BIOCHEMICAL PHARMACOLOGY
·
2025
·
IF 5.6
Dapeng Lu,Lin Ma,Qingyue Zhang,Chengzhong Xing,Yanke Li
5-Fluorouracil (5-FU) is an effective drug in the treatment of colorectal cancer (CRC); however, the development of acquired resistance to 5-FU poses a great challenge in clinical practice. Through the analysis of public datasets, we found that reduced 3-Hydroxybutyrate Dehydrogenase 2 (BDH2) expression in CRC tissues predicted poor survival in CRC patients. Low expression of BDH2 in clinical CRC tissue samples predicted a higher degree of malignancy. In addition, public dataset analysis showed that GLI Pathogenesis Related 1 (GLIPR1) expression was elevated in CRC patients following 5-FU treatment, contrasting with the expression pattern of BDH2. We reported that in 5-FU-resistant CRC cell lines (LOVO/5-FU and HCT15/5-FU), BDH2 was downregulated, while the expression of GLIPR1 was increased. To explore the regulatory relationship between BDH2 and GLIPR1 in 5-FU resistance, BDH2 and GLIPR1 overexpression plasmid vectors were constructed to transfect 5-FU resistant CRC cell lines. BDH2 led to enhanced 5-FU sensitivity in 5-FU-resistant CRC cell lines and inhibited the malignant behavior of CRC-resistant cells in vitro . In nude mice with subcutaneous tumors and intraperitoneal injections of 5-FU, tumor tissues formed by BDH2-overexpressing cells exhibited slower growth and increased apoptosis. Mechanistically, the upregulation of BDH2 increases GLIPR1 promoter methylation, mediated by DNA methyltransferases, thereby inhibiting GLIPR1 expression. High expression of GLIPR1 reduces 5-FU sensitivity in 5-FU-resistant CRC cell lines, which abolished the impact of BDH2 expression. These results suggest that BDH2 inhibits GLIPR1 expression by increasing GLIPR1 promoter methylation, thereby enhancing 5-FU sensitivity of 5-FU-resistant CRC cell lines and inhibiting CRC progression.
研究领域:
肿瘤学
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分子生物学
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药理学
·
表观遗传学
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产品关联
DOI
PubMed
高影响因子
ONCOLOGY REPORTS
·
2015
·Vol. 34
·期 6
·3147-3155
·
IF 2.301
Lili Zhang,Jie Zhang,Li Chen,Jianli Wang
Autophagy is an intracellular multi-step catabolic degradation process that involves the degradation and recycling of cellular proteins and cytoplasmic damaged organelles to maintain cellular homeostasis and reduction of metabolic stress. Numerous studies have indicated the importance of autophagy in cancer, but the role of autophagy in human skin squamous cell carcinoma (SSCC) development and response to therapy it is still unclear. In the present study, we investigated the role of autophagy in SSCC and the relationship with chemotherapy sensitivity. The present study demonstrated that autophagy related gene the microtubule-associated protein 1 light chain 3 (LC3) expression was low in SSCC. The negative correlation with Bcl2 and survivin, and the chemotherapy drug 5-FU increased the level of autophagy and the autophagy inhibitor 3-MA inhibited this effect in SSCC cells, time- and dose-dependently. When SSCC cells were treated first with 3-MA and then with 5-FU, the inhibition of proliferation, migration, invasion and apoptosis of SSCC cells was enhanced. Our results suggested the possibility of autophagy as a potential target in SSCC therapy and 3-MA and 5-FU combination treatment may be an effective SSCC therapy via autophagy modulating.
