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Magnolol and 5-fluorouracil synergy inhibition of metastasis of cervical cancer cells by targeting PI3K/AKT/mTOR and EMT pathways

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Chinese Herbal Medicines 2024年第1期16卷 94-105页

作者： Yuanyuan Chen Shanshan Chen Kaiting Chen Lanfang Ji Shuna Cui Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases Medical College of Yangzhou UniversityYangzhou 225009China Department of Gynecology and Obstetrics Affiliated Hospital of Yangzhou UniversityYangzhou 225009China

Objective: This study is designed to investigate the mode of action of the synergistic effect of 5-fluorouracil(5-FU) and magnolol against cervical cancer.Methods: Network pharmacological approach was applied to predict the molecular mechanism of 5-FU combined with magnolol against cervical cancer. CCK-8 assay, colony formation assay, immunofluorescence staining, adhesion assay, wound healing mobility assay, cell migration and invasion assay and Western blot analysis were conducted to validate the results of in silico study.Results: Phosphatidylinositol 3 kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR) signaling pathway was identified as the key pathway in silico study. The experimental results showed that 5-FU combined with magnolol strongly inhibited cervical cancer cell proliferation, induced the morphological change of HeLa cells by down-regulating the expression of a-actinin, tensin-2 and vinculin. Moreover, magnolol enhanced inhibitory effect of 5-FU on the cell adhesion, migration and invasion. The phosphorylation of AKT and PI3K and the expression of mTOR were strongly inhibited by the combination of 5-FU and magnolol. Moreover, the expression of E-cadherin and β-catenin was upregulated and the expression of Snail, Slug and vimentin was down-regulated by the 5-FU together with magnolol.Conclusion: Taken together, this study suggests that 5-FU combined with magnolol exerts a synergistic anti-cervical cancer effect by regulating the PI3K/AKT/mTOR and epithelial-mesenchymal transition(EMT) signaling pathways.

关键词： cervical cancer 5-fluorouracil EMT pathway magnolol network pharmacology PI3K/AKT/mTOR pathway

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Anti-osteosarcoma trimodal synergistic therapy using NiFe-LDH and MXene nanocomposite for enhanced biocompatibility and efficacy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1329-1344页

作者： Yani Xu Lan Yang Min Li Haozhou Shu Na Jia Yunzhen Gao Rongying Shi Xiaojia Yang Zhirong Zhang Ling Zhang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry West China School of PharmacySichuan UniversityChengdu 610041China Med-X Center for Materials College of Polymer Science and EngineeringSichuan UniversityChengdu 610065China

Osteosarcoma is usually resistant to immunotherapy and,thus primarily relies on surgical resection and high-dosage chemotherapy.Unfortunately,less invasive or toxic therapies such as photothermal therapy(PTT)and chemodynamic therapy(CDT)generally failed to show satisfactory outcomes.Adequate multimodal therapies with proper safety profiles may provide better solutions for osteosarcoma.Herein,a simple nanocomposite that synergistically combines CDT,PTT,and chemotherapy for osteosarcoma treatment was fabricated.In this composite,small 2D Ni Fe-LDH flakes were processed into 3D hollow nanospheres via template methods to encapsulate 5-fluorouracil(5-FU)with high loading capacity.The nanospheres were then adsorbed onto larger 2D Ti3C2MXene monolayers and finally shielded by bovine serum albumin(BSA)to form 5-FU@Ni Fe-LDH/Ti3C2/BSA nanoplatforms(5NiTiB).Both in vitro and in vivo data demonstrated that the 5-FU induced chemotherapy,Ni Fe-LDH driven chemodynamic effects,and MXene-based photothermal killing collectively exhibited a synergistic“all-in-one”anti-tumor effect.5NiTiB improved tumor suppression rate from5%by 5-FU alone to~80.1%.This nanotherapeutic platform achieved higher therapeutic efficacy with a lower agent dose,thereby minimizing side effects.Moreover,the composite is simple to produce,enabling the fine-tuning of dosages to suit different requirements.Thus,the platform is versatile and efficient,with potential for further development.

