Abstract

 
 
 
 Purpose: To investigate the anticancer effects of 7-hydroxycoumarin against cisplatin-resistant ovarian cancer cell line, and the underlying mechanism(s).
 Methods: Cell proliferation was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The 4’,6-diamidino-2-phenylindole (DAPI) and acridine orange/ethidium bromide (AO/EB) dual staining methods were used for measuring cell apoptosis in terms of DNA damage. Flow cytometry was used for analysis of mitosis of cancer cells, while protein expression levels were assayed with western blotting.
 Results: The 7-hydroxycoumarin preferentially inhibited the proliferation of the ovarian cancer cells, but had significantly less prominent effects on normal cells (p < 0.05). The decrease in cell proliferation was due to induction of cell apoptosis via caspase-linked apoptotic pathway. Treatment with 7- hdoxycoumarin further led to the arrest of cancer cell cycle at G2/M stage (p < 0.05) via down-regulation of the expressions of regulatory proteins that promote mitotic entry.
 Conclusion: 7-Hydroxycoumarin exerts significant anticancer effect against cisplatin-resistant ovarian cancer cells via decrease in cell proliferation, induction of apoptosis and mitotic cell cycle arrest. Thus, the compound could emerge as a vital lead molecule in the treatment of cisplatin-resistant type of human ovarian cancer.
 
 
 
Highlights
Ovarian cancer is one of the most dominant malignancies in women [1]
Effect of 7-hydroxycoumarin on proliferation of cisplatin-resistant ovarian cancer cells hydroxycoumarin showed that hydroxycoumarin induced apoptosis of the cancer cells (Figure 3)
Apoptosis of the cancer cells was evident as deformation of nuclear morphology, with the effects being comparatively greater at high concentrations of 7-hydroxycoumarin
Summary
Ovarian cancer is one of the most dominant malignancies in women [1]. The disease has a prevalence of approximately 2.5 % among women worldwide [2]. Studies have reported that in some instances, ovarian cancer cells developed resistance to cisplatin [7]. It is necessary to evolve anticancer agents that will be effective against cisplatin-resistant ovarian cancer cells. 7-hydroxycoumarin was shown to negatively affect the proliferation of cisplatinresistant ovarian cancer cells, with no effect on normal ovarian cells. The anti-proliferative effects of 7-hydroxycoumarin were evident in terms of its potential to induce caspase-driven apoptosis of cisplatin-resistant ovarian cancer cells. The results showed that 7-hydroxycoumarin restricted the growth of cisplatin-resistant ovarian cancer cells through induction of apoptosis and cell cycle arrest. The effect of 7- hydroxycoumarin on the cell cycle of cisplatin-resistant ovarian cancer cells was determined flow cytometrically by culturing the cells with 6, 12 or 18 μM 7-hydroxycoumarin in 6-well plates for 24 h at 37 oC. Values of p < 0.05 were taken as indicative of statistically significant difference
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