injection of alginate-encapsulated SCs has raised concerns about the exclusivity of these markers for SCs. Here we report that expression of and SAβG in macrophages is acquired as part of a physiological response to immune stimuli rather than through senescence, consistent with reports that p16 plays a role in macrophage polarization and response. Unlike SCs, /SAβG-positive macrophages can be induced in p53-null mice. Macrophages, but not mesenchymal SCs, lose both markers in response to M1- [LPS, IFN-α, Poly(I:C)] and increase their expression in response to M2-inducing stimuli (IL-4, IL-13). Moreover, interferon-inducing agent Poly(I:C) dramatically reduced expression in our alginate bead model and in the adipose tissue of aged mice. These observations suggest that the antiaging effects following eradication of -positive cells may not be solely attributed to SCs but also to non-senescent /SAβG-positive macrophages.
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http://dx.doi.org/10.18632/aging.101268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611982PMC
August 2017

Murine mesenchymal cells that express elevated levels of the CDK inhibitor p16(Ink4a) in vivo are not necessarily senescent.

Cell Cycle 2017 Aug 26;16(16):1526-1533. Epub 2017 Jun 26.

a Everon Biosciences, Inc. , Buffalo , NY , USA.

Age-related health decline has been attributed to the accumulation of senescent cells recognized in vivo by p16(Ink4a) expression. The pharmacological elimination of p16(Ink4a)-positive cells from the tissues of mice was shown to extend a healthy lifespan. Here, we describe a population of mesenchymal cells isolated from mice that are highly p16(INK4a)-positive are proficient in proliferation but lack other properties of cellular senescence. These data, along with earlier reports on p16(Ink4a)-positive macrophages, indicate that p16(Ink4a)-positive and senescent cell populations only partially intersect, therefore, extending the list of potential cellular targets for anti- aging therapies.
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http://dx.doi.org/10.1080/15384101.2017.1339850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584871PMC
August 2017

Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice.

Aging (Albany NY) 2017 03;9(3):615-626

Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.

The development of healthspan-extending pharmaceuticals requires quantitative estimation of age-related progressive physiological decline. In humans, individual health status can be quantitatively assessed by means of a (FI), a parameter which reflects the scale of accumulation of age-related deficits. However, adaptation of this methodology to animal models is a challenging task since it includes multiple subjective parameters. Here we report a development of a quantitative non-invasive procedure to estimate biological age of an individual animal by creating (PFI). We demonstrated the dynamics of PFI increase during chronological aging of male and female NIH Swiss mice. We also demonstrated acceleration of growth of PFI in animals placed on a high fat diet, reflecting aging acceleration by obesity and provide a tool for its quantitative assessment. Additionally, we showed that PFI could reveal anti-aging effect of mTOR inhibitor rapatar (bioavailable formulation of rapamycin) prior to registration of its effects on longevity. PFI revealed substantial sex-related differences in normal chronological aging and in the efficacy of detrimental (high fat diet) or beneficial (rapatar) aging modulatory factors. Together, these data introduce PFI as a reliable, non-invasive, quantitative tool suitable for testing potential anti-aging pharmaceuticals in pre-clinical studies.
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http://dx.doi.org/10.18632/aging.101206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5391222PMC
March 2017
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