关键词： Osteosarcoma NiFe-LDH MXene Chemodynamic therapy Photothermal therapy Chemotherapy 5-fluorouracil Nanocomposite

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Influence of 6-shogaol potentiated on 5-fluorouracil treatment of liver cancer by promoting apoptosis and cell cycle arrest by regulating AKT/mTOR/MRP1 signalling

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Chinese Journal of Natural Medicines 2022年第5期20卷 352-363页

作者： ZHANG Yi QU Yong CHEN Yun-Zhong Pharmacy Faculty Hubei University of Chinese MedicineWuhan 430065China Department of Pharmacy CR&WISCO General HospitalWuhan 430000China

Currently, chemoresistance seriously attenuates the curative outcome of liver cancer. The purpose of our work was to investigate the influence of 6-shogaol on the inhibition of 5-fluorouracil (5-FU) in liver cancer. The cell viability of cancer cells was determined by MTT assay. Liver cancer cell apoptosis and the cell cycle were examined utilizing flow cytometry. Moreover, qRT–PCR and western blotting was used to analyse the mRNA and protein expression levels, respectively. Immunohistochemistry assays were used to examine multidrug resistance protein 1 (MRP1) expression in tumour tissues. In liver cancer cells, we found that 6-shogaol-5-FU combination treatment inhibited cell viability, facilitated G0/G1 cell cycle arrest, and accelerated apoptosis compared with 6-shogaol or 5-FU treatment alone. In cancer cells cotreated with 6-shogaol and 5-FU, AKT/mTOR pathway- and cell cycle-related protein expression levels were inhibited, and MRP1 expression was downregulated. AKT activation or MRP1 increase reversed the influence of combination treatment on liver cancer cell viability, apoptosis and cell cycle arrest. The inhibition of AKT activation to the anticancer effect of 6-shogaol-5-FU could be reversed by MRP1 silencing. Moreover, our results showed that 6-shogaol-5-FU combination treatment notably inhibited tumour growth in vivo. In summary, our data demonstrated that 6-shogaol contributed to the curative outcome of 5-FU in liver cancer by inhibiting the AKT/mTOR/MRP1 signalling pathway.

关键词： Liver cancer 6-Shogaol 5-fluorouracil Multidrug resistance protein 1

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Low-dose intralesional injection of 5-fluorouracil and triamcinolone reduces tissue resident memory T cells in chronic eczema

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World Journal of Clinical Cases 2022年第1期10卷 166-176页

作者： Yun Wu Guo-Jiang Wang Hui-Qiong He Hai-Hong Qin Wen-Tong Shen Yue Yu Xun Zhang Mao-Lin Zhou Jian-Biao Fei Department of Dermatology Shanghai University of Medicine&Health Sciences Affiliated Zhoupu HospitalShanghai 201318China

BACKGROUND Tissue resident memory T(TRM)cells have been reported to play a significant role in the pathogenesis and relapse of chronic eczema.AIM To compare the efficacy and safety of the intralesional injection of 5-fluorouracil(5-FU)and triamcinolone(TA)with those associated with TA alone for the treatment of chronic eczema.METHODS A total of 168 patients were randomized to 5-FU+TA or TA groups and received a one-time intralesional injection of 5-FU+TA or TA only.Biopsies were collected before and 2 wk after treatment for evaluation of histopathological changes.All patients were followed up monthly for up to 1 year.RESULTS No serious adverse event was observed in either group.Although the mean atopic dermatitis severity index scores and effective rates were comparable between the two groups after 2 wk of treatment,the relapse rate was significantly lower in the 5-FU+TA group than in the TA group.Histological examination showed significantly fewer CD8^(+)and CD103^(+)T cells but not CD4^(+)T cells in the 5-FU+TA group.CONCLUSION One-time intralesional injection of 5-FU+TA is effective and safe for chronic eczema treatment and can further reduce the retention of T_(RM) cells in the lesional skin and the relapse rate of chronic eczema.

关键词： Chronic eczema 5-fluorouracil Triamcinolone Intralesional injection Tissue resident memory T cell

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Hydrogen-rich water exerts anti-tumor effects comparable to 5-fluorouracil in a colorectal cancer xenograft model

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World Journal of Gastrointestinal Oncology 2022年第1期14卷 242-252页

作者： Fereshteh Asgharzadeh Alex Tarnava Asma Mostafapour Majid Khazaei Tyler W LeBaron Department of Physiology Faculty of MedicineMashhad University of Medical SciencesMashhad ***Iran Drink HRW New WestminsterBC V3j0b6 Canada Department of Medical Genetics and Molecular Medicine Faculty of MedicineMashhad University of Medical SciencesMashhad ***Iran Centre of Experimental Medicine Institute for Heart Research Slovak Academy of SciencesBratislava 984104Slovakia Department of Kinesiology and Outdoor Recreation Southern Utah UniversityUT 84720United States Biological Research Molecular Hydrogen InstituteUT 84721United States Department of Physical Science Southern Utah UniversityUT 84720United States

