Apigenin causes necroptosis by inducing ROS accumulation, mitochondrial dysfunction, and ATP depletion in malignant
Yoon-Jin Lee1, Kwan-Sik Park1, Hae-Seon Nam2
1Department of Biochemistry, Soonchunhyang University College of Medicine, Cheonan 31151, Korea.
Abstract:
Apigenin, a naturally occurring flavonoid, is known to exhibit significant anticancer activity. This study was designed to determine the effects of apigenin on two malignant mesothelioma cell lines, MSTO-211H and H2452, and to explore the underlying mechanism(s). Apigenin significantly inhibited cell viability with a concomitant increase in intracellular reactive oxygen species (ROS) and caused the loss of mitochondrial membrane potential (Δ𝚿m), and ATP depletion, resulting in apoptosis and necroptosis in monolayer cell culture. Apigenin upregulated DNA damage response proteins, including the DNA double strand break marker phospho (p)- histone H2A.X. and caused a transition delay at the G2/M phase of cell cycle. Western blot analysis showed that apigenin treatment upregulated protein levels of cleaved caspase-3, cleaved PARP, p-MLKL, and p-RIP3 along with an increased Bax/Bcl-2 ratio. ATP supplementation restored cell viability and levels of DNA damage-, apoptosisand necroptosis-related proteins that apigenin caused. In addition, N-acetylcysteine reduced ROS production and improved Δ𝚿m loss and cell death that were caused by apigenin. In a 3D spheroid culture model, ROS-dependent necroptosis was found to be a mechanism involved in the anti-cancer activity of apigenin against malignant mesothelioma cells. Taken together, our findings suggest that apigenin can induce ROS-dependent necroptotic cell death due to ATP depletion through mitochondrial dysfunction. This study provides us a possible mechanism underlying why apigenin could be used as a therapeutic candidate for treating malignant mesothelioma.
Insights
Apigenin, a flavonoid, combats mesothelioma by inducing cell death through reactive oxygen species (ROS) and mitochondrial dysfunction. This natural compound shows promise as a potential therapeutic agent for this cancer.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Apigenin is a flavonoid with known anticancer properties.
- Malignant mesothelioma is an aggressive cancer with limited treatment options.
Purpose of the Study:
- To investigate the anticancer effects of apigenin on malignant mesothelioma cell lines.
- To elucidate the mechanisms underlying apigenin's anti-mesothelioma activity.
Main Methods:
- Cell viability assays, reactive oxygen species (ROS) measurement, mitochondrial membrane potential (Δ𝚿m) assessment, and ATP level quantification.
- Western blot analysis to detect DNA damage, apoptosis, and necroptosis markers.
- 3D spheroid culture model to evaluate apigenin's efficacy in a more complex environment.
Main Results:
- Apigenin significantly reduced mesothelioma cell viability, increased ROS production, and depleted ATP, leading to apoptosis and necroptosis.
- Apigenin induced DNA damage response and cell cycle arrest at G2/M phase.
- Apigenin upregulated key proteins involved in apoptosis (caspase-3, PARP, Bax/Bcl-2 ratio) and necroptosis (p-MLKL, p-RIP3).
- ATP supplementation and N-acetylcysteine (ROS scavenger) partially reversed apigenin's effects, confirming the roles of ATP depletion and ROS.
Conclusions:
- Apigenin induces malignant mesothelioma cell death via ROS-dependent necroptosis, driven by mitochondrial dysfunction and ATP depletion.
- Apigenin's ability to trigger these pathways suggests its potential as a therapeutic candidate for malignant mesothelioma.
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