School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan, 671000, China.
School of Basic Medicine, Dali University, Dali, Yunnan, 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan, 671000, China.
Int Immunopharmacol. 2023 Aug;121:110465. doi: 10.1016/j.intimp.2023.110465. Epub 2023 Jun 17.
5-Fluorouracil (5-Fu) is the preferred drug in colorectal cancer treatment. Although 5-Fu treatment contributes to the increase in survival rates, long-term use of 5-Fu causes severe intestinal damage, eventually decreasing long-term survival. There is no standardtreatmentfor intestinal damage induced by 5-Fu. Our previous study found that 5-Fu-induced intestinal damage was connected to an increase in senescent cells, and antiaging drugs could relieve some adverse side effects caused by 5-Fu. Hence, it is essential to discover novel, potential antiaging therapeutic drugs for 5-Fu side effect treatment. According to the current study, Atorvastatincalcium (Ator) alleviated cellular senescence in human intestinal epithelial cells (HUVECs) and human umbilical vein endothelial cells (HIECs) caused by oxidative stress and 5-Fu. 5-Fu resulted in an increase in SA-β-Gal-positive cells, synchronously increased expression of aging-related proteins (p16), aging-related genes (p53, p21), and the senescence-associated secretory phenotype (SASP: IL-1β, IL-6, TNF-α), while Atorvastatincalcium (Ator) reversed the increase in these indicators. In the BALB/c mouse model, we confirmed that intestinal damage caused by 5-Fu is related to the increase in senescent cells and drug-induced inflammation, with the therapeutic effects of Ator. In addition, Ator increased the sensitivity of 5-Fu to chemotherapy in vitro and in vivo. Combination therapy significantly reduced HCT116 cell viability. Furthermore, Ator and 5-Fu present a cooperative effect on preventing the growth of tumors in CRC xenograft nude mice. In conclusion, our study demonstrates the value of Ator for treating intestinal damage. Moreover, Ator combined with 5-Fu increased the antitumor ability in CRC cells. Additionally, we provide a novel therapeutic protocol for CRC.
5-氟尿嘧啶（5-Fu）是结直肠癌治疗的首选药物。虽然 5-Fu 治疗有助于提高生存率，但长期使用 5-Fu 会导致严重的肠道损伤，最终降低长期生存率。目前尚无针对 5-Fu 引起的肠道损伤的标准治疗方法。我们之前的研究发现，5-Fu 诱导的肠道损伤与衰老细胞的增加有关，而抗衰老药物可以缓解 5-Fu 引起的一些不良反应。因此，发现新型、潜在的抗衰老治疗药物来治疗 5-Fu 的副作用至关重要。根据目前的研究，阿托伐他汀钙（Ator）减轻了氧化应激和 5-Fu 引起的人肠上皮细胞（HUVECs）和人脐静脉内皮细胞（HIECs）的细胞衰老。5-Fu 导致 SA-β-Gal 阳性细胞增加，同时衰老相关蛋白（p16）、衰老相关基因（p53、p21）和衰老相关分泌表型（SASP：IL-1β、IL-6、TNF-α）的表达增加，而阿托伐他汀钙（Ator）逆转了这些指标的增加。在 BALB/c 小鼠模型中，我们证实了 5-Fu 引起的肠道损伤与衰老细胞的增加和药物诱导的炎症有关，阿托伐他汀钙（Ator）具有治疗作用。此外，Ator 增加了 5-Fu 在体外和体内的化疗敏感性。联合治疗显著降低了 HCT116 细胞的活力。此外，Ator 和 5-Fu 在 CRC 异种移植裸鼠模型中对预防肿瘤生长具有协同作用。综上所述，我们的研究表明 Ator 具有治疗肠道损伤的价值。此外，Ator 与 5-Fu 联合使用可增强 CRC 细胞的抗肿瘤能力。此外，我们为 CRC 提供了一种新的治疗方案。