BACKGROUND Colorectal cancer(CRC)is the third leading cause of cancer-related deaths in the world.Tumor removal remains the preferred frontline treatment;however,effective non-surgical interventions remain a high priority.5-fluorouracil(5-FU)is a widely used chemotherapy agent,and molecular hydrogen(H2)has been recognized for its antioxidant and anti-inflammatory effects,with research also suggesting its potential anti-tumor effects.Therefore,H2 dissolved in water[hydrogen-rich water(HRW)],with or without 5-FU,may present itself as a novel therapeutic for CRC.AIM To investigate the effects of HRW,with or without 5-FU,as a novel therapeutic for CRC.METHODS CRC was induced in the left flank of inbred Balb/c mice.A total of 24 mice bearing tumors were randomly divided into four groups(n=6 per group)and treated as follows:(1)Control group;(2)5-FU group that received intraperitoneal injection of 5-FU(5 mg/kg)every other day;(3)H2 group that received HRW,created and delivered via dissolving the H2-generating tablet in the animals’drinking water,with 200μL also delivered by oral gavage;and(4)The combination group,H2(administered in same way as for group three)combined with 5-FU administered same way as group two.RESULTS Administration of HRW+5-FU significantly improved tumor weight,tumor size,collagen content and fibrosis as compared to the CRC control group.Specifically,HRW attenuated oxidative stress(OS)and potentiated antioxidant activity(AA),whereas 5-FU treatment exacerbated OS and blunted AA.The combination of HRW+5-FU significantly reduced tumor weight and size,as well as reduced collagen deposition and the degree of fibrosis,while further increasing OS and decreasing AA compared to administration of 5-FU alone.CONCLUSION Administration of HRW,with or without 5-FU,may serve as a therapeutic for treating CRC.

关键词： Colorectal cancer Molecular hydrogen 5-fluorouracil Oxidative stress Antioxidants Inflammation

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Curcumin Reverses 5-fluorouracil Resistance by Promoting Human Colon Cancer HCT-8/5-FU Cell Apoptosis and Down-regulating Heat Shock Protein 27 and P-Glycoprotein

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Chinese Journal of Integrative Medicine 2019年第6期25卷 416-424页

作者： HE Wen-ting ZHU Yan-hua ZHANG Tong ABULIMITI Patima ZENG Fan-ye ZHANG Li-ping LUO Ling-juan XIE Xin-mei ZHANG Hong-liang Second Department of Oncology Traditional Chinese Medicine Hospital of Xinjiang Uyghur Autonomous Region Uyghur (830000) China Department of Oncology Xiyuan Hospital China Academy of Chinese Medical Sciences Beijing (100091) China

Objective: To investigate the potential mechanisms that curcumin reverses 5-fluorouracil(5-FU) multidrug resistance(MDR). Methods: Cell growth and the inhibitory rate of curcumin(2–25 μg/mL) and/or5-FU(0.05–1000 μg/mL) on human colon cancer HCT-8 and HCT-8/5-FU(5-FU-resistant cel line) were determined using cel counting kit-8(CCK-8) assay. Apoptosis and cel cycle after 5-FU and/or curcumin treatment were detected by ?ow cytometry(FCM) and transmission electron microscopy(TEM). The expression of the multidrug resistance related factors p-glycoprotein(P-gp) and heat shock protein 27(HSP-27) genes and proteins were analyzed by reverse transcription polymerase chain reaction(RT-PCR) and Western blotting(WB), respectively. Results: The inhibitory rate of curcumin or 5-FU on HCT-8 and HCT-8/5-FU cells proliferation at exponential phase were in a dosedependent manner, HCT-8 cell line was more sensitive to curcumin or 5-FU when compared the inhibitory rate of HCT-8/5-FU. The 50% inhibitory concentration(IC50) of combination 5-FU and curcumin(4.0 μg/mL)in HCT-8/5-FU was calculated as 179.26 μg/mL, with reversal fold of 1.85. Another IC50 of combination 5-FU and curcumin(5.5 μg/mL) in HCT-8/5-FU was calculated as 89.25 μg/mL, with reversal fold of 3.71. Synergistic effect of 5-FU and curcumin on HCT-8 and HCT-8/5-FU cells were found. The cell cycle analysis performed by FCM showed that HCT-8 and HCT-8/5-FU cel s mostly accumulated at G0/G1 phase, which suggested a synergistic effect of curcumin and 5-FU to induce apoptosis. FCM analysis found that the percentage of apoptosis of cel s treated with curcumin, 5-FU and their combination were signi?cantly increased compared to the control group(P5), and the percentage of apoptosis of the combination groups were slightly higher than other groups(P5). The m RNA levels of P-gp(0.28±0.02) and HSP-27(0.28±0.09) in HCT-8/5-FU cel s treated with combination drugs were lower than cel s treated with 5-FU alone(P-gp, 0.48±0.07, P=0.009;HSP-27, 0.57±0.10, P=0.007). The protein lev

