Potent Inhibition of Nitric Oxide-Releasing Bifendate Derivatives against Drug-Resistant K562/A02 Cells in Vitro and in Vivo

  • J Med Chem. 2017 Feb 9;60(3):928-940. doi: 10.1021/acs.jmedchem.6b01075.
Xiaoke Gu  1  2 ,  Zhangjian Huang  1 ,  Zhiguang Ren  3 ,  Xiaobo Tang  1 ,  Rongfang Xue  1 ,  Xiaojun Luo  1 ,  Sixun Peng  1 ,  Hui Peng  3 ,  Bin Lu  4 ,  Jide Tian  5 ,  Yihua Zhang  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University , 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
  • 2. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University , Xuzhou 221004, People's Republic of China.
  • 3. Department of Environment and Pharmacy, Tianjin Institute of Health and Environmental Medicine , Tianjin 300050, People's Republic of China.
  • 4. Institute of Biophysics, School of Laboratory Medicine and Life Sciences, Wenzhou Medical College , Wenzhou 325035, People's Republic of China.
  • 5. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles , Los Angeles, California 90095, United States.
PMID: 28068095 DOI: 10.1021/acs.jmedchem.6b01075
Abstract

Multidrug resistance is a major obstacle to successful chemotherapy for leukemia. In this study, a series of nitric oxide (NO)-releasing bifendate derivatives (7a-n) were synthesized. Biological evaluation indicated that the most active compound (7a) produced relatively high levels of NO and significantly inhibited the proliferation of drug-resistant K562/A02 cells in vitro and in vivo. In addition, 7a induced the mitochondrial tyrosine nitration and the intracellular accumulation of rhodamine 123 by inhibiting P-gp activity in K562/A02 cells. Furthermore, 7a remarkably down-regulated Akt, NF-κB, and ERK activation and HIF-1α expression in K562/A02 cells, which are associated with the tumor cell proliferation and drug resistance. Notably, the antitumor effects were dramatically attenuated by an NO scavenger or elimination of the NO-releasing capability of 7a, indicating that NO produced by 7a contributed to, at least partly, its cytotoxicity against drug-resistant K562/A02 cells. Overall, 7a may be a potential agent against drug-resistant myelogenous leukemia.