JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS
·
2016
·Vol. 105
·期 5
·1114-1125
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IF 2.881
Shu-Di Yang,Wen-Jing Zhu,Qiao-Ling Zhu,Wei-Liang Chen,Zhao-Xiang Ren,Fang Li,Zhi-Qiang Yuan,Ji-Zhao Li,Yang Liu,Xiao-Feng Zhou,Chun Liu,Xue-Nong Zhang
The development of effective and stable carriers of small interfering RNA (siRNA) is important for treating cancer with multidrug resistance (MDR). We developed a new gene and drug co-delivery system and checked its characteristics. Low-density lipoprotein (LDL) was coupled with N-succinyl chitosan (NSC) Lipoic acid (LA) micelles and co-delivered MDR1 siRNA and paclitaxel (PTX-siRNA/LDL-NSC-LA) to enhance antitumor effects by silencing the MDR gene of tumors (Li et al., Adv Mater 2014;26:8217-8224). In our study, we developed a new type of containing paclitaxel-loaded micelles and siRNA-loaded LDL nanoparticle. This “binary polymer” is pH and reduction dual-sensitive core-crosslinked micelles. PTX-siRNA/LDL-NSC-LA had an average particle size of (171.6 ± 6.42) nm, entrapment efficiency of (93.92 ± 1.06) %, and drug-loading amount of (12.35% ± 0.87) %. In vitro, MCF-7 cells, high expressed LDL receptor, were more sensitive to this delivery system than to taxol ® and cell activity was inhibited significantly. Fluorescence microscopy showed that PTX-siRNA/LDL-NSC-LA was uptaken very conveniently and played a key role in antitumor activity. PTX-siRNA/LDL-NSC-LA protected the siRNA from degradation by macrophage phagocytosis and evidently down-regulated the level of mdr1 mRNA as well as the expression of P-gp. We tested the target ability of PTX-siRNA/LDL-NSC-LA in vivo in tumor-bearing nude mice. Results showed that this system could directly deliver siRNA and PTX to cancer cells. Thus, new co-delivering siRNA and antitumor drugs should be explored for solving MDR in cancer. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1114–1125, 2017.
研究领域:
药学
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生物医学工程
·
肿瘤学
·
纳米技术
·
药物递送系统
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DOI
PubMed
高影响因子
Cell Chemical Biology
·
2026
·Vol. 33
·期 2
·227-240
·
IF 9
Jinyao Chen,Ming Zhang,Yeji Wang,Zhiyu Xie,Fei Yang,Hongjun Yu,Di Zhang,Min Fang,Xiaoyi Luan,Xueyang Jin,Xue Wang,Yanan Qiao,Shicun Zheng,Xiuyun Li,Wenqiang Chang,Hongxiang Lou
The overexpression of drug exporters is a well-known mechanism driving antifungal drug resistance. Here, we investigate that converting the exporter to function as a drug importer provides an alternative approach to combat drug resistance. Using high-throughput screening, we identified quaternary ammonium compounds exhibiting hypersensitivity in Candida albicans strains overexpressing MDR1 . Further experiments involving CRISPR-Cas9-mediated deletion in C. albicans , heterologous expression of Ca Mdr1 in Saccharomyces cerevisiae and construction of Ca Mdr1-containing proteoliposomes confirmed Mdr1 acts as an importer of MKT-077, a potent cyanine derivative highly selective against MDR1 -overexpressing strains. By combining computational simulations and the site-directed mutagenesis, critical residues within the transmembrane domains of Ca Mdr1 involved in MKT-077 import were further identified. Moreover, MKT-077 exhibited therapeutic efficacy in Galleria mellonella infected with Mdr1-overexpressing C. albicans . This work opens an avenue to convert drug resistance into drug sensitivity-a paradigm-shifting strategy in antifungal drug discovery.
