title: Discovery of piperlongumine as a potential novel lead for the development of senolytic agents.
abstract: Accumulating evidence indicates that senescent cells play an important role in many age-associated diseases. The pharmacological depletion of senescent cells (SCs) with a "senolytic agent", a small molecule that selectively kills SCs, is a potential novel therapeutic approach for these diseases. Recently, we discovered ABT-263, a potent and highly selective senolytic agent, by screening a library of rationally-selected compounds. With this screening approach, we also identified a second senolytic agent called piperlongumine (PL). PL is a natural product that is reported to have many pharmacological effects, including anti-tumor activity. We show here that PL preferentially killed senescent human WI-38 fibroblasts when senescence was induced by ionizing radiation, replicative exhaustion, or ectopic expression of the oncogeneRas. PL killed SCs by inducing apoptosis, and this process did not require the induction of reactive oxygen species. In addition, we found that PL synergistically killed SCs in combination with ABT-263, and initial structural modifications to PL identified analogs with improved potency and/or selectivity in inducing SC death. Overall, our studies demonstrate that PL is a novel lead for developing senolytic agents.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Xingui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Suping
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: Guangrong
authors.initials: G
authors.lastname: Zheng
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D016922:Cellular Senescence / Q000187:drug effects*; D004148:Dioxolanes / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D011905:Genes, ras; D006801:Humans; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D010881:Piperidones
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D004148:Dioxolanes; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C498077:piperlongumine; D010881:Piperidones; C528561:navitoclax
keywords: ABT-263; aging; piperlongumine; reactive oxygen species; senescent cells; senolytic agents; synergistic effect