MOLECULAR MEDICINE
·
2025
·
IF 6.4
Yufei Deng,Xiaoying Hou,Qian Fang,Haiping Wang,Xiaoxuan Li,Zhiyong Hu,Zhaolu Liu,Limei Fan,Yunyi Liu,Zhengqi Fu,Xiji Shu,Binlian Sun,Lijun Huang,Yuchen Liu
Background FOLFOX is the recommended chemotherapy regimen for colorectal cancer (CRC), but its response rate remains low. Our previous studies have established a close relationship between gut microbiota and the anti-CRC effect of FOLFOX, though the underlying mechanisms remain unclear. Diet has been confirmed as a key factor influencing gut microbiota, and high-salt diets, representative of western dietary habits, has been shown to affect gut microbiota, immune function, and the risk of developing CRC. However, the impact of high-salt diets on the anti-CRC efficacy of FOLFOX remains unstudied. Therefore, we aimed to investigate the effect and mechanism of high-salt diets on the anti-CRC effect of FOLFOX. Methods We performed 16 S rRNA sequencing and T500 targeted metabolomics analysis on fecal samples from CRC patients and healthy adults. A CRC orthotopic xenograft mouse model was used to study the effect of a high-salt diet on FOLFOX’s anti-CRC efficacy. 16 S rRNA sequencing and non-targeted metabolomics were conducted on mouse fecal samples. Flow cytometry was used to assess immune cell infiltration in tumor and paracancerous tissues. A mouse macrophage conditioned medium system, with tryptophan metabolites, was employed to annotate the functional metabolites, followed by in vivo verification using the orthotopic xenograft mouse model. Results The structure and metabolic profiles of gut microbiota are significantly different between 9 healthy adults and 6 CRC patients. A high-salt diet significantly reduced the efficacy of FOLFOX in mice, with notable changes in gut microbiota and related metabolites. Correlation analysis revealed a significant relationship between gut microbiota, tryptophan metabolites and FOLFOX efficacy. Flow cytometry indicated that a high-salt diet altered macrophage infiltration (CD45 + F4/80 + ) in both the tumor and paracancerous tissues. In vitro experiments confirmed that the tryptophan metabolite SK reduced FOLFOX efficacy, while IPA enhanced it through macrophage-conditioned medium. In vivo, we verified that under a high-salt diet, SK inhibited the efficacy of FOLFOX, while IPA promoted it. Conclusion A high-salt diet reduces the anti-CRC efficacy of FOLFOX through gut bacterial tryptophan metabolism mediated macrophage immunomodulation. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-025-01122-8.
研究领域:
肿瘤学
·
微生物学
·
免疫学
·
代谢组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
·
2025
·
IF 10.5
Qian Fang,Xiaoying Hou,Limei Fan,Yufei Deng,Xiaoxuan Li,Hongyun Zhang,Haiping Wang,Zhengqi Fu,Binlian Sun,Xiji Shu,Hongzhi Du,Yuchen Liu
FOLFOX (5-Fluorouracil, Calcium Folinate combined with Oxaliplatin) is a preferred chemotherapy regimen for colon cancer, but its limited efficacy remains a major challenge, significantly impairs patient outcomes. There is an urgent need to identify strategies to improve its therapeutic effectiveness. Our previous studies have suggested that gut microbiota-derived bile acids may be involved in the anticancer effect of FOLFOX in vitro , however, the underlying mechanism remains unclear. In this study, we investigated the role of bile acids in modulating FOLFOX efficacy and the related mechanisms. We first demonstrated that bile acids depletion (cholestyramine treatment) enhanced FOLFOX efficacy in an orthotopic colon cancer mouse model, suggesting that bile acids play a key role in FOLFOX’s therapeutic effects. Further, based on the system screen of 15 bile acids on FOLFOX efficacy via MTT, colony formation and flow cytometry assay, Deoxycholic Acid (DCA) and Glycodeoxycholic Acid (GDCA) were annotated as potential modulators of FOLFOX efficacy. Among these, DCA was further validated to significantly enhance FOLFOX’s anti-colon cancer effects in vivo . Transcriptomic analysis and subsequent biological experiments revealed that DCA enhanced FOLFOX efficacy via Ugt1a6b. In conclusion, our findings establish that gut microbiota-derived DCA enhances the efficacy of FOLFOX potentially via Ugt1a6b mediated enterohepatic circulation, providing novel insights into a synergistic therapeutic strategy for improving colon cancer treatment.
