title: Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors.
abstract: Clearing senescent cells extends healthspan in mice. Using a hypothesis-driven bioinformatics-based approach, we recently identified pro-survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro-survival regulators identified was Bcl-xl. Here, we tested whether the Bcl-2 family inhibitors, navitoclax (N) and TW-37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl-xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl-2, Bcl-xl, and Bcl-w, while T targets Bcl-2, Bcl-xl, and Mcl-1. The combination of Bcl-2, Bcl-xl, and Bcl-w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl-2, Bcl-xl, and Mcl-1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl-2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type-restricted manner. The hypothesis-driven, bioinformatics-based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type-specific senolytic agents.
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Fuhrmann-Stroissnigg
authors.affiliation: Center of Medical Physics and Technology, Hefei Institutes of Physical Sciences, Hefei, China.
authors.forename: Haiming M
authors.initials: HM
authors.lastname: Dai
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Yuanyuan Y
authors.initials: YY
authors.lastname: Ling
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stout
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nino
authors.initials: N
authors.lastname: Giorgadze
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kurt O
authors.initials: KO
authors.lastname: Johnson
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Cory B
authors.initials: CB
authors.lastname: Giles
authors.affiliation: Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000166:cytology; D004720:Endonucleases / Q000172:deficiency / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008954:Models, Biological; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D004268:DNA-Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; D011794:Quercetin; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D000069439:Dasatinib; C528561:navitoclax
keywords: ABT-263; Bcl-2 family; TW-37; dasatinib; quercetin; senescent cells