Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, 210023 Nanjing, Jiangsu, China.
Jiangsu Joint International Research Laboratory of Chinese Medicine and Regenerative Medicine, Nanjing University of Chinese Medicine, 210023 Nanjing, Jiangsu, China.
Front Biosci (Landmark Ed). 2022 May 17;27(5):160. doi: 10.31083/j.fbl2705160.
The interactions between platelets and tumor cells are well-known to play important roles in the progression of malignant tumors. Danshensu, a main water-soluble component of , can resist platelet aggregation and exert significant anti-tumor effects on various types of tumors. However, whether Danshensu could inhibit the progression of malignant tumors by suppressing the activities of platelets had not been reported.
The effects of Danshensu on the platelet activity and epithelial-mesenchymal transformation (EMT)-like invasive phenotype of SW620 colon cancer cells were assessed by stimulating with the supernatants from co-cultured platelets and SW620 cells with direct contact (SCP). The expression and secretion of proteins were determined by western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Hematoxylin and eosin (H&E) staining was performed to analyzed the histopathology of tumor tissues and immunohistochemical staining was conducted to examine the protein expression in tumors.
Co-incubation of SW620 cells with platelets directly or SCP both generated long spindle-shaped invasive phenotype. Pretreatment of platelets with Danshensu (25 μM) inhibited the morphological changes of SW620 cells induced by SCP, which was associated with the inhibitory effects of Danshensu on platelet secretion. Danshensu diminished the secretion of a list of biological factors in SCP, including interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), IL-1β and vascular endothelial growth factor (VEGF) that are all involved in tumor cell EMT and chemoresistance. Moreover, Danshensu up-regulated the expression of E-cadherin but down-regulated the levels of N-cadherin and Vimentin, resulting in the repression of SW620 cell migration. It was also shown that Danshensu enhanced the sensitivity of SW620 cells to oxaliplatin by suppressing the expression of MDR1. Furthermore, Danshensu could not only reduced the growth of subcutaneous tumors and liver metastasis that induced by SCP, but also down-regulated the expression of MDR1 . Mechanistic studies revealed that Danshensu suppressed the activation of the TGF-β/Smad signaling pathway.
Danshensu attenuated EMT-like characteristics and chemoresistance by inhibiting secretion capability of platelets and activation of the TGF-β/Smad signaling pathway, suggesting that it may be optimized to be a therapeutic agent for fighting against colon cancer.
血小板与肿瘤细胞的相互作用在恶性肿瘤的进展中起着重要作用。丹参素是丹参的主要水溶性成分之一，能抑制血小板聚集，并对多种肿瘤发挥显著的抗肿瘤作用。然而，丹参素是否能通过抑制血小板的活性来抑制恶性肿瘤的进展尚未有报道。
通过与直接接触的共培养血小板和 SW620 结肠癌细胞上清液（SCP）刺激，评估丹参素对 SW620 结肠癌细胞血小板活性和上皮-间充质转化（EMT）样侵袭表型的影响。通过 Western blot 和酶联免疫吸附试验（ELISA）分别测定蛋白的表达和分泌。苏木精和伊红（H&E）染色分析肿瘤组织的组织病理学，免疫组织化学染色检测肿瘤中的蛋白表达。
SW620 细胞与血小板直接共孵育或 SCP 共孵育均产生长梭形侵袭表型。丹参素（25 μM）预处理血小板可抑制 SCP 诱导的 SW620 细胞形态变化，这与丹参素抑制血小板分泌有关。丹参素减少了 SCP 中包括白细胞介素（IL）-6、肿瘤坏死因子-α（TNF-α）、IL-1β 和血管内皮生长因子（VEGF）等多种生物因子的分泌，这些因子均参与肿瘤细胞 EMT 和化疗耐药。此外，丹参素上调 E-钙黏蛋白的表达，下调 N-钙黏蛋白和波形蛋白的水平，从而抑制 SW620 细胞迁移。研究还表明，丹参素通过抑制多药耐药基因 1（MDR1）的表达增强了 SW620 细胞对奥沙利铂的敏感性。此外，丹参素不仅降低了由 SCP 诱导的皮下肿瘤生长和肝转移，还下调了 MDR1 的表达。机制研究表明，丹参素通过抑制 TGF-β/Smad 信号通路的激活来抑制 EMT 样特征和化疗耐药性。
丹参素通过抑制血小板的分泌能力和 TGF-β/Smad 信号通路的激活，减弱 EMT 样特征和化疗耐药性，提示其可能被优化为治疗结肠癌的药物。