研究领域:
肿瘤学
·
药理学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
·
IF 10.5
Weiran Cao,Xue Zhang,Rui Li,Zijie Li,An Lu,Fei Yu,Lu Sun,Jiancheng Wang,Zhiyu Wang,Huining He
FOLFOX regimen, composed of folinic acid, 5-fluorouracil (5-FU) and oxaliplatin (OXP), has been used as clinical standard therapeutic regimen in treatments of colorectal cancer (CRC) and esophageal squamous cell carcinoma (ESCC). To further improve its therapeutic outcomes, FOLFOX was combined with anti-PD-1 antibody to form an advanced chemo-immune combination strategy, which has been proven more efficient in controlling cancer progression and prolonging patients' survival in various clinical trials. However, bad tumor accumulation, relative high toxicity, numerous treatment cycles with high fees and low compliance as well as drug resistance seriously limit the prognosis of FOLFOX regimen. The “all-in-one” formulations, which could precisely delivery multidrug regimen into tumor sites and cells, showed a promising application prospect for targeted drug delivery as well as reducing side effects. However, the design and preparation of the “all-in-one” formulation with high drug encapsulation efficiencies for all drugs was still challenging. Herein, a lipid core-shell nanoparticle codelivery platform was designed for simultaneous encapsulation of variant FOLFOX composed of miriplatin (MiPt), 5-Fluoro-2′-deoxyuridine 5′-monophosphate (FdUMP), calcium folinate ( CF ) and PD-L1 siRNA (siPD-L1) with high efficiencies, and their synergistic anti-tumor mechanisms were studied, respectively. MiPt, a precursor of OXP, was validated capable of inducing efficient immunogenic cell death (ICD) in this work. Additionally, ICD-mediated release of damage associated molecular patterns functionalized synergistically with PD-L1 silence by siPD-L1 to overcome chemoresistance, reverse suppressive tumor microenvironment and recruit more CD8 + T cells. FdUMP, as the intracellular active form of 5-FU, could induce large amounts of reactive oxygen species to enhance the ICD. CF worked as the sensitizer of FdUMP. The enhanced long-term anti-tumor effect of the prepared “all-in-one” formulation compared to free drug regimen and other controls, was verified in heterotopic CRC mice models and ESCC mice models, providing new thoughts for researchers and showing a promising prospect of translation into clinical applications.
研究领域:
纳米技术
·
癌症研究
·
药学
·
免疫疗法
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2026
·
IF 29.1
Shiyao Song,Yan-Lai Tang,Xiaoting Liu,Jiayi Zheng,Chong Wu,Tang Li,Junhong Ye,Dianmin Xia,Yong Mei,Jingxuan Ma,Libin Huang,Xuequn Luo,Liheng Chen,Yanlin Qin,Weiling He
FOLFOX has served as the standard chemotherapy regimen for advanced stages, specifically in the treatment of pancreatic, colorectal, and bladder cancers. However, the issues of excessive toxicity and prolonged treatment cycles persist. To address this limitation, we developed a novel methylated amino acid-modified lignin inspired by biological methylation, creating a pH-responsive charge-reversal drug delivery system for FOLFOX chemotherapy. This system stabilizes thymidylate synthase (TS) and combines with deoxyuridine monophosphate (dUMP) to demonstrate significantly improved therapeutic outcomes of FOLFOX against colorectal cancer (CRC). The FOLFOX-loaded nanodrug showed targeted antitumor activity against CRC and induced tumor cell death through multiple mechanisms, including apoptosis, necrosis, cell cycle regulation, DNA damage, and reactive oxygen species generation. Furthermore, the nano-formulation activated immune responses to enhance chemotherapeutic potency and effectively reducing renal toxicity associated with chemotherapy drugs. These findings suggest that protein methylation-mimicked lignin could be a valuable addition to current first-line chemotherapy options and holds promise for enhancing chemotherapy against solid tumors.
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）