DMXAA-pyranoxanthone hybrids enhance inhibition activities against human cancer cells with multi-target functions

Eur J Med Chem. 2018 Jan 1:143:1768-1778. doi: 10.1016/j.ejmech.2017.10.074.

Jie Liu ¹, Fan Zhou ¹, Lei Zhang ¹, Huailing Wang ², Jianrun Zhang ¹, Cao Zhang ¹, Zhenlei Jiang ¹, Yanbing Li ¹, Zhijun Liu ¹, Heru Chen ³

Affiliations

1 Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China.
2 School of Food Sciences and Engineering, South China University of Technology, Guangzhou 510641, PR China.
3 Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, PR China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou 510632, PR China. Electronic address: thrchen@jnu.edu.cn.

PMID: 29129511 DOI: 10.1016/j.ejmech.2017.10.074

Abstract

Four 5,6-dimethylxanthone-4-acetic acid (D) and pyranoxanthone (P) hybrids (D-P-n) were design-synthesized based on multi-target-addressed strategy. D-P-4 was confirmed as the most active agent against HepG-2 cell line growth with an IC₅₀ of 0.216 ± 0.031 μM. Apoptosis analysis indicated different contributions of early/late Apoptosis/necrosis to cell death for both monomers, the combination (D + P in 1:1 mol ratio) and D-P-4. They all arrested more cells on S phase. Western Blot implied that D-P-4 regulated p53/MDM2 to a better healthy state. Moreover, it improved Bax/Bcl-2 signaling pathway to increase Cancer cell Apoptosis. In all cases studied, D-P-4 showed the best activity and synergistic effect. All the evidences support that D-P-4 is a better anti-cancer therapy with multi-target functions.

Keywords

Anti-cancer; Bax/Bcl-2; Multi-targets-addressed ligand; Synergistic effect; Xanthones; p53/MDM2.

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