Research Paper Volume 11, Issue 2 pp 771—782
The curcumin analog EF24 is a novel senolytic agent
- 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.101787How to Cite
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.