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      Therapeutic strategies targeting cellular senescence for cancer and other diseases

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          Abstract

          Cellular senescence occurs in response to endogenous or exogenous stresses and is characterized by stable cell cycle arrest, alterations in nuclear morphology and secretion of proinflammatory factors, referred to as the senescence-associated secretory phenotype (SASP). An increase of senescent cells is associated with the development of several types of cancer and aging-related diseases. Therefore, senolytic agents that selectively remove senescent cells may offer opportunities for developing new therapeutic strategies against such cancers and aging-related diseases. This review outlines senescence inducers and the general characteristics of senescent cells. We also discuss the involvement of senescent cells in certain cancers and diseases. Finally, we describe a series of senolytic agents and their utilization in therapeutic strategies.

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          The senescence-associated secretory phenotype: the dark side of tumor suppression.

          Jean-Philippe Coppe, Pierre-Yves Desprez, Ana Krtolica … (2010)
          Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
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            The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

            Yi-Yi Zhu, Tamara Tchkonia, Tamar Pirtskhalava … (2015)
            The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1 −/Δ mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1 −/Δ mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
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              The serial cultivation of human diploid cell strains.

              L Hayflick, P.S. Moorhead (1961)
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                Author and article information

                Contributors
                Xuebing Wang
                Takeshi Fukumoto
                Ken-ichi Noma
                Journal
                Journal ID (nlm-ta): J Biochem
                Journal ID (iso-abbrev): J Biochem
                Journal ID (publisher-id): jbchem
                Title: Journal of Biochemistry
                Publisher: Oxford University Press
                ISSN (Print): 0021-924X
                ISSN (Electronic): 1756-2651
                Publication date Collection: 01 May 2024
                Publication date (Electronic): 15 February 2024
                Publication date PMC-release: 15 February 2024
                Volume: 175
                Issue: 5
                Pages: 525-537
                Affiliations
                Institute for Genetic Medicine, Hokkaido University , Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan
                Division of Dermatology, Department of Internal Related, Graduate School of Medicine, Kobe University , 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
                Institute for Genetic Medicine, Hokkaido University , Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan
                Institute of Molecular Biology, University of Oregon , 1370 Franklin Blvd, Eugene, OR 97403, USA
                Author notes
                Ken-ichi Noma, Institute for Genetic Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-Ku, Sapporo 060-0815, Japan. Tel.: +81-11-706-5071, Fax: +81-11-706-7540, email: noma@ 123456igm.hokudai.ac.jp
                Takeshi Fukumoto, Division of Dermatology, Department of Internal Related, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. Tel.: +81-78-382-6134, Fax: +81-78-382-6149, email: fuku@ 123456med.kobe-u.ac.jp
                Article
                Publisher ID: mvae015
                DOI: 10.1093/jb/mvae015
                PMC ID: 11058315
                PubMed ID: 38366629
                SO-VID: 134bc41b-32ca-45d7-b159-10acf139f93a
                Copyright © © The Author(s) 2024. Published by Oxford University Press on behalf of the Japanese Biochemical Society.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Date received : 17 November 2023
                Date accepted : 30 January 2024
                Date revision requested : 15 February 2024
                Page count
                Pages: 13
                Categories
                Subject: JB Review
                Subject: AcademicSubjects/SOC00730

                Keywords: aging,cancer,cellular senescence,premature aging (progeria) syndromes,senescence- and aging-related diseases,senolytic agents
                Data availability:
                Keywords: aging, cancer, cellular senescence, premature aging (progeria) syndromes, senescence- and aging-related diseases, senolytic agents

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