DataSheet_1_Asparagus officinalis Exhibits Anti-Tumorigenic and Anti-Metastatic Effects in Ovarian Cancer.pdf

Ovarian cancer is one of the leading causes of female cancer death. Emerging evidence suggests that many dietary natural products have anti-tumorigenic activity, including that of asparagus officinalis. The current study aimed to assess the anti-tumorigenic and anti-metastatic effects of asparagus officinalis on serous ovarian cancer cell lines and a transgenic mouse model of high grade serous ovarian cancer. Asparagus officinalis decreased cellular viability, caused cell cycle G1 phase arrest and induced apoptosis in the OVCAR5 and SKOV3 cells. Induction of apoptosis and inhibition of cell proliferation was rescued by the pan-caspase inhibitor, Z-VAD-FMK, implying that its cytotoxic effects were mainly dependent on caspase pathways. Asparagus officinalis increased levels of ROS and decreased mitochondrial membrane potential with corresponding increases in PERK, Bip, Calnexin PDI and ATF4 in both cell lines. Treatment with asparagus officinalis also reduced ability of adhesion and invasion through epithelial–mesenchymal transition and reduction of VEGF expression. The combination of Asparagus officinalis with paclitaxel had synergistic anti-proliferative activity. Furthermore, Asparagus officinalis significantly inhibited tumor growth and reduced serum VEGF in a genetically engineered mouse model of ovarian cancer under obese and lean conditions, accompanied with a decrease in the expression of Ki67, VEGF and phosphorylated S6, and in an increase in phosphorylation of AMPK in the ovarian tumor tissues. Overall, our data provide a pre-clinical rationale for asparagus officinalis in the prevention and treatment of ovarian cancer as a novel natural product.

卵巢癌是女性恶性肿瘤相关死亡的主要诱因之一。日益增多的研究证据表明，诸多膳食来源天然产物具备抗肿瘤活性，其中包括石刁柏（Asparagus officinalis）。本研究旨在评估石刁柏对浆液性卵巢癌（serous ovarian cancer）细胞系，以及高级别浆液性卵巢癌（high grade serous ovarian cancer）转基因小鼠模型的抗肿瘤与抗转移效应。石刁柏可降低OVCAR5与SKOV3细胞的细胞活力，引发细胞周期G1期阻滞，并诱导细胞凋亡。泛半胱天冬酶抑制剂Z-VAD-FMK能够逆转石刁柏介导的细胞凋亡与增殖抑制作用，提示其细胞毒性效应主要依赖半胱天冬酶通路。石刁柏可升高两种细胞系内的活性氧（Reactive Oxygen Species, ROS）水平，降低线粒体膜电位，同时上调PERK、Bip、Calnexin PDI及ATF4的蛋白表达水平。经石刁柏处理后，细胞的黏附与侵袭能力也有所下降，这一效应与上皮间质转化（Epithelial-Mesenchymal Transition, EMT）受抑制以及血管内皮生长因子（Vascular Endothelial Growth Factor, VEGF）表达下调相关。石刁柏与紫杉醇（paclitaxel）联合使用时，可展现出协同抗增殖活性。此外，在肥胖与正常体重两种状态下的卵巢癌基因工程小鼠模型中，石刁柏均可显著抑制肿瘤生长并降低血清VEGF水平；同时卵巢肿瘤组织内Ki67、VEGF及磷酸化S6蛋白的表达量下调，腺苷酸活化蛋白激酶（AMP-activated Protein Kinase, AMPK）的磷酸化水平升高。综上，本研究数据为石刁柏作为新型天然产物应用于卵巢癌的预防与治疗提供了临床前理论支撑。