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PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2022
·Vol. 29
·期 11
·2177-2189
·
IF 12.067
Yang Yang,Yuan Hongyu,Zhao Lianmei,Guo Shichao,Hu Sijun,Tian Miaomiao,Nie Yongzhan,Yu Jiarui,Zhou Chaoxi,Niu Jian,Wang Guiying,Song Yongmei
P53 mutation is an important cause of chemoresistance in colorectal cancer (CRC). The investigation and identification of the downstream targets and underlying molecular mechanism of chemoresistance induced by P53 abnormalities are therefore of great clinical significance. In this study, we demonstrated and reported for the first time that leucine-rich pentatricopeptide repeat-containing protein (LRPPRC) is a key functional downstream factor and therapeutic target for P53 mutation-induced chemoresistance. Due to its RNA binding function, LRPPRC specifically bound to the mRNA of multidrug resistance 1 (MDR1), increasing MDR1 mRNA stability and protein expression. In normal cells, P53 induced by chemotherapy inhibited the expression of LRPPRC via miR-34a and in turn reduced the expression of MDR1. However, chemotherapy-induced P53/miR-34a/LRPPRC/MDR1 signalling pathway activation was lost when P53 was mutated. Additionally, the accumulated LRPPRC and MDR1 promoted drug resistance. Most importantly, gossypol-acetic acid (GAA) was recently reported by our team as the first specific inhibitor of LRPPRC. In CRC cells with P53 mutation, GAA effectively induced degradation of the LRPPRC protein and reduced chemoresistance. Both in vivo and in vitro experiments revealed that combination chemotherapy with GAA and 5-fluorouracil (5FU) yielded improved treatment outcomes. In this study, we reported a novel mechanism and target related to P53-induced drug resistance and provided corresponding interventional strategies for the precision treatment of CRC.
研究领域:
肿瘤学
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分子生物学
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药理学
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DOI
PubMed
高影响因子
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
·
2016
·Vol. 60
·期 10
·
IF 4.415
Xi Yang,Zhiyuan Ma,Sisi Zhou,Yayun Weng,Hongmei Lei,Su Zeng,Liping Li,Huidi Jiang
Entecavir (ETV) is a first-line antiviral agent for the treatment of chronic hepatitis B virus infection. Renal excretion is the major elimination path of ETV, in which tubular secretion plays the key role. However, the secretion mechanism has not been clarified. We speculated that renal transporters mediated the secretion of ETV. Therefore, the aim of our study was to elucidate which transporters contribute to the renal disposition of ETV. Our results revealed that ETV (50 μM) remarkably reduced the accumulation of probe substrates in MDCK cells stably expressing human multidrug and toxin efflux extrusion proteins (hMATE1/2-K), organic cation transporter 2 (hOCT2), and carnitine/organic cation transporters (hOCTNs) and increased the substrate accumulation in cells transfected with multidrug resistance-associated protein 2 (hMRP2) or multidrug resistance protein 1 (hMDR1). Moreover, ETV was proved to be a substrate of the above-described transporters. In transwell studies, the transport of ETV in MDCK-hOCT2-hMATE1 showed a distinct directionality from BL (hOCT2) to AP (hMATE1), and the cellular accumulation of ETV in cells expressing hMATE1 was dramatically lower than that of the mock-treated cells. The accumulation of ETV in mouse primary renal tubular cells was obviously affected by inhibitors of organic anion transporter 1/3 (Oat1/3), Oct2, Octn1/2, and Mrp2. Therefore, the renal uptake of ETV is likely mediated by OAT1/3 and OCT2 while the efflux is mediated by MATEs, MDR1, and MRP2, and OCTN1/2 may participate in both renal secretion and reabsorption.
