Opening of the CLC-3 chloride channel induced by dihydroartemisinin contributed to early apoptotic events in human poorly differentiated nasopharyngeal carcinoma cells

J Cell Biochem. 2018 Nov;119(11):9560-9572. doi: 10.1002/jcb.27274. Epub 2018 Sep 1.

Abstract

Nasopharyngeal carcinoma (NPC) is a specific type of head and neck cancer that is prevalent in Southeast Asia. Dihydroartemisinin (DHA), a semisynthetic derivative of artemisinin, has specific anticancer activity. Here, we aimed to investigate the role of the CLC-3 chloride channel in the anticancer effect of DHA in poorly differentiated NPC CNE-2Z cells. First, we observed that DHA could specifically inhibit the proliferation, induce apoptosis, and increase cleaved caspase-3 expression in the CNE-2Z cells. Then, we found that DHA could activate chloride channels, which led to Cl- efflux and apoptotic volume decrease (AVD) in the early stage in the CNE-2Z cells. DHA also specifically increased CLC-3 chloride channel protein expression in the CNE-2Z cells. Silencing of the CLC-3 protein expression depleted the Cl- currents, and decreased the AVD capacity and cell apoptosis induced by DHA. Finally, we revealed that the [Ca2+ ]i increased after around 6 hours of treatment with DHA, which was also inhibited by silencing of the CLC-3 protein expression. Our data demonstrated that the selective antitumor activities of DHA in NPC may occur through the specific activation of the CLC-3 Cl- channel, leading to Cl- efflux, and induced AVD, then led to [Ca2+ ]i accumulation and caspase-3 activation, and finally induced apoptosis. The activation of the CLC-3 chloride channel played an essential and proximal upstream role in the antitumor activities of DHA.

Keywords: CLC-3 chloride channel; apoptosis; dihydroartemisinin; nasopharyngeal carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Artemisinins / therapeutic use*
  • Blotting, Western
  • Cell Line
  • Cell Survival / drug effects
  • Chloride Channels / metabolism*
  • Flow Cytometry
  • Humans
  • Nasopharyngeal Carcinoma / drug therapy*
  • Nasopharyngeal Carcinoma / metabolism*
  • RNA, Small Interfering

Substances

  • Artemisinins
  • Chloride Channels
  • ClC-3 channel
  • RNA, Small Interfering
  • artenimol