关键词： curcumin Chinese medicine 5-fluorouracil multidrug resistance HCT-8 HCT-8/5-FU col on cancer P-gp HSP-27

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Concurrent chemoradiotherapy comparison of taxanes and platinum versus 5-fluorouracil and platinum in nasopharyngeal carcinoma treatment

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Chinese Medical Journal 2014年第1期127卷 142-149页

作者： Chen Xichuang Hong Yuan Feng Jinhua Ye Jianlin Zheng Panpan Guan Xiyin You Xiaohong Song Huizhu Department of Pharmacy Affiliated Wuxi No. 9 People's HospitalSoochow University & Wuxi Hand Surgery Hospital Wuxi Jiangsu214062 China Department of Pharmacy Affilated Wuxi People's Hospital Nanjing Medical University Wuxi Jiangsu 214023 China Department of Pharmacy Ningbo No. 6 Hospital Ningbo Zhejiang315450 China Department of Radiation Oncology Shanghai Cancer CenterShanghai Medical College Fudan University Shanghai 200032China

Background Nasopharyngeal carcinoma （NPC） is a squamous-cell carcinoma especially prevailing among the natives of southern China.The regimen of concurrent chemoradiotherapy （CCRT） that include platinum and 5-fluorouracil （5-FU）is considered to be the standard treatment for NPC.However,its clinical use is limited by its toxicity.Our purpose was to evaluate the efficacy and safety of the regimen of CCRT with taxanes and platinum versus the regimen of CCRT with 5-FU and platinum in NPC treatment.Methods Medline,the Cochrane library,and the Chinese medical literature database were searched for eligible studies.Meta-analysis was performed using Review Manager （Version 5.2）.Results Six random controlled trials （RCTs） including 514 patients met our criteria.Meta-analysis showed that the regimen of CCRT with taxanes and platinum had an improved significant difference in complete remission （CR） and less incidence rate in adverse reactions such as gastrointestinal impairment grades Ⅲll-Ⅳ,liver and kidney impairment grades Ⅰ-Ⅱ,and radiodermatitis grades Ⅲ-Ⅳ versus the conventional regimen of CCRT with 5-FU and platinum,while the long-term effectiveness rate of overall survival,Iocoregional failure-free survival,or distant metastasis failure-free survival between the two groups was therapeutic equivalence.Conclusions The regimen of CCRT with taxanes and platinum in NPC therapy may be more efficient and safe compared to the conventional modality of 5-FU and platinum in CCRT.However,we need more high-quality studies of multi-center and randomized double-blind clinical trials to further compare,analyze,and confirm the findings.

关键词： chemoradiotherapy platinum taxanes 5-fluorouracil nasopharyngeal carcinoma meta-analysis

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Autophagy in 5-fluorouracil Therapy in Gastrointestinal Cancer： Trends and Challenges

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Chinese Medical Journal 2016年第4期129卷 456-463页

作者： Jia-Cheng Tang Yi-Li Feng Xiao Liang Xiu-Jun Cai Department of General Surgery Zhejiang Province Key Laboratory of Laparosopic Technology Sir Run Run Shaw Hospital Zhejiang University Hangzhou Zhejiang 310016 China

Objective： 5-fluorouracil （5-FU）-based combination therapies are standard treatments for gastrointestinal cancer, where the modulation of autophagy is becoming increasingly important in offering effective treatment for patients in clinical practice.This review focuses on the role of autophagy in 5-FU-induced tumor suppression and cancer therapy in the digestive system.Data Sources： All articles published in English from 1996 to date those assess the synergistic effect ofautophagy and 5-FU in gastrointestinal cancer therapy were identified through a systematic online search by use of PubMed.The search terms were ＆quot;autophagy＆quot; and ＆quot;5-FU＆quot; and （＆quot;colorectal cancer＆quot; or＆quot;hepatocellular carcinoma＆quot; or＆quot;pancreatic adenocarcinoma＆quot; or＆quot;esophageal cancer＆quot; or＆quot;gallbladder carcinoma＆quot; or ＆quot;gastric cancer＆quot;）.Study Selection： Critical reviews on relevant aspects and original articles reporting in vitro and/or in vivo results regarding the efficiency ofautophagy and 5-FU in gastrointestinal cancer therapy were reviewed, analyzed, and summarized.The exclusion criteria for the articles were as follows：（1） new materials （e.g., nanomaterial）-induced autophagy;（2） clinical and experimental studies on diagnostic and/or prognostic biomarkers in digestive system cancers;and （3） immunogenic cell death for anticancer chemotherapy.Results： Most cell and animal experiments showed inhibition ofautophagy by either pharmacological approaches or via genetic silencing of autophagy regulatory gene, resulting in a promotion of 5-FU-induced cancer cells death.Meanwhile, autophagy also plays a pro-death role and may mediate cell death in certain cancer cells where apoptosis is defective or difficult to induce.The dual role of autophagy complicates the use of autophagy inhibitor or inducer in cancer chemotherapy and generates inconsistency to an extent in clinic trials.Conclusion： Autophagy might be a therapeutic target that sensitizes the 5-FU treatment in gastrointestinal cancer.