研究领域:
药理学
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肾脏生理学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULES
·
2019
·Vol. 24
·期 9
·1661
·
IF 3.06
Mengmeng Xia,Yajing Fang,Weiwei Cao,Fuqiang Liang,Siyi Pan,Xiaoyun Xu
P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure–activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3′-OH, 4′-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.Keywords:flavonoids;P-gp;inhibitory activity;QSAR
研究领域:
药理学
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肿瘤学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Huazhang Qiu,Namei Wu,Yanjie Zheng,Min Chen,Shaohuang Weng,Yuanzhong Chen,Xinhua Lin
A robust and versatile signal-on fluorescence sensing strategy was developed to provide label-free detection of various target analytes. The strategy used SYBR Green I dye and graphene oxide as signal reporter and signal-to-background ratio enhancer, respectively. Multidrug resistance protein 1 (MDR1) gene and mercury ion (Hg2+) were selected as target analytes to investigate the generality of the method. The linear relationship and specificity of the detections showed that the sensitive and selective analyses of target analytes could be achieved by the proposed strategy with low detection limits of 0.5 and 2.2 nM for MDR1 gene and Hg2+, respectively. Moreover, the strategy was used to detect real samples. Analytical results of MDR1 gene in the serum indicated that the developed method is a promising alternative approach for real applications in complex systems. Furthermore, the recovery of the proposed method for Hg2+ detection was acceptable. Thus, the developed label-free signal-on fluorescence sensing strategy exhibited excellent universality, sensitivity, and handling convenience.
研究领域:
生物化学
·
分析化学
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分子生物学
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DOI
PubMed
高影响因子
Small Methods
·
2020
·Vol. 5
·期 4
·2001047
·
IF 12.13
Jianqiao Chang,Yu Zhang,Yike Li,Ziwei Han,Fei Tian,Chao Liu,Qiang Feng,Yuguang Wang,Jiashu Sun,Lu Zhang
Detection of mRNA expression in live cells during treatment is a challenging task, despite its importance in tumor biology and potential therapeutic leads. Here a multilayer ratiometric fluorescent nanomachine for live-cell perturbation and imaging of mRNA at single cell resolution is reported. The nanomachines fabricated by microfluidic approaches consist of fluorescent polymeric cores and multiple lipid layers, which can efficiently deliver siRNA and molecular beacons (MBs) to cytosol and then release the cargo in a sequential way. The siRNA molecules released from the outer lipid layers lead to silencing of multidrug resistance 1 (MDR1) gene, and the MBs from the middle lipid layers detect the presence of MDR1 mRNA. The fluorescent ratio of MBs to fluorescent polymeric cores positively correlates with the expression level of MDR1 mRNA in MCF-7/ADR cells during siRNA treatment. The nanomachines provide comparable results with traditional qPCR for quantifying mRNA, showing great potential for modulation and imaging of intratumoral mRNA in vitro and in vivo.
研究领域:
生物技术
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分子生物学
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癌症研究
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纳米技术
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 6.8
Wenge Zhang,Jinyao Chen,Min Fang,Minghui Song,Zongxu Gao,Jingru Hao,Zejun Xu,Xiuyun Li,Shicun Zheng,Wenqiang Chang,Hongxiang Lou
Overexpression of efflux pump genes drives azole resistance in Candida albicans, highlighting the need for efflux pump inhibitors. We identified pleopcin A (PA), a novel spirodioxynaphthalene from Pleopunctum brunnescens, which reverses Mdr1-mediated azole resistance. To enhance potency, we achieved its first total synthesis and designed 82 derivatives via target–ligand analysis. Among them, PA36–2 emerged as the most potent lead compound, showing 64-fold greater activity than PA in combination with fluconazole against MDR1-overexpressing C. albicans strains. Mechanistic studies confirmed PA36–2 as a specific Mdr1 inhibitor. In addition, PA36–2 combined with fluconazole exhibited potent in vivo activity against Galleria mellonella and mice infected with MDR1-overexpressing C. albicans strain. These findings support further pharmaceutical investigation of the potential value of PA36–2 as an Mdr1 inhibitor for overcoming azole resistance in C. albicans infections.
