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Updated: Aug 1, 2026
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Antimalarial agent artesunate induces G0/G1 cell cycle arrest and apoptosis via increasing intracellular ROS levels
1College of Veterinary Medicine, 38043Yangzhou University, Yangzhou, People's Republic of China.
Abstract:
Artesunate (ARS) has been shown to be highly effective against chloroquine-resistant malaria. In vitro studies reported that ARS has anticancer effects; however, its detrimental action on cancer cells may also play a role in its toxicity toward normal cells and its potential toxicity has not been sufficiently researched. In this study, we investigated the possible cytotoxic effects using normal BRL-3A and AML12 liver cells. The results showed that ARS dose-dependently inhibited cell proliferation and arrested the G0/G1 phase cell cycle in both BRL-3A and AML12 liver cells. Western blotting demonstrated that ARS induced a significant downregulation of cyclin-dependent kinase-2 (CDK2), CDK4, cyclin D1, and cyclin E1 in various levels and then caused apoptosis when the Bcl-2/Bax ratio decreased. Conversely, the levels of intracellular reactive oxygen species (ROS) were increased. The ROS scavenger N-acetylcysteine can significantly inhibit cell cycle arrest and apoptosis induced by ARS. Thus, the data confirmed that ARS exposure impairs normal liver cell proliferation by inducing G0/G1 cell cycle arrest and apoptosis, and this detrimental action may be associated with intracellular ROS accumulation. Collectively, the possible side effects of ARS on healthy normal cells cannot be neglected when developing therapies.
Insights
Artesunate (ARS) impairs normal liver cell proliferation by halting cell cycle progression and inducing apoptosis. This toxicity is linked to increased reactive oxygen species (ROS) and warrants consideration in therapy development.
Area of Science:
- Pharmacology
- Toxicology
- Cell Biology
Background:
- Artesunate (ARS) is effective against malaria.
- ARS exhibits in vitro anticancer effects.
- Potential toxicity of ARS on normal cells requires investigation.
Purpose of the Study:
- To investigate the cytotoxic effects of ARS on normal liver cells (BRL-3A and AML12).
- To elucidate the mechanisms underlying ARS-induced normal cell toxicity.
Main Methods:
- Cell proliferation assays.
- Cell cycle analysis (G0/G1 phase arrest).
- Western blotting for cell cycle regulators (CDK2, CDK4, cyclin D1, cyclin E1) and apoptosis markers (Bcl-2/Bax ratio).
- Measurement of intracellular reactive oxygen species (ROS) levels.
- Assessment of ROS scavenger (N-acetylcysteine) effects.
Main Results:
- ARS dose-dependently inhibited proliferation and induced G0/G1 cell cycle arrest in BRL-3A and AML12 cells.
- ARS downregulated key cell cycle proteins (CDK2, CDK4, cyclin D1, cyclin E1) and decreased the Bcl-2/Bax ratio, promoting apoptosis.
- ARS increased intracellular ROS levels, and N-acetylcysteine treatment mitigated ARS-induced cell cycle arrest and apoptosis.
Conclusions:
- ARS impairs normal liver cell proliferation via G0/G1 cell cycle arrest and apoptosis.
- Intracellular ROS accumulation is implicated in ARS-induced normal cell toxicity.
- The potential side effects of ARS on healthy cells should be considered during therapeutic development.