研究领域:
肿瘤学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
APPLIED BIOCHEMISTRY AND BIOTECHNOLOGY
·
2025
·
IF 3.3
Gahlot Himanshi,Kang Sun Chul
Synergistic therapy is unwaveringly developing as a potential approach to enhance the effectiveness of anticancer medications in chemotherapy. Incorporating adjuvants alongside conventional anticancer medications has demonstrated selective cytotoxicity toward cancer cells while mitigating adverse effects such as DNA damage and systemic toxicity in normal cells. The extended use of 5-FU, a synthetic medicine used in chemotherapy, has many adverse effects, which limit its long-term use in clinical settings. Numerous investigations have demonstrated that luteolin exhibits anticancer effects and alleviates inflammation in mammalian cells. In this study, we provide the first experimental evidence of the synergistic interaction between luteolin and 5-FU in murine melanoma (B16F10) cells, compared to monotherapies (luteolin and 5-FU alone). Using MTT assay for cell viability, flow cytometry for cell cycle analysis, and Western blotting for apoptosis markers, we demonstrate that simultaneous exposure to luteolin and 5-FU speeds up oxidative stress and enhances the production of endogenous ROS. The combination therapy induced the G1-phase cell cycle arrest (65.39%) and decreased the cell viability of B16F10 cells to 34.6%. This, in turn, activates the DNA damage response and initiates the apoptotic pathway by suppressing autophagy and the DNA repair system. Further, the co-treatment of luteolin and 5-FU significantly decreases the mitochondrial membrane potential and reduces ATP production. The results indicate that the combination of luteolin and 5-FU may improve treatment efficacy while potentially decreasing the necessary dosage of 5-FU, therefore reducing its toxicity in clinical settings.
研究领域:
肿瘤学
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药理学
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生物化学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Drug Delivery and Translational Research
·
2024
·
IF 5.7
Chen Siwei,Huang Hongwu,Li Qi,Cai Jia,Miao Zhuolin,Xie Peikang,Tang Shengsong,He Dongxiu
5-Fluorouracil (5-FU) is commonly used as a chemotherapeutic drug for advanced HCC. However, the effectiveness of 5-FU is limited by the emergence of resistance and poor targeting efficiency. Combining 5-FU with natural compounds has shown promise in HCC treatment. In this study, we prepared carrier-free nanoparticles (GEN-Cu-GEN@FUA) containing 5-FU and genistein (GEN) in a synergistic ratio via a green synthesis procedure. The resulting GEN-Cu-GEN@FUA nanoparticles had a spherical or near spherical shape, a dynamic size of 129.3 ± 40.1 nm, and a high drug loading content of approximately 21.40% (5-FU) and 61.48% (GEN). These nanoparticles exhibited approximately 3.6-fold lower IC50 value than 5-FU alone in Bel-7402 cells and resulted in a 3.7-fold greater reduction in tumor weight compared to 5-FU alone in Bel-7402 tumor-bearing BALB/c mice. Importantly, the nanoparticles showed negligible systemic toxicity due to their synergistic effect on cancer cell dysfunction and significant amplification of intracellular glutathione consumption. Our findings suggest that the developed carrier-free nanomedicines offer a highly promising platform for the co-delivery of genistein (GEN) copper(II) complexes and 5-FU, with easy fabrication and great potential for clinical translation in HCC synergistic therapy. Graphical abstract
研究领域:
药理学
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纳米技术
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癌症研究
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化疗
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
OncoTargets and Therapy
·
2020
·
IF 3.337
Xia Tian,Meng Liu,Xiaodong Huang,Qingxi Zhu,Weijie Liu,Wei Chen,Yanli Zou,Yishan Cai,Shasha Huang,Aifang Chen,Ting Zhan,Min Huang,Xiaoli Chen,Zheng Han,Jie Tan
Background Noscapine is an opium alkaloid that has recently been shown to potentiate anti-cancer therapeutic effects by inducing apoptosis in various malignant cells without any detectable toxicity. However, the mechanism by which noscapine induces apoptosis in colon cancer cells remains unclear. Materials and Methods In this study, we explored the anti-cancer activity of noscapine in 5-fluorouracil (5-FU)-resistant human colon cancer cell lines HT29/5-FU and LoVo/5-FU and investigated the possible underlying mechanism. The apoptosis and mitochondrial morphology of cells were detected by TUNEL assay and transmission electron microscopy (TEM). The mitochondrial membrane potential (MMP) was determined using JC-1. The mitochondrial permeability transition pore (mPTP) opening was detected by the calcein-AM/cobalt assay. The levels of glucose, lactic, and ATP in cells were evaluated by ELISA kits. Relative protein expression levels were detected by Western blot. Results We verified that PTEN was involved in noscapine-induced apoptosis in HT29/5-FU and LoVo/5-FU cells. Noscapine greatly increased mitochondrial damage by altering mitochondrial morphology, inducing mitochondrial membrane potential depolarization, and enabling mitochondrial permeability transition pore opening in HT29/5-FU and LoVo/5-FU cells. In addition, noscapine inhibited the Warburg effect by decreasing the levels of glucose, lactic acid, and ATP and inhibiting the protein expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in HT29/5-FU and LoVo/5-FU cells. However, PTEN interference counteracted the effect of noscapine on mitochondrial damage and the Warburg effect in HT29/5-FU and LoVo/5-FU cells by decreasing the activation of PI3K/mTOR signaling. Conclusion These results indicated that noscapine induced the apoptosis of HT29/5-FU and LoVo/5-FU human colon cancer cells by regulating mitochondria damage and the Warburg effect via PTEN, and the process is closely related to the PI3K/mTOR signaling pathway.
