In Vitro and In Vivo Effects of Quillaja saponaria Bark Saponin Against Ovarian Cancer Cells

Background: Ovarian cancer is one of the most lethal gynecologic cancers in the world. It has also characterized by late diagnosis, high recurrence rate, and poor  prognosis. The advanced stage at diagnosis and the development of chemoresistance are major challenges in its treatment, leading to limited therapeutic options and decreased survival rates. Natural products have emerged as a promising source of novel anticancer agents due to their diverse bioactive compounds and potential to target multiple signaling pathways involved in cancer initiation and progression. Objectives: Ovarian cancer metastasis is the leading cause of cancer-related deaths in women worldwide. The effects of Quillaja saponaria bark saponin (QBS) on the viability and epithelial-mesenchymal transition (EMT) potential of human ovarian epithelial SKOV-۳ and A۲۷۸۰ cells, and the cytotoxicity effect of QBS in the rat ovarian cancer model have been investigated. Methods: The cytotoxicity of QBS against SKOV۳ and A۲۷۸۰ cells was evaluated using the ۳-(۴, ۵-dimethylthiazol-۲-yl)-۲,۵-diphenyltetrazolium bromide (MTT) assay to calculate IC۵۰ values. The scratch assay assessed cell migration. To explore molecular changes in metastasis, the expression of key EMT-related genes, including ITGA۵, MMP۲, Zeb۱, and CDH۱ was measured by real-time polymerase chain reaction. For the in vivo assay, the ۷,۱۲-dimethylbenz[a]anthracene (DMBA)-induced ovarian cancer rat model was used.  Results: The MTT assay demonstrated that QBS did not exert significant toxicity on NIH۳T۳ as normal cells; nevertheless, it induced cytotoxicity against A۲۷۸۰ and SKOV۳ cells in a dose and time-dependent manner; IC۵۰ was determined as ۸۲ and ۷۷ μg/mL for SKOV۳ and A۲۷۸۰ cells, respectively. The scratch assay revealed that QBS significantly attenuated cell invasion at sub-IC۵۰ concentrations (۲۰ and ۳۰ µg/mL). Gene expression indicated down-regulation of Zeb۱, ITGA۵, and MMP۲ at the IC۵۰ value of both SKOV۳ and A۲۷۸۰ cells (P≤۰.۰۰۱). Also, up-regulation of CDH۱ in A۲۷۸۰ cells at the IC۵۰ value was significant (P≤۰.۰۰۱). The in vivo assay showed that QBS significantly reduced tumor growth (P≤۰.۰۱) and protected rats against ۷,۱۲- DMBA-induced ovarian cancer, with optimal effect of ۱۶ mg/kg. Conclusion: Overall, QBS can offer a potent cytotoxic agent against ovarian cancer cells in vitro and in vivo. However, this hypothesis requires further investigation to discover the molecular signaling pathway in human ovarian cancer cells.

کلیدواژه ها:

Ovarian cancer ، Migration ، Quillaja saponaria bark saponin (QBS) ، ITGA۵ ، MMP۲ ، Zeb۱ ، CDH۱