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Artemisinin Derivatives Inhibit Non-small Cell Lung Cancer Cells Through Induction of ROS-dependent
Qiuting Zhang1,2,3, Huimei Yi1,2, Hui Yao1,2
1Key Laboratory of Translational Cancer Stem Cell Research, Hunan Normal University, Changsha, Hunan 410013, China.
Abstract:
Non-small cell lung cancer (NSCLC) is one of the major cancer-related causes of morbidity and mortality worldwide. Despite the progress in lung cancer treatment, there is still an urgent need to discover novel therapeutic agents for NSCLC. Natural products represent a rich source of bioactive compounds. Through a natural compound library screening assay, we found that a group of anti-insect drugs had significant inhibitory effect on the proliferation of NSCLC cells. Among the anti-insect drugs, two derivatives of artemisinin, i.e., artesunate (ART) and dihydroartemisinin (DHA), a group of well-known anti-malarial drugs, have been shown to possess selective anti-cancer properties. Mechanistically, we found that ART and DHA induced apoptosis of A549 cells as evidenced by decreased protein level of VDAC and increased caspase 3 cleavage. Furthermore, cystine/glutamate transporter (xCT), a core negative regulator of ferroptosis, was downregulated by ART and DHA. The mRNA level of transferrin receptor (TFRC), a positive regulator of ferroptosis, was upregulated by ART and DHA. ART/DHA-induced apoptosis and ferroptosis in NSCLC cells were partly reversed by N-Acetyl-L-cysteine (NAC), a ROS scavenger, and ferrostatin-1, a ferroptosis inhibitor, respectively. These results suggest that artemisinin derivatives have anti-NSCLC activity through induction of ROS-dependent apoptosis/ferroptosis. Our findings provide the experimental basis for the potential application of artemisinin derivatives as a class of novel therapeutic drugs for NSCLC.
Insights
Artemisinin derivatives like artesunate and dihydroartemisinin show promise in treating non-small cell lung cancer (NSCLC). These compounds induce cell death via apoptosis and ferroptosis, offering a new therapeutic avenue for NSCLC patients.
Area of Science:
- Oncology
- Pharmacology
- Natural Products Chemistry
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality globally.
- Existing treatments for NSCLC necessitate the discovery of novel therapeutic agents.
- Natural products are a valuable source for identifying new bioactive compounds.
Purpose of the Study:
- To investigate the anti-cancer properties of natural compounds against NSCLC cells.
- To explore the therapeutic potential of artemisinin derivatives (artesunate and dihydroartemisinin) in NSCLC treatment.
Main Methods:
- Screening of a natural compound library to identify compounds inhibiting NSCLC cell proliferation.
- Treatment of A549 NSCLC cells with artesunate (ART) and dihydroartemisinin (DHA).
- Analysis of apoptosis markers (VDAC, cleaved caspase-3) and ferroptosis regulators (xCT, TFRC).
- Assessment of the effects of N-Acetyl-L-cysteine (NAC) and ferrostatin-1 on ART/DHA-induced cell death.
Main Results:
- ART and DHA significantly inhibited NSCLC cell proliferation.
- ART and DHA induced apoptosis in A549 cells, indicated by altered VDAC and caspase-3 levels.
- ART and DHA downregulated cystine/glutamate transporter (xCT) and upregulated transferrin receptor (TFRC), key regulators of ferroptosis.
- ART/DHA-induced apoptosis and ferroptosis were partially reversed by NAC and ferrostatin-1, respectively.
- Artemisinin derivatives trigger Reactive Oxygen Species (ROS)-dependent apoptosis and ferroptosis in NSCLC cells.
Conclusions:
- Artemisinin derivatives exhibit significant anti-NSCLC activity.
- The anti-cancer effects are mediated through the induction of ROS-dependent apoptosis and ferroptosis.
- Artemisinin derivatives represent a promising class of novel therapeutic agents for NSCLC.
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