研究领域:
肿瘤学
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细胞生物学
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药理学
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癌症生物学
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产品关联
DOI
PubMed
高影响因子
Nanoscale
·
2020
·Vol. 12
·期 24
·12779-12789
·
IF 6.895
Yi Cao,Zhenqi Jiang,Yanying Li,Yinjie Wang,Yong Yang,Ozioma Udochukwu Akakuru,Juan Li,Aiguo Wu
Zeolitic imidazolate frameworks (ZIFs) as emerging porous materials have attracted remarkable attention for their unprecedented porosity and acidic sensitive degradation that enables high drug loading and microenvironment responsive fast payload release. However, the limited functions and disadvantages of ZIFs such as early drug release, potential cytotoxicity inducing damage to major organs, and even death of animals, impede their further biomedical application. In this work, we report the first tandem post-synthetic modification of ZIF-7 with both metal ions and organic ligands. Inspired by the benzimidazole-like inhibitors that are similar to the organic ligand of ZIF-7, a chemokine (C-X-C motif) receptor 4 (CXCR4) inhibitor AMD-070 (AMD) and magnesium ions (Mn2+) were successfully tandem exchanged to the ZIF-7 framework, forming an active-targeting framework AMD-ZIF-7(Mn) for CXCR4-overexpressed esophageal squamous cell cancer. The obtained AMD-ZIF-7(Mn) showed good biocompatibility in vitro and in vivo. Meanwhile, it exhibited an excellent T1-weighted magnetic resonance imaging performance and CXCR4 targeting ability. With 5-Fu loading, AMD-ZIF-7(Mn)/5-Fu showed a synergistic therapeutic effect in DNA damage and CXCR4 inhibition of esophageal squamous cell cancer. Therefore, we propose a structural reconstruction method to effectively explore and improve the biomedical application of ZIFs in esophageal squamous cell cancer theranostics.
研究领域:
生物材料学
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癌症治疗学
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医学影像学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF ONCOLOGY
·
2022
·Vol. 61
·期 3
·1-13
·
IF 5.884
Min Li,Mingyue Xia,Ziyu Zhang,Yanyin Tan,Enjie Li,Zhigang Guo,Mingzhi Fang,Yong Zhu,Zhigang Hu
Colorectal cancer (CRC) is one of top five leading causes of cancer‑associated mortalities worldwide. 5‑Fluorouracil (5‑FU) is the first‑line chemotherapeutic drug in the treatment of CRC; however, its antineoplastic efficiency is limited due to acquired drug resistance. The regulatory mechanism underlying 5‑FU chemotherapeutic response and drug resistance in CRC remains largely unknown. The present study identified that silencing of methyltransferase‑like 3 (METTL3) suppressed the proliferation and migration of CRC HCT‑8 cells. Using cell survival assays, flow cytometric and colony formation analyses, it was revealed that inhibition of METTL3 sensitized HCT‑8 cells to 5‑FU by enhancing DNA damage and inducing apoptosis in HCT‑8 cells under 5‑FU treatment. Furthermore, the expression of METTL3 was upregulated in 5‑FU‑resistant CRC cells (HCT‑8R), which contributed to drug resistance through regulation of RAD51 associated Protein 1 (RAD51AP1) expression. Western blotting, immunofluorescence staining and drug sensitivity assays demonstrated that knockdown of METTL3 augmented 5‑FU‑induced DNA damage and overcame 5‑FU‑resistance in HCT‑8R cells, which could be mimicked by inhibition of RAD51AP1. The present study revealed that the METTL3/RAD51AP1 axis plays an important role in the acquisition of 5‑FU resistance in CRC, and targeting METTL3/RAD51AP1 may be a promising adjuvant therapeutic strategy for patients with CRC, particularly for those with 5‑FU‑resistant CRC.
