Sinularin Induces Oxidative Stress-Mediated Apoptosis and Mitochondrial Dysfunction, and Inhibits Angiogenesis in Glioblastoma Cells.
Shih-Yuan HsuZhi-Hong WenPo-Chang ShihHsiao-Mei KuoSung-Chun LinHsin-Tzu LiuYi-Hsin LeeYi-Jen WangWu-Fu ChenNan-Fu ChenPublished in: Antioxidants (Basel, Switzerland) (2022)
Glioblastoma multiforme (GBM) is a cancer of largely unknown cause that leads to a 5-year survival rate of approximately 7% in the United States. Current treatment strategies are not effective, indicating a strong need for the development of novel therapies. In this study, the outcomes of sinularin, a marine-derived product, were evaluated against GBM. Our cellular studies using GBM cells revealed that sinularin induces cell death. The measured half maximal inhibitory concentrations (IC 50 ) values ranged from 30 to 6 μM at 24-72 h. Cell death was induced via the generation of ROS leading to mitochondria-mediated apoptosis. This was evidenced by annexin V/propidium iodine staining and an upregulation of cleaved forms of the pro-apoptotic proteins caspase 9, 3, and PARP, and supported by CellROX TM Green, MitoSOX TM Red, and CM-H 2 DCFDA staining methods. In addition, we observed a downregulation of the antioxidant enzymes SOD1/2 and thioredoxin. Upon treatment with sinularin at the ~IC 50 concentration, mitochondrial respiration capacities were significantly reduced, as shown by measuring the oxygen consumption rates and enzymatic complexes of oxidative phosphorylation. Intriguingly, sinularin significantly inhibited indicators of angiogenesis such as vessel tube formation, cell migration, and cell mobility in human umbilical vein endothelial cells or the fusion cell line EA.Hy926. Lastly, in a transgenic zebrafish model, intersegmental vessel formation was also significantly inhibited by sinularin treatment. These findings indicate that sinularin exerts anti-brain cancer properties that include apoptosis induction but also antiangiogenesis.
Keyphrases
- cell death
- cell cycle arrest
- oxidative stress
- induced apoptosis
- endothelial cells
- cell migration
- dna damage
- high glucose
- endoplasmic reticulum stress
- diabetic rats
- papillary thyroid
- vascular endothelial growth factor
- signaling pathway
- single cell
- cell proliferation
- squamous cell
- pi k akt
- nitric oxide
- computed tomography
- magnetic resonance
- poor prognosis
- cell therapy
- magnetic resonance imaging
- mesenchymal stem cells
- blood pressure
- resistance training
- body composition
- ischemia reperfusion injury
- white matter
- blood brain barrier
- wound healing
- heat stress
- flow cytometry
- weight loss
- subarachnoid hemorrhage
- reactive oxygen species
- cerebral ischemia
- dna repair
- combination therapy
- lymph node metastasis