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23-Hydroxyursolic Acid Isolated from the Stem Bark of Cussonia bancoensis Induces Apoptosis through Fas/Caspase-8-Dependent Pathway in HL-60 Human Promyelocytic Leukemia Cells

1
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea
2
Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea
3
Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea
4
Department of Chemistry, Faculty of Science, University of Dschang, Box 183, Dschang, Cameroon
5
Division of Applied Plant Sciences, Sang-Ji University, Wonju 220-702, Korea
6
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa 920-1181, Japan
7
Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea
8
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
*
Author to whom correspondence should be addressed.
These authors contributed equally to this study.
Academic Editor: Francesca Giampieri
Molecules 2018, 23(12), 3306; https://doi.org/10.3390/molecules23123306
Received: 20 November 2018 / Revised: 12 December 2018 / Accepted: 12 December 2018 / Published: 13 December 2018
(This article belongs to the Section Natural Products Chemistry)
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Abstract

The natural product 23-hydroxyursolic acid (23-HUA) is a derivative of ursolic acid, which is known to induce cancer cell apoptosis. However, apoptotic effects and mechanisms of 23-HUA have not been well characterized yet. Herein, we investigated the molecular mechanisms of 23-HUA-induced apoptosis in HL-60 human promyelocytic leukemia cells. 23-HUA-treated HL-60 cells showed apoptotic features including internucleosomal DNA condensation and fragmentation as well as externalization of phosphatidylserine residues. 23-HUA induced a series of mitochondrial events including disruption of mitochondrial membrane potential (ΔΨm), cytochrome c and Smac/DIABLO release and loss of balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins in HL-60 cells. In addition, 23-HUA activated caspase-8, caspase-9 and caspase-3. Pretreatment with a broad caspase inhibitor (z-VAD-fmk), a caspase-3 inhibitor (z-DEVD-fmk), and a caspase-8 inhibitor (z-IETD-fmk) significantly attenuated 23-HUA-induced DNA fragmentation. After 23-HUA-induced apoptosis, proteins expression levels of FasL, Fas and FADD constituting the death-inducing signaling complex (DISC) were upregulated in HL-60 cells. Moreover, transfection with Fas or FADD siRNA significantly blocked 23-HUA-induced DNA fragmentation and caspases activation. Taken together, these findings indicate that 23-HUA induces apoptosis in HL-60 human promyelocytic leukemia cells through formation of DISC and caspase-8 activation leading to loss of ΔΨm and caspase-3 activation. View Full-Text
Keywords: 23-hydroxyursolic acid; apoptosis; caspase; Bcl-2; mitochondria; death-inducing signaling complex 23-hydroxyursolic acid; apoptosis; caspase; Bcl-2; mitochondria; death-inducing signaling complex
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Won, J.-H.; Chung, K.-S.; Park, E.-Y.; Lee, J.-H.; Choi, J.-H.; Tapondjou, L.A.; Park, H.-J.; Nomura, M.; Hassan, A.H.; Lee, K.-T. 23-Hydroxyursolic Acid Isolated from the Stem Bark of Cussonia bancoensis Induces Apoptosis through Fas/Caspase-8-Dependent Pathway in HL-60 Human Promyelocytic Leukemia Cells. Molecules 2018, 23, 3306.

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