研究领域:
肿瘤学
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分子生物学
·
癌症研究
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DOI
PubMed
高影响因子
American Journal of Cancer Research
·
2024
·Vol. 14
·期 12
·5752
·
IF 3.6
Xiaobo Cai,Min Cao,Qingliang Yang,Xiazhen Yu,Xin-Hua Feng,Robert Yongxin Zhao
Gastric cancer is a common malignant tumor with high incidence and mortality. The overexpression of Human epidermal growth factor receptor 2 (HER2) is associated with increased metastatic potential and poor clinical outcome in gastric cancer. Despite the proven clinical response rates of approved HER2-targeted therapies, including Trastuzumab combined with chemotherapy, their limited long-term clinical benefits and inevitable disease progression still pose significant challenges to the clinical treatment of gastric cancer. Hence, exploring novel strategies to enhance therapeutic outcomes for HER2-positive patients is extremely crucial and urgent. Here, we reported that DX126-262, a novel HER2-targeted antibody-drug conjugate, generated by conjugating a potent Tubulysin B analogue (Tub-114) to humanized anti-HER2 monoclonal antibody, exhibited a significant synergistic inhibitory effect with both Cisplatin and 5-FU in HER2-positive gastric cancer NCI-N87 cells. Moreover, the triple-drug combination strategy of DX126-262 combined with Cisplatin and 5-FU showed much better in vitro and in vivo therapeutic efficacy than monotherapy or double-drug combination (Cisplatin plus 5-FU) or first-line standard-of-care (SOC, Herceptin plus Cisplatin and 5-FU), and comparable or even superior in vivo efficacy than third-line SOC (DS-8201a) in NCI-N87 cells and xenograft models. Meanwhile, the triple-drug combination therapy did not exhibit superimposed toxicity. Taken together, our findings provide compelling evidence that DX126-262 in combination with Cisplatin and 5-FU exerts synergistic antitumor activity and is a promising strategy to improve the clinical efficacy of HER2-positive advanced or metastatic gastric cancer.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
COLLOID AND POLYMER SCIENCE
·
2024
·Vol. 302
·期 5
·819-828
·
IF 2.2
Ji Xinyuan,Yang Zhe,Fang Jiahui,Hu Sheng
In this study, a novel molecularly imprinted polymer (MIP) was synthesized with attapulgite (ATP) and acrylamide (AM) and ethyl methacrylate (MMA) for controlled release carrier of 5-fluorouracil (5-FU). The MIPs (PAM-PMMA) were characterized by XRD, FESEM, HRTEM, and FTIR. The drug loading and in vitro controlled release ability of MIP on 5-FU was investigated by adsorption property analysis and in vitro release analysis. MIPs (PAM-PMMA) reached a maximum drug loading of 12 mg/g and a maximum release of 80% at an ATP dosage of 0.2 g (0.4%), an initial concentration of 5-FU of 100 mg/L, and an adsorption time of 240 min. Cytotoxicity analysis showed that the maximum inhibition of cells could reach 25% at 72 h of cell culture time under the above conditions. The results showed that MIPs synthesized with ATP as the substrate and AM and MMA as the functional monomers were successfully synthesized and could be used as a drug delivery system for 5-FU. Graphical
研究领域:
材料科学
·
高分子科学
·
药剂学
·
纳米技术
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DOI
高影响因子
NANO
·
2021
·
IF 1.556
Wenlong Li,Weiwei Zhang,Weihao Jin,Longbao Zhu,Wanzhen Li,Ping Song,Yugui Tao,Fei Ge
Design of high-performance drug delivery system is necessary to improve the anticancer ability of 5-fluorouracil (5-FU). In this work, we developed a pH-responsive 5-FU loaded and sodium alginate (SA) modified mesoporous silica nanoparticles (MSNs) drug delivery system (5-FU@MSN-SA). After 5-FU was loaded into the pores, MSNs were successfully functionalized with amino groups and then capped by sodium alginate. Compared to acidic conditions, the drug release rate in the neutral environment was quite low. Moreover, detailed investigations confirmed that 5-FU@MSN-SA can easily be up-taken by cancer cells and proved the high cytotoxicity to 4T1 cells. The calculated IC 5 0 values for 5-FU and 5-FU@MSN-SA were 34.67 μ g/mL and 54.95 μ g/mL, respectively. These results indicated that 5-FU@MSNs-SA can be a promising nanoplatform in cancer therapy.
