School of Basic Medicine, Dali University, Dali, 671000, Yunnan, China.
Microbiology Research Institute, Guangxi Academy of Agricultural Science, Nanning, 530007, Guangxi Province, China.
Sci Rep. 2024 Sep 19;14(1):21852. doi: 10.1038/s41598-024-72536-3.
5-Fluorouracil (5-FU) is used as a standard first-line drug for colorectal cancer malignancy (CRC), but it brings a series of side effects such as severe diarrhea and intestinal damage. Our previous study found that a large number of senescent cells increased while 5-Fu induced intestinal damage, and anti-senescence drugs can alleviate its side effects of inflammatory damage. Oleanolic acid (OA) is a common pentacyclic triterpenoid mainly derived from food fungi and medicinal plants, and studies have shown that it mainly possesses hepatoprotective, enzyme-lowering, anti-inflammatory, and anti-tumor effects. But its role in senescence is still unclear. In the present study, we demonstrated for the first time that OA ameliorated 5-Fu-induced human umbilical vein endothelial cells (HUVECs) and human normal intestinal epithelial cells (NCM460) in a 5-Fu-induced cellular senescence model by decreasing the activity of SA-β-gal-positive cells, and the expression of senescence-associated proteins (p16), senescence-associated genes (p53 and p21), and senescence-associated secretory phenotypes (SASPs: IL-1β, IL-6, IL-8, IFN-γ and TNF-α). Meanwhile, in this study, in a BALB/c mouse model, we demonstrated that 5-FU induced intestinal inflammatory response and injury, which was also found to be closely related to the increase of senescent cells, and that OA treatment was effective in ameliorating these adverse phenomena. Furthermore, our in vivo and in vitro studies showed that OA could alleviate senescence by inhibiting mTOR. In colon cancer cell models, OA also enhanced the ability of 5-FU to kill HCT116 cells and SW480 cells. Overall, this study demonstrates for the first time the potential role of OA in counteracting the side effects of 5-FU chemotherapy, providing a new option for the treatment of colorectal cancer to progressively achieve the goal of high efficacy and low toxicity of chemotherapy.
5-氟尿嘧啶（5-FU）被用作结直肠癌（CRC）恶性肿瘤的标准一线药物，但它会带来一系列副作用，如严重腹泻和肠道损伤。我们之前的研究发现，在 5-Fu 诱导肠道损伤时，大量衰老细胞增加，而抗衰老药物可以减轻其炎症损伤的副作用。齐墩果酸（OA）是一种常见的五环三萜类化合物，主要来源于食品真菌和药用植物，研究表明它主要具有保肝、降酶、抗炎和抗肿瘤作用。但其在衰老中的作用尚不清楚。在本研究中，我们首次证明，OA 通过降低 SA-β-半乳糖阳性细胞的活性和衰老相关蛋白（p16）、衰老相关基因（p53 和 p21）和衰老相关分泌表型（SASPs：IL-1β、IL-6、IL-8、IFN-γ 和 TNF-α）的表达，改善了 5-Fu 诱导的人脐静脉内皮细胞（HUVECs）和人正常肠上皮细胞（NCM460）的细胞衰老模型。同时，在本研究中，在 BALB/c 小鼠模型中，我们证明了 5-FU 诱导肠道炎症反应和损伤，这也与衰老细胞的增加密切相关，OA 治疗可有效改善这些不良反应。此外，我们的体内和体外研究表明，OA 通过抑制 mTOR 来减轻衰老。在结肠癌细胞模型中，OA 还增强了 5-FU 杀死 HCT116 细胞和 SW480 细胞的能力。总的来说，本研究首次证明了 OA 对抗 5-FU 化疗副作用的潜在作用，为治疗结直肠癌提供了一种新的选择，以逐步实现化疗高效低毒的目标。
