Abd El-Salam Mohamed A, El-Tanbouly Ghada S, Bastos Jairo K, Metwaly Heba A
Department of Pharmacognosy, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt; Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; Department of Medicine, Harvard Medical School, Boston, 02115, MA, USA; Department of Medicine, VA Boston Healthcare System, Boston, MA 02132, USA.
Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa 11152, Egypt.
Life Sci. 2022 Jun 15;299:120497. doi: 10.1016/j.lfs.2022.120497. Epub 2022 Mar 23.
This study aims to investigate the potential synergistic effect of the combined treatment of galloylquinic acid compounds from Copaifera lucens with doxorubicin via the modulation of the Notch pathway in solid Ehrlich carcinoma-bearing mice model.
The solid tumor model was induced by subcutaneous inoculation of Ehrlich carcinoma cells in the right hind limb of mice, after serial syngeneic cell passages in the peritoneal cavity. Sixty mice were allocated into five groups including treated groups with galloylquinic acid compounds, doxorubicin, and their combination. Normal and tumor control groups were also assigned. Tissue homogenates were collected to measure the levels of the Notch-1, Hes-1, Jagged-1, TNF-α, IL-6 and VEGF, as well as SOD, MDA, and GSH. Histopathological and immunohistochemical examinations of tumor or control tissues were also performed for the levels of NF-κB p65, cyclin D1 and caspase 3 activity.
Our results showed that the combined treatment of galloylquinic acid compounds with doxorubicin significantly decreased the levels of the Notch-1, Hes-1, Jagged-1, TNF-α, IL-6, VEGF, NF-κB p65, and cyclin D1 in tumor tissues. Moreover, the compounds induced cancer cell death as evidence by increasing the caspase 3 activity, and they possessed potent inhibitory effects on oxidative stress.
Galloylquinic acid compounds exhibited promising antineoplastic effects and promoted the chemosensitivity of doxorubicin, mainly by modulating the Notch signaling pathway and its downstream effectors. These compounds may be considered in solid tumors treatment for improving the efficacy and reducing the side effects of chemotherapeutic agents.
本研究旨在通过调节 Notch 通路，探讨来自亮叶 Copaifera lucens 的没食子酰奎宁酸化合物与阿霉素联合治疗对荷实体艾氏癌小鼠模型的潜在协同作用。
在小鼠腹腔内进行同基因细胞连续传代后，将艾氏癌细胞皮下接种于小鼠右后肢诱导建立实体瘤模型。60 只小鼠分为五组，包括没食子酰奎宁酸化合物治疗组、阿霉素治疗组及其联合治疗组，还设置了正常对照组和肿瘤对照组。收集组织匀浆以测量 Notch-1、Hes-1、Jagged-1、TNF-α、IL-6 和 VEGF 的水平，以及 SOD、MDA 和 GSH 的水平。还对肿瘤或对照组织进行了组织病理学和免疫组织化学检查，以检测 NF-κB p65、细胞周期蛋白 D1 和半胱天冬酶 3 的活性水平。
我们的结果表明，没食子酰奎宁酸化合物与阿霉素联合治疗显著降低了肿瘤组织中 Notch-1、Hes-1、Jagged-1、TNF-α、IL-6、VEGF、NF-κB p65 和细胞周期蛋白 D1 的水平。此外，这些化合物通过增加半胱天冬酶 3 的活性诱导癌细胞死亡，并且它们对氧化应激具有强大的抑制作用。
没食子酰奎宁酸化合物表现出有前景的抗肿瘤作用，并提高了阿霉素的化疗敏感性，主要是通过调节 Notch 信号通路及其下游效应分子。这些化合物可用于实体瘤治疗，以提高化疗药物的疗效并减少其副作用。
