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Dihydrotanshinone induces p53-independent but ROS-dependent apoptosis in colon cancer cells
1Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, China.
Aims:
The therapeutic potential of various tanshinones was examined and compared for their anti-cancer activities on colon cancer cells. The role of ROS generation in the pro-apoptotic activity of dihydrotanshinone (DHTS) was further studied.
Main Methods:
Cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis and poly-ADP-ribose-polymerase (PARP) cleavage were respectively measured by flow cytometer and Western blot. Changes of mitochondrial membrane potential (MMP), mitochondrial ROS (mitoROS) and total ROS were determined by confocal system under an inverted microscope.
Key Findings:
Among the different tanshinones examined, DHTS produced the most potent anti-cancer effect. DHTS induced a selective cytotoxicity and apoptosis in both HCT116 p53(-/-) and HCT116 p53(+/+) colon cancer cells. A time- and concentration-dependent PARP cleavage further confirmed the apoptotic activity. In this regard, it was found DHTS provoked mitochondrial dysfunction in the early stage by decreasing MMP and mitoROS levels. This was followed by a time-dependent increase in intracellular ROS generation. Pretreatment with N-acetyl-l-cysteine (NAC) or catalase-PEG, the free radical scavengers, reduced apoptotic cell death. From these findings, it seems that leakage of ROS from mitochondria into cytosol by DHTS represents the major contributory factor leading to cell death in colon cancer cells.
Significance:
We report for the first time that DHTS induces apoptosis in colon cancer cells through a p53-independent pathway. Disturbance of ROS generation at the oxidative phosphorylation (OXPHOS) complex in mitochondria followed by the decrease of MMP and increase of intracellular ROS accumulation are suggested to be involved in the pro-apoptotic activity of DHTS.
Insights
Dihydrotanshinone (DHTS) effectively combats colon cancer by inducing apoptosis, a process linked to mitochondrial dysfunction and reactive oxygen species (ROS) generation. This study reveals DHTS
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Tanshinones are natural compounds with potential anti-cancer properties.
- Colon cancer remains a significant global health challenge, necessitating novel therapeutic strategies.
- Understanding the mechanisms of action for anti-cancer agents is crucial for drug development.
Purpose of the Study:
- To evaluate and compare the anti-cancer activities of various tanshinones against colon cancer cells.
- To investigate the role of reactive oxygen species (ROS) generation in dihydrotanshinone (DHTS)-induced apoptosis.
- To elucidate the specific molecular pathways involved in DHTS-mediated cell death.
Main Methods:
- Cell viability assessed using the MTT assay.
- Apoptosis and poly-ADP-ribose-polymerase (PARP) cleavage measured by flow cytometry and Western blot, respectively.
- Mitochondrial membrane potential (MMP), mitochondrial ROS (mitoROS), and total ROS quantified using confocal microscopy.
Main Results:
- Dihydrotanshinone (DHTS) exhibited the most potent anti-cancer effect among tested tanshinones.
- DHTS induced selective cytotoxicity and apoptosis in colon cancer cells, irrespective of p53 status.
- DHTS triggered mitochondrial dysfunction (decreased MMP and mitoROS) followed by increased intracellular ROS, leading to apoptosis.
Conclusions:
- DHTS induces apoptosis in colon cancer cells via a p53-independent pathway.
- Mitochondrial dysfunction and subsequent ROS accumulation are key mechanisms in DHTS-induced apoptosis.
- DHTS demonstrates significant therapeutic potential for colon cancer treatment.
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