研究领域:
药剂学
·
肿瘤学
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纳米医学
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DOI
高影响因子
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2025
·Vol. 29
·期 6
·e70470
·
IF 4.2
Chuchu Xu,Renjun Zhu,Qingfeng Dai,Yaoqing Li,Gengyuan Hu,Kelong Tao,Yuhong Xu,Guangen Xu,Guolin Zhang
The main reason for the failure of chemotherapy therapies based on 5-Fluorouracil (5-Fu) is the development of resistance to 5-Fu in cancer patients, particularly those with colorectal cancer. Tissue inhibitor of metalloproteinases 2 (TIMP-2) has been shown to be associated with colorectal cancer (CRC), but its correlation with 5-Fu resistance in colorectal cancer has not been thoroughly studied. We screen the expression of different cytokines through Cytokine array. CCK-8 assay was conducted to evaluate the IC 50 of 5-Fu and cell proliferation. ELISA and RT-qPCR were performed to detect TIMP-2 expression levels in cells and patient serum. Western blotting was utilised to analyse the differences in the expression of proteins related to signalling pathways in cells. Through cytokine array screening, we found that the expression of TIMP-2 was significantly increased in CRC drug-resistant cell lines. In addition, the expression of TIMP-2 in the serum of patients with CRC resistance to 5-Fu was significantly increased. Subsequent mechanistic experiments showed that TIMP-2 regulated the resistance of CRC cells to 5-Futhrough the JAK–STAT signalling pathway. Moreover, anti-TIMP-2 antibody or small molecule drug LY2784544 targeting the JAK–STAT signalling pathway can effectively reverse the resistance of CRC cells to 5-Fu. It is exactly TIMP-2 that mediates the resistance of CRC to 5-Fu through the JAK–STAT signalling pathway. Targeting drugs for TIMP-2 or the JAK–STAT signalling pathway are expected to be opportunities to reverse 5-Fu resistance in CRC.
研究领域:
肿瘤学
·
分子生物学
·
药物研发
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产品关联
DOI
PubMed
高影响因子
REACTIVE & FUNCTIONAL POLYMERS
·
2026
·
IF 5.4
Huidong Fang,Shiai Xu,Siyu Han,Bin Zhao,Chao Zhang,Wanji Zhou
T-shaped droplet microfluidic device was used for preparing 5-Fu-loaded chitosan microspheres. • 5-Fu-loaded chitosan microspheres exhibit pH-responsive release patterns and sustainable release characteristics for up to 60 days. • The average particle size of the microspheres is 3.90 ± 0.57 μm, and the particle size distribution is narrow. • Drug-loaded microspheres of different particle sizes have different drug release rates and cycles. Microsphere formulations are a promising drug delivery system for targeted response and prolonged sustained release. However, conventional emulsification crosslinking methods for microsphere preparation usually result in a broad particle size distribution, large particle size, poor uniformity, and consequently erratic drug release kinetics. In this investigation, chitosan microspheres encapsulating 5-Fluorouracil (5-Fu CS-MS) were fabricated using a T-type droplet microfluidic device, and the formulation was optimized by single-factor experiments. The resulting microspheres had a consistent drug release profile, a smooth surface, high monodispersity, and a uniform particle size distribution with an average particle size of 3.90 ± 0.57 μm. The polymer-drug interaction in 5-Fu CS-MS was analyzed using FTIR and XRD. The XPS and EDS results confirmed the occurrence of a Schiff base reaction between glutaraldehyde (GA) and chitosan (CS), indicating successful encapsulation. TGA results revealed that the cross-linking reaction enhanced the thermal stability of the microspheres. Biocompatibility assessments using Human umbilical vein endothelial cells (HUVEC) line demonstrated the safety and compatibility of the fabricated microspheres. More importantly, the in vitro release results illustrated a pH-responsive drug release profile and sustained release of 5-Fu CS-MS for a period up to 60 days. In summary, the CS sustained-release microspheres produced using the microfluidic technique have the potential for intelligent response, precise drug delivery, and prolonged sustained release of small-molecule drugs. Download: Download high-res image (197KB) Download: Download full-size image
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DOI
高影响因子
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