사람 두경부 편평세포암종 FaDu에서 cimifugin의 항암효과 분석

Abstract

Head and neck squamous cell cancer (HNSCC) is a common cancer that are affecting various parts of the head and neck, and its treatment typically involves surgery, radiation therapy, chemotherapy, or a combination of these approaches. However, these treatments often cause side effects, including facial deformities, dry mouth, nausea, and loss of taste, highlighting the need for effective chemotherapeutic agents that induce cancer-specific apoptosis with fewer side effects. Flavonoids are natural substances that exhibit biological safety and pharmacological effects, making them an interesting option for the development of anticancer drugs with minimal side effects. Cimifugin is a physiologically active substance derived from Saposhnikovia divaricata (Turcz.) Schischk, with known anti-allergy and anti-inflammatory effects, but its potential anticancer effects against HNSCC have not yet been explored. Therefore, the main goal of this study was to investigate the effect of cimifugin on cell growth and apoptosis induction in FaDu human head and neck squamous cell carcinoma.

Cimifugin significantly increased FaDu cell death while not affecting the viability of the L929 mouse fibroblast cell line. Treatment with cimifugin for 24 hours resulted in morphological changes, nuclear condensation, and an increase in the apoptotic population, which are typical characteristics of apoptosis. FasL, an apoptosis inducer, was significantly increased in a dose-dependent manner in FaDu cells, confirming that death receptor-mediated apoptosis was mediated through the activation of caspase-8. Furthermore, cimifugin activated Bid, a cell death factor, into tBid by the activated caspase-8, increasing expression of Bax and Bad, and reducing expression of Bcl-2 and Bcl-xL, which are cell death inhibitors. By reducing the mitochondria membrane potential and secreting cytochrome c into the cytoplasm, it was confirmed that FaDu cell death was mediated by mitochondria dependent intrinsic apoptosis through caspase-9 activation. Finally, it was confirmed that stepwise activation of caspase-3 and poly (ADP ribose) polymerase (PARP) was mediated by death receptor-mediated apoptosis and mitochondria dependent intrinsic apoptosis, caspase-8 and caspase-9, respectively. In particular, cimifugin-induced apoptosis of FaDu cells not only inhibited phosphorylation of mitogen-activated protein kinase (MAPK) including ERK1/2 and p38 but also was regulated by Akt and nuclear factor (NF)-κB cell signaling pathways.

These findings suggest that cimifugin inhibits cell proliferation and induces apoptotic cell death in FaDu human head and neck squamous cell carcinomas through both the death receptor-mediated (extrinsic) apoptotic pathway and the mitochondria-dependent (intrinsic) apoptotic pathway. These results indicate that cimifugin could be a candidate for a chemical treatment with biological safety and excellent anticancer effects for the treatment of HNSCC.