Antiovarian cancer mechanism of esculetin: inducing G0/G1 arrest and apoptosis via JAK2/STAT3 signalling pathway

Abstract

Objectives Esculetin is a coumarin derivative, which is extracted from the dried barks of fraxinus chinensis Roxb. Although it is reported esculetin possesses multiple pharmacological activities, its associated regulatory mechanism on ovarian cancer isn’t well investigated. Methods Cytotoxicity is evaluated by MTT, clonogenic and living/dead cells staining assays. Migration and invasion effects are investigated by wound healing, and transwell assays. The effect of cell cycle and apoptosis are analyzed by flow cytometry and western blotting. Mitochondrial membrane potential and intracellular reactive oxygen species (ROS) is assessed by fluorescence microscope. Analysis of animal experiments are carried out by various pathological section assays. Key findings Esculetin exerts an anti- ovarian cancer effect. It is found that apoptosis induction is promoted by the accumulation of excessive ROS and inhibition of JAK2/STAT3 signalling pathway. In addition, exposure to esculetin leads to the cell viability reduction, migration and invasion capability decrease and G0/G1 phase cell cycle arrest induced by down-regulating downstream targets of STAT3. In vivo experimental results also indicate esculetin can inhibit tumour growth of mice. Conclusions Our study provides some strong evidences to support esculetin as a potential anti-cancer agent in ovarian cancer.

Therapeutic potential of esculetin in various cancer types (Review)

“…Esc also delayed wound healing in these cells, indicating its migration-inhibitory properties. Transwell assays also demonstrated that Esc suppressed the migration and invasion of SKOV3 cells ( 35 , 37 ). Furthermore, flow cytometry and western blotting analysis revealed that Esc treatment decreased the expression of cyclin D1, CDK4, CDK2 and cyclin E, suggesting its role in regulating the cell cycle in SKOV3 and HeLa cells ( 35 ).…”

“…Studies conducted by Yin et al ( 35 ), Jiang et al ( 36 ) and Yang et al ( 37 ) revealed that Esc inhibited the proliferation of SKOV3 ovarian cancer cells, Ishikawa and HEC-1B endometrial cancer cells, and HeLa cervical adenocarcinoma cells in a time- and dose-dependent manner, but Esc showed low cytotoxicity towards human L02 normal hepatocyte cells ( 35 ). In addition to inhibiting cell proliferation, a single cell colony formation assay showed that Esc exerted an inhibiting effect on the colony forming ability of SKOV3 ovarian cancer cells.…”

“…Esc also exhibits antimitogenic effects on ovarian, endometrial and cervical cancer cells. Treatment with Esc led to an increase in the ratio of red to green fluorescence, indicating a reduction in the mitochondrial membrane potential by Mitochondrial Membrane Potential Detection Kit (JC-10) ( 35 ). Western blotting analysis confirmed that Esc induced apoptosis, as concentration-dependent increase of apoptosis-related proteins and a decrease of anti-apoptosis proteins was induced in SKOV3 ovarian cancer cells, Ishikawa and HEC-1B endometrial cancer cells by causing mitochondrial membrane potential collapse.…”

Esculetin unveiled: Decoding its anti‐tumor potential through molecular mechanisms—A comprehensive review

“…82 Esculetin had shown to diminish cell viability and promote apoptosis via a G0/G1 cell cycle arrest characterized by increased ROS generation in both in vitro and in vivo studies. 83 In conclusion, esculetin has the potential to function as a therapeutic agent for the treatment of ovarian cancer by inhibiting cell growth and triggering apoptosis via the activation of caspases and the JAK2/STAT3 signaling pathway.…”

“…Esculetin induced apoptosis and inhibited cell proliferation in HO‐8910 cells in vitro by enhancing the expression of caspase‐3, ‐9, and Bax/Bcl‐2 82 . Esculetin had shown to diminish cell viability and promote apoptosis via a G0/G1 cell cycle arrest characterized by increased ROS generation in both in vitro and in vivo studies 83 …”