关键词： 5-fluorouracil Autophagy Gastrointestinal Cancer Tumor

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Effects of thymidine phosphorylase on tumor aggressiveness and 5-fluorouracil sensitivity in cholangiocarcinoma

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World Journal of Gastroenterology 2010年第13期16卷 1631-1638页

作者： Jongkonnee Thanasai Temduang Limpaiboon Patcharee Jearanaikoon Banchob Sripa Chawalit Pairojkul Srisurang Tantimavanich Masanao Miwa Department of Clinical Microbiology Faculty of Medical Technology Mahidol University Department of Clinical Chemistry Centre for Research and Development of Medical Diagnostic Laboratories Faculty of Associated Medical Sciences Khon Kaen University Department of Clinical Chemistry Centre for Research and Development of Medical Diagnostic Laboratories Faculty of Associated Medical SciencesKhon Kaen University Department of Pathology Liver Fluke and Cholangiocarcinoma Research Center Faculty of Medicine Khon Kaen University Nagahama Institute of Bio-Science and Technology

AIM: To evaluate the role of thymidine phosphorylase (TP) in cholangiocarcinoma using small interfering RNA (siRNA). METHODS: A human cholangiocarcinoma-derived cell line KKU-M139, which has a naturally high level of endogenous TP, had TP expression transiently knocked down using siRNA. Cell growth, migration, in vitro angiogenesis, apoptosis, and cytotoxicity were assayed in TP knockdown and wild-type cell lines. RESULTS: TP mRNA and protein expression were decreased by 87.1% ± 0.49% and 72.5% ± 3.2%, respectively, compared with control cells. Inhibition of TP significantly decreased migration of KKU-M139, and suppressed migration and tube formation of human umbilical vein endothelial cells. siRNA also reduced the ability of TP to resist hypoxia-induced apoptosis, while suppression of TP reduced the sensitivity of KKU-M139 to 5-fluorouracil. CONCLUSION: Inhibition of TP may be beneficial in decreasing angiogenesis-dependent growth and migration of cholangiocarcinoma but may diminish the response to 5-fluorouracil chemotherapy.

关键词： Liver fluke Cholangiocarcinoma Thymidine phosphorylase 5-fluorouracil siRNA Tumor aggressiveness Cell migration

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In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting

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Acta Pharmaceutica Sinica B 2015年第1期5卷 79-88页

作者： Mohamed Nasr Mohamed K.Ghorab Ahmed Abdelazem Department of Pharmaceutics and Industrial Pharmacy Faculty of Pharmacy Helwan University Department of Pharmaceutical Chemistry Faculty of Pharmacy Helwan University

The objective of this study was to prepare cubosomal nanoparticles containing a hydrophilic anticancer drug 5-fluorouracil(5-FU) for liver targeting. Cubosomal dispersions were prepared by disrupting a cubic gel phase of monoolein and water in the presence of Poloxamer 407 as a stabilizer.Cubosomes loaded with 5-FU were characterized in vitro and in vivo. In vitro, 5-FU-loaded cubosomes entrapped 31.21% drug and revealed nanometer-sized particles with a narrow particle size distribution. In vitro 5-FU release from cubosomes exhibited a phase of rapid release of about half of the entrapped drug during the first hour, followed by a relatively slower drug release as compared to 5-FU solution. In vivo biodistribution experiments indicated that the cubosomal formulation significantly(Po 0.05) increased5-FU liver concentration, a value approximately 5-fold greater than that observed with a 5-FU solution.However, serum serological results and histopathological findings revealed greater hepatocellular damage in rats treated with cubosomal formulation. These results demonstrate the successful development of cubosomal nanoparticles containing 5-FU for liver targeting. However, further studies are required to evaluate hepatotoxicity and in vivo antitumor activity of lower doses of 5-FU cubosomal formulation in treatment of liver cancer.

关键词： 5-fluorouracil Hydrophilic drug Cubosomes Liver targeting Hepatotoxicity

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