Cited by 124Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsAutophagy in Disease and Therapy

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Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

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Carpenter, Valerie J., Saleh, Tareq, Gewirtz, David A.·2021·Cancers

DOI 10.3390/cancers13040723PMC PMC7916462

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Abstract

Senolytics represent a group of mechanistically diverse drugs that can eliminate senescent cells, both in tumors and in several aging-related pathologies. Consequently, senolytic use has been proposed as a potential adjuvant approach to improve the response to senescence-inducing conventional and targeted cancer therapies. Despite the unequivocal promise of senolytics, issues of universality, selectivity, resistance, and toxicity remain to be further clarified. In this review, we attempt to summarize and analyze the current preclinical literature involving the use of senolytics in senescent tumor cell models, and to propose tenable solutions and future directions to improve the understanding and use of this novel class of drugs.

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Figure 1 Limitations of current senolytics and potential approaches for circumvention. Although senolytic agents have shown promise as adjuvant cancer therapies preclinically, careful review of the literature has elucidated common limitations. The above figure outlines four outstanding issues with current senolytics, defines these issues, and summarizes the approaches that may mitigate or circumvent these issues, as outlined in detail in Section 3.CC BY · PubMed Central

Figure 2 Validated and potential therapeutic targets to eliminate senescent cells. The accumulation of senescent cells is arguably disadvantageous to patient outcome due to the potential for proliferative recovery, the development of cell-autonomous stemness, SASP-driven stimulation of neighboring cells, and SASP-mediated immunogenicity. Despite evidence that SASP can drive immune-cell driven elimination of senescent cells, the SASP can also be strongly immunosuppressive. Further, elevated matrix-metalloprotease secretion and HLA-E expression have been demonstrated mechanisms by which senescent cells continue to evade immune cell detection. Multiple small molecule drugs have been identified and validated as senolytics (blue bolded text), but we propose that specific targeting of the more detrimental features of senescent cells (red bolded text) may prove efficacious alternatives or supplementations to the identified drug targets. This figure was generated through biorender.com.CC BY · PubMed Central

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Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts
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A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
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A Novel Indication for Panobinostat as a Senolytic Drug in NSCLC and HNSCC
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Interleukin 17 and senescent cells regulate the foreign body response to synthetic material implants in mice and humans
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Cellular senescence impairs the reversibility of pulmonary arterial hypertension
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The Senolytic Drug Navitoclax (ABT-263) Causes Trabecular Bone Loss and Impaired Osteoprogenitor Function in Aged Mice
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Polyploidy road to therapy‐induced cellular senescence and escape
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Oxidation resistance 1 is a novel senolytic target
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Small-molecule PROTAC degraders of the Bromodomain and Extra Terminal (BET) proteins — A review
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Pharmacological or genetic depletion of senescent astrocytes prevents whole brain irradiation–induced impairment of neurovascular coupling responses protecting cognitive function in mice
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Adjustment of the lysosomal-mitochondrial axis for control of cellular senescence
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Preclinical antitumor efficacy of senescence-inducing chemotherapy combined with a nanoSenolytic
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Cellular senescence predicts treatment outcome in metastasised colorectal cancer
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Cellular senescence: a promising strategy for cancer therapy
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Vemurafenib Induces Senescence Features in Melanoma Cells
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Senolytic Cocktail Dasatinib+Quercetin (D+Q) Does Not Enhance the Efficacy of Senescence-Inducing Chemotherapy in Liver Cancer
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Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents
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Navitoclax (ABT263) reduces inflammation and promotes chondrogenic phenotype by clearing senescent osteoarthritic chondrocytes in osteoarthritis
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Senescence-associated secretory factors induced by cisplatin in melanoma cells promote non-senescent melanoma cell growth through activation of the ERK1/2-RSK1 pathway
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Regulation of senescence escape by TSP1 and CD47 following chemotherapy treatment
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Current overview on the clinical update of Bcl-2 anti-apoptotic inhibitors for cancer therapy
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Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse
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Hyperoxia-Induced Cellular Senescence in Fetal Airway Smooth Muscle Cells
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Non-cell autonomous effects of the senescence-associated secretory phenotype in cancer therapy.
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Cellular senescence-mediated exacerbation of Duchenne muscular dystrophy
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Senolytics (DQ) Mitigates Radiation Ulcers by Removing Senescent Cells
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Is senescence reversible?
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Depletion of senescent-like neuronal cells alleviates cisplatin-induced peripheral neuropathy in mice
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Senolytic Agent Navitoclax Inhibits Angiotensin II-Induced Heart Failure in Mice
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Targeting tumor cell senescence and polyploidy as potential therapeutic strategies
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Cisplatin-induced senescence in ovarian cancer cells is mediated by GRP78
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Androgen deprivation induces senescence characteristics in prostate cancer cells in vitro and in vivo
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Premature senescence in human breast cancer and colon cancer cells by tamoxifen-mediated reactive oxygen species generation
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Irinotecan treatment and senescence failure promote the emergence of more transformed and invasive cells that depend on anti-apoptotic Mcl-1
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DNA Damage- But Not Enzalutamide-Induced Senescence in Prostate Cancer Promotes Senolytic Bcl-xL Inhibitor Sensitivity
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See all 124

Authors: Carpenter, V. J., Saleh, T., & Gewirtz, D. A.
Affiliations: Virginia Commonwealth University (US)
Hashemite University (JO)
Corresponding author: Gewirtz, David A.
ORCID: Saleh, Tareq
Gewirtz, David A.
Venue: Cancers
Publisher: MDPI AG
Published: 2021-02-10
Volume: 13
Issue: 4
Pages: 723
ISSN: 2072-6694 (ISSN-L)
DOI: 10.3390/cancers13040723
PMC: PMC7916462
OpenAlex: W3128445174
Cited by: 124
References: 179
Citations by year: 2026: 17 · 2025: 24 · 2024: 21 · 2023: 18 · 2022: 28 · 2021: 16
FWCI: 2.77
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cancers (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institutes of Health (CA-239706)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords: senolytics, senescent cells, cancer therapy, senescence, tumor cell models, drug selectivity, drug resistance, drug toxicity, aging, adjuvant therapy

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Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

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