Medicinal Chemistry Research

, Volume 26, Issue 7, pp 1427–1436 | Cite as

Autophagy promotes apoptosis induction through repressed nitric oxide generation in the treatment of human breast cancer MCF-7 cells with L-A03, a dihydroartemisinin derivative

  • Guodong Yao
  • Hao Chen
  • Ling Chen
  • Mengyao Ge
  • Jing Yang
  • Weiwei Liu
  • Mingyu Xia
  • Toshihiko Hayashi
  • Chun Guo
  • Takashi Ikejima
Original Research
  • 157 Downloads

Abstract

The scaffold of 4-quinolylhydrazone was attached to dihydroartemisinin by the combination and bioisosterism principles to get a dihydroartemisinin derivative called L-A03. The previous study demonstrated that L-A03 inhibited cysteine protease falcipain-2 of Plasmodium falciparum. Our preliminary assay showed that this compound exhibited significant antitumor activity in some cancer cell lines. Besides, cytotoxicity was low against human peripheral blood mononuclear cells. These suggest that L-A03 could be used as a potent antitumor drug. This study indicated that L-A03 induced both apoptosis and autophagy in human breast cancer MCF-7 cells. L-A03 caused autophagy prior to the onset of apoptotic cell death. In the presence of chloroquine, an autophagic inhibitor, L-A03-induced apoptosis was attenuated, indicating that autophagy was indispensable for apoptosis induction. Nitric oxide generation blocked apoptotic cell death, but did not affect autophagy, suggesting that autophagy may take place in the upstream of nitric oxide generation. Moreover, autophagy decreased the generation of nitric oxide. This study provided a new insight on the mechanism of anti-tumor effect of L-A03.

Keywords

Dihydroartemisinin derivative L-A03 Apoptosis Autophagy Nitric oxide 

Notes

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81573292) and the National Fund for Talent Training in Basic Science (NO. J1103606)

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

44_2017_1868_MOESM1_ESM.docx (17 kb)
Supplementary Information

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Guodong Yao
    • 1
  • Hao Chen
    • 1
  • Ling Chen
    • 1
  • Mengyao Ge
    • 1
  • Jing Yang
    • 1
  • Weiwei Liu
    • 1
  • Mingyu Xia
    • 1
  • Toshihiko Hayashi
    • 1
  • Chun Guo
    • 2
  • Takashi Ikejima
    • 1
  1. 1.China-Japan Research Institute of Medical and Pharmaceutical SciencesShenyang Pharmaceutical UniversityShenyangChina
  2. 2.Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of EducationShenyang Pharmaceutical UniversityShenyangChina

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