Discovery of piperlongumine as a potential novel lead for the development of senolytic agents

• Published in: Aging (Albany, NY.) Vol. 8; no. 11; pp. 2915 - 2926
• Main Authors: Wang, Yingying, Chang, Jianhui, Liu, Xingui, Zhang, Xuan, Zhang, Suping, Zhang, Xin, Zhou, Daohong, Zheng, Guangrong
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 19.11.2016
• Subjects: Aniline Compounds - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Cellular Senescence - drug effects; Dioxolanes - pharmacology; Fibroblasts - drug effects; Fibroblasts - physiology; Genes, ras; Humans; Reactive Oxygen Species - metabolism; Research Paper; Sulfonamides - pharmacology; senolytic agents; reactive oxygen species; piperlongumine; senescent cells; aging; ABT-263; synergistic effect
• ISSN: 1945-4589; 1945-4589
• DOI: 10.18632/aging.101100

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 oncogene . 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.