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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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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