摘要
Abstract
Background and Aims:Valeric acid activates the nuclear factor E2-related factor 2(Nrf2)pathway.Recent studies have demonstrated its potent antitumor activity in breast and oral cancers.However,its role in gastric cancer treatment remains unclear.This study aimed to investigate the effects of valeric acid on inflammatory responses and survival in a gastric cancer xenograft model in nude mice and to explore the potential underlying mechanisms to provide new insights for gastric cancer therapy.
Methods:A xenograft model was established by subcutaneous injection of human gastric cancer MKN-45 cells into 80 Balb/c nude mice,which were then equally randomized into four groups:control and low-,medium-,and high-dose valeric acid groups(10,20,and 40 mg/kg,respectively).The mice received daily intraperitoneal injections of either saline or valeric acid for 30 days.Tumor growth was monitored during the treatment period.Twelve hours after the final administration,five mice from each group were sacrificed by cervical dislocation;blood was collected via eyeball removal,and tumors were excised and weighed.Histopathological changes in the tumors were observed by HE staining.Serum levels of macrophage inflammatory protein-2(MIP-2),interleukin-10(IL-10),and tumor necrosis factor α(TNF-α)were measured by ELISA.mRNA and protein expression levels of Nrf2 and its downstream molecules,quinone oxidoreductase-1(NQO-1)and heme oxygenase-1(HO-1),were assessed in tumor tissues using qRT-PCR and Western blot.The remaining 15 mice per group were monitored for survival analysis.
Results:Compared with the control group,all valeric acid-treated groups showed a significant reduction in tumor volumes at all observation time points and final tumor weight(all P＜0.05),with a dose-dependent trend.HE staining revealed densely arranged tumor cells with high cell density in the control group,while various degrees of tumor necrosis and reduced cell density were observed in valeric acid-treated groups,most pronounced in the high-dose group.ELISA results showed that serum levels of MIP-2 and TNF-α were significantly decreased,while IL-10 levels were significantly increased in valeric acid-treated groups compared to controls(all P＜0.05),exhibiting dose dependence.qRT-PCR and Western blot analyses demonstrated that the mRNA and protein expression levels of Nrf2,HO-1,and NQO-1 in tumors were significantly elevated in the valeric acid groups compared with the control group(all P＜0.05),also showing dose dependence.Survival analysis indicated that the median survival times were 47 d(control),68 d(low dose),81 d(medium dose),and 90 d(high dose),with all valeric acid groups having significantly prolonged survival compared to the control group(all P＜0.05).
Conclusion:Valeric acid effectively inhibits the growth of gastric cancer xenografts,attenuates systemic inflammatory responses,and prolongs the survival of nude mice,possibly through activation of the Nrf2 pathway and modulation of the tumor microenvironment.关键词
胃肿瘤/异种移植模型抗肿瘤试验/缬草酸/炎症/NF-E2相关因子2Key words
Stomach Neoplasms/Xenograft Model Antitumor Assays/Valeric Acid/Inflammation/NF-E2-Related Factor 2分类
医药卫生
