结直肠癌（CRC）是中国最常见的恶性肿瘤之一。目前CRC治疗药物SHP099、L-OHP、5-FU存在对肿瘤细胞不敏感的问题。联合用药是解决单独用药不敏感的重要手段。本项目的目的是探讨SHP099组合对L-OHP/5-FU耐药CRC菌株恶性生物学行为的影响和分子机制。HT29和SW480细胞在补充有L-OHP或5-FU的培养基中培养FU建立耐药菌株。将HT29和SW480耐药细胞以5×106剂量皮下注射至裸鼠腹神经，建立CRC耐药动物模型。采用CCK-8、Western blot、流式细胞术、Transwell和试剂盒检测检测耐药CRC细胞能量代谢重编程的调控机制。与非耐药株相比，L-OHP/5-FU耐药株表现出更大的代谢能力。重新编程。从功能上讲，SHP099可以抑制L-OHP/5-FU耐药菌株的代谢重编程，从而抑制L-OHP/5-FU耐药菌株的增殖、集落形成、迁移和球体形成。下游机制研究表明，SHP099通过抑制PI3K/AKT通路，干扰L-OHP/5-FU耐药菌株的代谢重编程，从而抑制L-OHP/5-FU耐药菌株的恶性生物学行为SHP099联合应用可以抑制L-OHP/5-FU耐药CRC细胞的恶性生物学行为，通过干扰能量代谢重编程来缓解CRC的进展。该研究首次探讨了SHP099组合对双耐药CRC细胞的作用，为解决SHP099对CRC细胞不敏感的问题提供了新的治疗思路。版权所有©2024 Elsevier Inc.保留所有权利。

Colorectal cancer (CRC) is one of the most common malignancies in China. At present, there is a problem that the CRC treatment drugs SHP099, L-OHP and 5-FU are insensitive to tumor cells. Combination medication is an important means to solve the insensitivity of medication alone. The purpose of this project was to explore the effect and molecular mechanism of SHP099 combination on the malignant biological behavior of L-OHP/5-FU resistant strains of CRC.HT29 and SW480 cells were cultured in media supplemented with L-OHP or 5-FU to establish drug-resistant strains. HT29 and SW480 drug-resistant cells were subcutaneously injected into the ventral nerves of nude mice at a dose of 5 × 106 to establish CRC drug-resistant animal models. CCK-8, Western blot, flow cytometry, Transwell and kit detection were used to detect the regulatory mechanism of energy metabolism reprogramming in drug-resistant CRC cells.Compared with nonresistant strains, L-OHP/5-FU-resistant strains exhibited greater metabolic reprogramming. Functionally, SHP099 can restrain the metabolic reprogramming of L-OHP/5-FU-resistant strains and subsequently restrain the proliferation, colony formation, migration and spheroid formation of L-OHP/5-FU-resistant strains. Downstream mechanistic studies have shown that SHP099 interferes with the metabolic reprogramming of L-OHP/5-FU drug-resistant strains by suppressing the PI3K/AKT pathway, thereby restraining the malignant biological behavior of L-OHP/5-FU drug-resistant strains and alleviating CRC.The combination of SHP099 can restrain the malignant biological behavior of L-OHP/5-FU-resistant CRC cells and alleviate the progression of CRC by interfering with the reprogramming of energy metabolism. This study explored the effect of SHP099 combination on dual-resistant CRC cells for the first time, and provided a new therapeutic idea for solving the problem of SHP099 insensitivity to CRC cells.Copyright © 2024 Elsevier Inc. All rights reserved.