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PubMed
高影响因子
BIOMATERIALS
·
2018
·
IF 8.806
Cuifeng Wang,Jiamin Wu,Zhongjuan Wang,Zeping Yang,Zhi Li,Huihui Deng,Long Li,Xiao Peng,Min Feng
Many human cancer cells exhibit an oncogenetic-driven addiction to glutamine (Gln) as rapidly proliferating cancer cells consume Gln at a dramatically increased rate compared to normal cells. Tumor cells, therefore, compete with host cells for Gln, which causes Gln to flux from normal tissues to the tumor. We have developed and characterized a Gln macromolecular analog polyglutamine (PGS) for the delivery of gene regulators , such as siRNAs, in our previous works. Here, we hypothesize that PGS can utilize the Gln transporter SLC1A5 to specifically deliver therapeutic compounds to Gln-addicted cancer cells. Compared to human lung fibroblast HLF cells, cisplatin-resistant human lung adenocarcinoma A549/DDP cells significantly overexpress SLC1A5, which has a high binding affinity to PGS, as confirmed through molecular docking analysis. Due to the differences in Gln metabolism between malignant and normal cells, PGS/siRNA complexes were remarkably increased in cancer cells, especially when cells were deprived of Gln, which mirrors the conditions that are commonly found in a tumor microenvironment . Furthermore, we identified that chemical and genetic inhibition of Gln transporter SLC1A5 reduced the cellular internalization of PGS/siRNA complexes, suggesting a critical role for SLC1A5 in PGS uptake in cells. In turn, PGS upregulated SLC1A5 expression. Increased uptake of PGS complexes profoundly decreased intracellular Gln levels. Decreased Gln caused a moderate reduction in cell growth. To restore drug sensitivity and further enhance anti-tumor effects, the hybrid siRNAs anti-Survivin and anti-MDR1 (siSM), as model therapeutics, were administered through the PGS delivery system, which resulted in knockdown of Survivin and MDR1 and further sensitized cancer cells to the drug cisplatin (DDP). Since PGS complexes administered i.v. mostly accumulated in the lung parenchyma, a lung orthotopic tumor model was established to evaluate their inhibitory effects on tumors in the lungs. PGS/siSM comparably decreased the rate of tumor growth, while concurrent administration of PGS/siSM and DDP enhanced this effect and insignificantly improved life span. Consistent with our hypothesis, this study demonstrated that PGS mimicked Gln in the SLC1A5 pathway and selectively ferried therapeutics to Gln-addicted cancer cells. Our findings identified a new lung cancer targeting strategy based on Gln metabolism and can be used as a drug/gene delivery system.
研究领域:
肿瘤学
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药学
·
分子生物学
·
癌症治疗
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产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2020
·Vol. 75
·期 5
·186-190
·
IF 1.198
Qin Yanjie,Wang Nanxi,Chen Fen,Han Xuemei,Zhu Ying,Rang Ying,Zhai Xuejia,Lu Yongning
Irinotecan (CPT-11) is a broad spectrum agent for the treatment of solid tumor malignancies, despite severe diarrhea is limiting its widespread usage. The local effects of SN-38 in the small intestine were considered to be responsible for the irinotecan-induced delayed diarrhea. It
was proposed that cyclosporin A (CsA) inhibiting biliary excretion could attenuate this side effect, but in fact, it could not improve the therapeutic index of irinotecan. At present, most studies focused on the inhibition of bile excretion by cyclosporin A through the transporters MRP2 and
MDR1 and its effect the irinotecan treatment in vivo. However, UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1) was related to a significantly altered disposition of irinotecan and its metabolites, and was therefore associated with irinotecan-induced toxicity. This study focused
on UGT1A1-mediated conversion of SN-38 to SN-38G, and systematically investigated the CsA-irinotecan interactions in vitro and in vivo. After treatment with 10 mg·kg-1 CsA for 7 days, the bile excretion of irinotecan and its metabolites decreased and AUC0-∞
increased significantly. The AUC0-∞ (SN-38G)/AUC0-∞ (SN-38) was significantly reduced when compared with that in vehicle-treated rats. In the liver microsome incubation system, the IC50 of CsA for UGT1A1 enzyme was 9.4 μM. Furthermore, the UGT1A1
mRNA and protein expression levels were significantly reduced. The present study indicated that CsA treatment could enhance the systemic exposure and toxicity of SN-38 by inhibiting the UGT1A1 enzyme. The inhibition of UGT1A1 enzyme might be a critical factor in the failure of CsA improving
irinotecan's treatment index.
