title: New agents that target senescent cells: the flavone, fisetin, and the BCL-XLinhibitors, A1331852 and A1155463.
abstract: Senescent cells accumulate with aging and at sites of pathology in multiple chronic diseases. Senolytics are drugs that selectively promote apoptosis of senescent cells by temporarily disabling the pro-survival pathways that enable senescent cells to resist the pro-apoptotic, pro-inflammatory factors that they themselves secrete. Reducing senescent cell burden by genetic approaches or by administering senolytics delays or alleviates multiple age- and disease-related adverse phenotypes in preclinical models. Reported senolytics include dasatinib, quercetin, navitoclax (ABT263), and piperlongumine. Here we report that fisetin, a naturally-occurring flavone with low toxicity, and A1331852 and A1155463, selective BCL-XLinhibitors that may have less hematological toxicity than the less specific BCL-2 family inhibitor navitoclax, are senolytic. Fisetin selectively induces apoptosis in senescent but not proliferating human umbilical vein endothelial cells (HUVECs). It is not senolytic in senescent IMR90 cells, a human lung fibroblast strain, or primary human preadipocytes. A1331852 and A1155463 are senolytic in HUVECs and IMR90 cells, but not preadipocytes. These agents may be better candidates for eventual translation into clinical interventions than some existing senolytics, such as navitoclax, which is associated with hematological toxicity.
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.|Faculty of Science and Engineering, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
authors.forename: Ewald J
authors.initials: EJ
authors.lastname: Doornebal
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Nino
authors.initials: N
authors.lastname: Giorgadze
authors.affiliation: Office of Research Regulatory Support, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Wentworth
authors.affiliation: Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Fuhrmann-Stroissnigg
authors.affiliation: Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.affiliation: Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology*; D044948:Flavonols; D006801:Humans; D013449:Sulfonamides / Q000494:pharmacology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D005419:Flavonoids; D044948:Flavonols; D013449:Sulfonamides; D051020:bcl-X Protein; C017875:fisetin; C528561:navitoclax
keywords: BCL-X inhibitors L; adipose-derived stem cells; aging; apoptosis; flavonoids; preadipocytes; senolytics