2. Academic Validation
  3. Combating P-glycoprotein-mediated multidrug resistance with 10-O-phenyl dihydroartemisinin ethers in MCF-7 cells

Combating P-glycoprotein-mediated multidrug resistance with 10-O-phenyl dihydroartemisinin ethers in MCF-7 cells

  • Eur J Med Chem. 2016 Jan 27:108:720-729. doi: 10.1016/j.ejmech.2015.10.040.
Hang Zhong 1,  Xuan Zhao 2,  Zhizhong Zuo 1,  Jingwei Sun 1,  Yao Yao 1,  Tao Wang 2,  Dan Liu 3,  Linxiang Zhao 4
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 2 School of Life Sciences and Biopharmaceutis, Shenyang Pharmaceutical University, Shenyang 110016, China.
  • 3 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sammyld@163.com.
  • 4 Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: linxiang.zhao@vip.sina.com.
PMID: 26741854 DOI: 10.1016/j.ejmech.2015.10.040
Abstract

A series of 10-β-phenyl ethers of dihydroartemisinin (DHA) with piperazine substitutions were synthesized with the goal of overcoming multidrug resistance in Cancer therapy. These novel compounds exerted significant antiproliferative activities in breast Cancer MCF-7 and MCF-7/Adr cell lines at the submicromolar level and were shown to be approximately 100- to 300-times more potent than the lead compound DHA. Remarkably, the P-gp-overexpressed MCF-7/Adr cell line showed collateral sensitivity towards these derivatives. Furthermore, compounds 3d and 5c, with the highest selectivity for MCF-7/Adr towards MCF-7 cells, were free from P-gp efflux in a MDCK-MDR1 assay. Flow cytometry and western blot assays suggested that the antiproliferative effects of 5c were associated with cell cycle arrest at G1 phase through the downregulation of Cyclin D1 and Cyclin B1.

Keywords

10-O-phenyl dihydroartemisinin ethers; Antiproliferative effects; Collateral sensitivity; MCF-7/Adr; MDCK-MDR1; Multidrug-resistance; P-glycoprotein.

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