研究领域:
药理学
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肿瘤学
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毒理学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2017
·Vol. 69
·期 6
·743-752
·
IF 2.405
Wang Meng,Huang Can,Su Yong,Yang Cui,Xia Quan,Xu Du-juan
ObjectivesInhibition of autophagy has been increasingly recognized as a potential therapeutic approach against cancer. Our previous reports showed that Astragaloside II improves hepatic cancer cells resistance by downregulating MDR1 and P-gp .The purpose of this study was to further investigated the effect of autophagy on AS-II reversing multidrug resistance and its molecular mechanism in hepatocellular carcinoma cells in vitro.MethodsBel-7402 and Bel-7402/FU cell lines were used in this study. Western blot was used to detect the expression of autophagy-related protein, p-mTOR and p-p79s6k, MTT was used to analyse cell viability, GFP-LC3 punctate dots distribution was observed by GFP-LC3 transient transfection under fluorescence microscopy and silencing of autophagy-related genes was detected by small interfering RNA transfection.Key findingsAstragaloside II was able to significantly decrease the expression of LC3-II and Beclin-1 in a dose-dependent manner, Astragaloside II (80 μm) further decreased LC3-II formation, Beclin-1 and GFP-LC3 puncta dots stimulated with 5-fluorouracil (0.2 mm) in Bel-7402/FU cells (P < 0.05). In addition, Astragaloside II is capable of sensitizing cells to 5-fluorouracil-induced cell death via inhibition of pro-survival autophagy involvement of MAPK-mTOR pathway.ConclusionsThese findings suggested that Astragaloside II could suppress autophagy by interfering with Beclin-1 and LC3 via MAPK-mTOR pathway, through which sensitized human cancer resistant cells to 5-FU-induced cell death.
研究领域:
肿瘤学
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药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY
·
2020
·
IF 2.365
Zhongjuan Wang,Yueqin Liang,Yanqiu Liu,Hongying Xia,Jianqi Liu,Xingfang Jin,Zhongkun Li
Multi-drug resistance (MDR) is one of the major challenges in the successful chemotherapy of non-small cell lung cancer (NSCLC). Although RNA interference (RNAi) has been widely used to silence resistance-related genes, the effect remains unsatisfactory. In this study, we attempted to overcome MDR of NSCLC by simultaneously interfering with two RNAs that have different functions. A new pH-triggered polyglutamate brush polymer dimethylmaleic anhydride-poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (DMA-mPEG-b-PG-g-spermine, DPPGS) was designed and synthesized. The DPPGS/small interfering RNA (siRNA) complex nanoparticles (DPPGSN) were prepared. The results demonstrated that DPPGSN could be transformed from a negatively charged form into a positively charged form in the slightly acidic tumor extracellular environment. The siRNA targeting MDR1 mRNA (siMDR1) and siRNA targeting survivin mRNA (siSurvivin) could be efficiently co-delivered by DPPGS to simultaneously interfere with two genes (p < 0.01). Furthermore, DPPGS co-delivery of siMDR1 and siSurvivin lowered the IC50 value of cisplatin (DDP) in A549/DDP (p < 0.01) cells and increased the apoptosis rate of the cells (p < 0.01). Therefore, co-delivery of siMDR1 and siSurvivin using DPPGS would be a promising approach for overcoming MDR of NSCLC.
研究领域:
肿瘤学
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药剂学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）