Department of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China.
Department of Colorectal Surgery, Yunnan Cancer Hospital (The Third Affiliated Hospital of Kunming Medical University), Kunming, 650118, China.
Biochem Biophys Res Commun. 2024 Oct 8;728:150262. doi: 10.1016/j.bbrc.2024.150262. Epub 2024 Jun 28.
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 × 10 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.
结直肠癌（CRC）是中国最常见的恶性肿瘤之一。目前存在 CRC 治疗药物 SHP099、L-OHP 和 5-FU 对肿瘤细胞不敏感的问题。联合用药是解决药物单独使用不敏感的重要手段。本项目旨在探讨 SHP099 联合用药对 CRC L-OHP/5-FU 耐药株恶性生物学行为的影响及分子机制。
用 L-OHP 或 5-FU 培养基培养 HT29 和 SW480 细胞，建立耐药株。将 HT29 和 SW480 耐药细胞以 5×10 的剂量皮下注射到裸鼠腹侧神经中，建立 CRC 耐药动物模型。用 CCK-8、Western blot、流式细胞术、Transwell 和试剂盒检测方法，检测药物耐药 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重编程。功能上，SHP099 可抑制 L-OHP/5-FU 耐药株的代谢重编程，进而抑制 L-OHP/5-FU 耐药株的增殖、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 耐药株的代谢重编程，从而抑制 L-OHP/5-FU 耐药株的恶性生物学行为，缓解 CRC。
SHP099 联合用药可通过干扰能量代谢重编程抑制 L-OHP/5-FU 耐药 CRC 细胞的恶性生物学行为，缓解 CRC 的进展。本研究首次探讨了 SHP099 联合用药对双重耐药 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。
