Polyphenols Extracted from Chinese Hickory (Carya cathayensis) Promote Apoptosis and Inhibit Proliferation through the p53-Dependent Intrinsic and HIF-1α-VEGF Pathways in Ovarian Cancer Cells

Abstract

Ovarian cancer is the second most common gynecologic cancer with an estimated 13,940 mortalities across the United States in 2020. Natural polyphenols have been shown to double the survival time of some cancer patients due to their anticancer properties. Therefore, the effect of polyphenols extracted from Chinese hickory seed skin Carya cathayensis (CHSP) on ovarian cancer was investigated in the present study. Cell viability results showed that CHSP is more effective in inhibiting ovarian cancer cells than normal ovarian cells, with the IC50 value for inhibition of cell proliferation of Ovarian cancer cells (OVCAR-3) being 10.33 ± 0.166 µg/mL for a 24 h treatment. Flow cytometry results showed that the apoptosis rate was significantly increased to 44.21% after 24 h treatment with 20 µg/mL of CHSP. Western blot analysis showed that CHSP induced apoptosis of ovarian cancer cells through a p53-dependent intrinsic pathway. Compared with control values, levels of VEGF excreted by OVCAR-3 cancer cells were reduced to 7.87% with a 40 µg/mL CHSP treatment. Consistent with our previous reports, CHSP inhibits vascular endothelial growth factor (VEGF) secretion by regulating the HIF-1α-VEGF pathway. In addition, we also found that the inhibitory effect of CHSP on ovarian cancer is related to the up-regulation of Phosphatase and tension homolog (PTEN) and down-regulation of nuclear factor kappa-B (NF-kappa B). These findings provide some evidence of the anti-ovarian cancer properties of CHSP and support the polyphenols as potential candidates for ovarian cancer adjuvant therapy.

HIF-1α Is a Rational Target for Future Ovarian Cancer Therapies

“…For many years, phenolic compounds extracted from plants have been shown to play a critical role in the fight against cancer (112). In 2020, research showed that polyphenol extracts of Carya cathayensis can inhibit the proliferation of ovarian cancer and suppress VEGF expression via the inhibition of HIF-1a (113). However, early in 2016, gallic acid, a main polyphenolic compound of C. cathayensis, was shown to upregulate PTEN expression and suppress the phosphorylation of AKT, which led to the downregulation of HIF-1a and VEGF to hamper angiogenesis in ovarian cancer (114) (Figure 4).…”

“…On the basis of the proposed concept of precision medicine, targeted drugs developed based on tumour characteristics have emerged in an endless stream, and among these drugs, antiangiogenic agents mainly target VEGF, thereby inhibiting a series of pathophysiological processes regulated by VEGF and benefiting patients with tumours such as ovarian or breast cancer (163,164). Because VEGF is a downstream gene of HIF-1a, VEGF expression is decreased when the expression or function of HIF-1a is inhibited (55,113,114,118), and HIF-1a can regulate the expression of other genes that promote tumour progression. Therefore, we concluded that targeting HIF-1a may effectively inhibit tumour development.…”

Gallic Acid Induces S and G2 Phase Arrest and Apoptosis in Human Ovarian Cancer Cells In Vitro

“…The mitochondrial intrinsic pathway is the main pathway for polyphenols to induce cell apoptosis [ 30 , 31 ]. In this research, we demonstrated marked elevation in pro-apoptotic proteins; namely, cleaved caspase-3 (4.53-fold), Bad (1.33-fold) and Bax (1.53-fold).…”

Dietary Polyphenols against Oxidative Stress in Head and Neck Cancer: What's New, What's Next

“…The scientific literature extensively deals with the potential anticancer activity of polyphenols on various types of cancer cells, including human colon cancer, lung cancer, breast cancer, ovarian cancer, and hepatocellular cell lines [92][93][94][95][96]. Polyphenol extracts have demonstrated effectiveness in preventing skin cancer and have shown utility in the treatment of this highly aggressive form of cutaneous cancer [97].…”