Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, 5 Fuxing Street, Guishan District, Taoyuan 33305, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Guishan, 259 Wenhua 1st Road, Taoyuan 33302, Taiwan.
Department of Veterinary Medicine, College of Veterinary Medicine, National Pingtung University of Science and Technology, 1 Shuefu Road, Neipu, Pingtung 912301, Taiwan.
Biomed Pharmacother. 2022 Jul;151:113128. doi: 10.1016/j.biopha.2022.113128. Epub 2022 May 24.
The haskap (Lonicera caerulea L., Caprifoliaceae) berry has been widely used in traditional medicine in Kuril Islands, Russia, Japan, and China. Cyanidin-3-O-glucoside (C3G) is the most abundant anthocyanin in haskap berries, and C3G induces antiproliferative pharmacological activity in various cancer cells. However, no study has investigated its anti-lung large-cell carcinoma (LCC) pharmacological role. Therefore, this study determined whether C3G alone or C3G combined with 5-fluorouracil (5-FU) inhibits human lung LCC. We determined the tumor growth, apoptosis, inflammation, and metastasis in the H661 lung LCC lines xenografted into BALB/c nude mice. The mice were administered saline (control), 5-FU, C3G, or both C3G and 5-FU. Relative to the control mice, those treated with C3G alone or both C3G and 5-FU exhibited impaired tumor growth; increased tumor apoptosis; decreased inflammatory cytokine levels (e.g., IL-1β, TNF-α, C-reactive protein, and IL-6); decreased inflammation-related factors, including cyclooxygenase-2 protein and nuclear factor-κB (NF-κB) mRNA; increased inhibition of NF-κB kinase α mRNA; and downregulated metastasis-related factors, such as transforming growth factor-β, CD44, epidermal growth factor receptor, and vascular endothelial growth factor. In addition, C3G alone or combined with 5-FU affected the expression of the tumor microenvironment-related factors Ki67, CD45, PDL1, and CD73. Compared with the mice treated with 5-FU or C3G alone, those treated with both C3G and 5-FU exhibited significantly impaired tumor growth, decreased tumor sizes, and increased tumor inhibition. This in vivo study demonstrated that C3G alone or combined with 5-FU may impair the growth of lung LCC and inhibit tumorigenesis. The findings indicate that C3G alone or C3G combined with 5-FU may be beneficial for treating human lung LCC.
红豆越橘（Lonicera caerulea L.，忍冬科）浆果在俄罗斯千岛群岛、日本和中国被广泛应用于传统医学。飞燕草素-3-O-葡萄糖苷（C3G）是红豆越橘浆果中最丰富的花青素，C3G 可诱导多种癌细胞的抗增殖药理活性。然而，尚无研究探讨其抗肺大细胞癌（LCC）的药理作用。因此，本研究旨在确定 C3G 单独或与 5-氟尿嘧啶（5-FU）联合使用是否能抑制人肺 LCC。我们检测了 C3G 单独或与 5-FU 联合使用对荷人肺 LCC 细胞 H661 裸鼠的肿瘤生长、细胞凋亡、炎症和转移的影响。与对照组相比，单独使用 C3G 或 C3G 与 5-FU 联合使用的小鼠肿瘤生长受损；肿瘤细胞凋亡增加；炎症细胞因子水平（如 IL-1β、TNF-α、C 反应蛋白和 IL-6）降低；炎症相关因子，包括环氧化酶-2 蛋白和核因子-κB（NF-κB）mRNA 减少；NF-κB 激酶α mRNA 的抑制作用增强；转移相关因子如转化生长因子-β、CD44、表皮生长因子受体和血管内皮生长因子下调。此外，C3G 单独或联合 5-FU 还影响肿瘤微环境相关因子 Ki67、CD45、PDL1 和 CD73 的表达。与单独使用 5-FU 或 C3G 的小鼠相比，同时使用 C3G 和 5-FU 的小鼠肿瘤生长明显受损，肿瘤体积减小，肿瘤抑制率增加。本体内研究表明，C3G 单独或联合 5-FU 可能会抑制肺 LCC 的生长并抑制肿瘤发生。这些发现表明，C3G 单独或与 5-FU 联合使用可能有益于治疗人类肺 LCC。
