Abstract
Natural dietary molecules such as flavonoids have been recognized for their immense potential in cancer therapeutics with several health benefits. Hes-1 and Notch-1 overexpression has been associated with the progression of cervical cancer. However, the apoptosis-inducing potential of one such potent flavanol against these two key components of the Notch signaling pathway in cervical cancer has not been elucidated to date. Therefore, in this study, we performed several in vitro assays to gain detailed insight about the apoptotic inducing effect of rutin as well as its modulatory effect on Notch-1 and Hes-1 in cervical cancer cells. The results indicated that rutin led to a dose-dependent antiproliferative effects on Caski cervical cancer cells. DAPI and Mitotracker red staining revealed that rutin induced significant apoptotic effects via caspase-3/9 activation, ROS generation, and alteration in Bax/Bcl2 mRNA expression. Cell cycle analysis resulted in the arrest of cell cycle progression in G0/G1 that was associated with a reduced expression of CDK4 and Cyclin D1. The gene expression analysis further revealed that rutin treatment decreases Notch-1 and Hes-1 mRNA expression. Altogether, these results showed that rutin showed potent anticancer effects in human cervical cancer Caski cells by triggering apoptosis, G0/G1 phase arrest, and downregulating the level of Notch-1 and Hes-1 of the Notch signaling pathway.
Highlights
To further enlighten the regulatory mechanism of rutin on the cell cycle, we investigated the changes in the mRNA expression level of Cyclin D1 and CDK4 following 24 h rutin treatment by qRT-PCR analysis (Figure 4C,D)
The results indicated that rutin decreased the mRNA expression of Cyclin D1 and CDK4, which suggested that rutin could halt the progression of the cell cycle at G0/G1 phase through the regulation of CDK4 and CyclinD1 gene expression
To provide insight into the association of the apoptosis-inducing effects of rutin with two key targets, Notch-1 and Hes-1, we examined the mRNA expression by qRT-PCR
Summary
Cervical cancer is the uncontrolled proliferation of malignant cells originating within the uterine cervix. Cervical cancer is the second most common malignancy and the leading cause of mortality among women worldwide [1,2,3]. The reason behind the increased mortality rate could be the mounting drug resistance in cancer cells which leads to cancer relapse. Drug resistance usually arises due to the stimulation of proto-oncogene, deregulated cell signaling pathways, alteration in drug targets, or due to variations in the tumor microenvironment [6]. Novel drug candidates with specific cellular targets and a concurrent impact on multiple signaling pathways need to be explored for the management of cervical cancer [7]
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