Potent proapoptotic actions of dihydroartemisinin in gemcitabine-resistant A549 cells

Chubiao Zhao1, Guiqi Qin1, Weijie Gao1

  • 1MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Life Science, South China Normal University, Guangzhou 510631, China.

Cellular Signalling
|July 15, 2014
PubMed

Insights

Dihydroartemisinin (DHA) triggers apoptosis more effectively in gemcitabine-resistant lung cancer cells by increasing reactive oxygen species (ROS). This pathway involves Bax and caspases, offering a potential therapeutic strategy.

Area of Science:

  • Cell Biology
  • Pharmacology
  • Cancer Research

Background:

  • Gemcitabine-resistant A549 cells exhibit altered redox status, including higher basal reactive oxygen species (ROS) and intracellular iron.
  • Previous studies identified ROS-mediated caspase-8- and Bax-dependent apoptosis in A549 cells treated with dihydroartemisinin (DHA).

Purpose of the Study:

  • To investigate the proapoptotic mechanisms of DHA in gemcitabine-resistant A549 (A549GR) cells.
  • To compare the effects of DHA on ROS generation and apoptosis induction in A549GR versus gemcitabine-sensitive A549 cells.

Main Methods:

  • Comparative analysis of ROS generation, intracellular Fe(2+), and antioxidant capacity in A549 and A549GR cells.
  • Assessment of DHA-induced apoptosis markers, including Bax activation, mitochondrial membrane potential (ΔΨm) loss, and caspase activation.
  • Evaluation of the protective effects of N-acetylcysteine (NAC) and the impact of Bax silencing or caspase inhibition on DHA-induced apoptosis.

Main Results:

  • DHA induced rapid and potent ROS generation in A549GR cells, exceeding that in A549 cells.
  • A549GR cells showed enhanced DHA-induced Bax activation, ΔΨm loss, caspase activation, and apoptosis compared to A549 cells.
  • NAC pretreatment, Bax silencing, or caspase inhibition significantly attenuated DHA-induced apoptosis, confirming the roles of ROS, Bax, and caspases.

Conclusions:

  • DHA exhibits preferential and potent proapoptotic effects in gemcitabine-resistant A549 cells over sensitive cells.
  • The proapoptotic action of DHA in A549GR cells is mediated by a ROS-dependent pathway involving Bax and caspases.
  • DHA represents a promising therapeutic agent for overcoming gemcitabine resistance in lung cancer.