Research Paper Volume 11, Issue 2 pp 771—782

The curcumin analog EF24 is a novel senolytic agent

Wen Li1,2,3, , Yonghan He2, , Rongping Zhang1, , Guangrong Zheng4, , Daohong Zhou2, ,

  • 1 School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, China
  • 2 Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
  • 3 Department of Endocrinology, The Third People’s Hospital of Yunnan Province, Kunming, Yunnan 650011, China
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA

Received: December 19, 2018       Accepted: January 15, 2019       Published: January 28, 2019      

https://doi.org/10.18632/aging.101787
How to Cite

Copyright: Li et al. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Cellular senescence is a hallmark of aging because senescent cells (SCs) accumulate with aging and play a causative role in age-related diseases. Selectively eliminating SCs has been emerging as a new strategy for treating age-related diseases and extending healthspan. Curcumin and its analogs have some anti-aging activities. However, the mechanisms of their action have not been fully elucidated. In the present study, we investigated whether various curcumin analogs can function as a senolytic agent. The results from our studies show that among these curcumin analogs EF24 is the most potent and broad-spectrum senolytic agent. Mechanistically, EF24 selectively kills SCs by inducing SC apoptosis in a reactive oxygen species (ROS) production independent manner but associated with an increase in the proteasome degradation of the Bcl-2 anti-apoptotic protein family proteins known to play an important role in protecting SCs from apoptosis. In addition, EF24 can synergistically kill SCs with ABT-263, a Bcl-2 and Bcl-xl inhibitor and a known senolytic agent. These findings provide new insights into the mechanisms by which curcumin analogs function as an anti-aging agent and suggest that the curcumin analog EF24 has the potential to be used as a novel senolytic agent for the treatment of age-related diseases.

Abbreviations

ATCC: American Type Culture Collection; CDI: coefficient of drug interaction; DHR: dihydrorhodamine 123; DIMC: dimethoxycurcumin; DMEM: Dulbecco’s modified Eagle medium; FBS: fetal bovine serum; HREC: human renal epithelial cells; HUVEC: human umbilical vein endothelial cells; IR-SCs: ionizing radiation induced senescent cells; MFI: mean fluorescence intensity; NCs: non-senescent cells; PBS: phosphate buffered saline; PCR: polymerase chain reaction; PI: propidium iodide; QVD: Q-VD-OPh; Ras-SCs: Ras oncogene induced senescent cells; Rep-SCs: extensive replication induced senescent cells; ROS: reactive oxygen species; SCs: senescent cells.