Advanced Science
·
2025
·
IF 14.1
Yijing Zhang,Han Gao,Aiwen Tang,Haiwen Lyu,Zongmin Fan,Jiahui Guo,Yuzhi Wang,Hairong Yi,Qihao Pan,Haidan Luo,Baifu Qin,Boyu Zhang,Xiangqi Meng,Qingxin Liu,Mong-Hong Lee
Pancreatic ductal adenocarcinoma (PDAC) is a fatal cancer with poor prognosis. COP9 signalosome subunit 6 (CSN6), a key regulator of different E3 ubiquitin ligases, plays oncogenic roles in various cancers. However, its function in PDAC remains elusive. Here, this demonstrates that human PDAC tumors expressing high levels of CSN6 present with poor prognosis and gemcitabine resistance. Conditional knockout (KO) of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model. Proteomic analysis indicates that CSN6 promotes ribosome biogenesis by activating rDNA transcription and protein synthesis. Mechanistically, CSN6 antagonizes DDB1-CUL4 associated factor 1 (DCAF1)-mediated ubiquitination of Nucleophosmin (NPM1), thereby promoting NPM1-orchestrated ribosome biogenesis. In line with CSN6-mediated gemcitabine resistance, CSN6-NPM1 axis enhances ribosome biogenesis, thereby promoting translation of gemcitabine resistance genes, including Cytidine deaminase (CDA), Ribonucleotide reductase subunit M1/2 (RRM1/2). Significantly, combining gemcitabine with NPM1 inhibitor NSC348884 synergistically suppresses CSN6-high pancreatic cancer xenografts. Clinically, CSN6 expression positively correlates with NPM1 in PDAC tissues, and their concurrent high expression is significantly associated with poor clinical outcomes. This study characterizes CSN6 as an oncogenic protein that promotes NPM1 stabilization by interacting with DCAF1, thereby enhancing ribosome biogenesis and cellular resistance to gemcitabine in PDAC. NPM1 may serve as a therapeutic target for CSN6 high PDAC that exhibits gemcitabine drug resistance.
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高影响因子
Nano Today
·
2022
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IF 18.962
Juqun Xi,Yanqiu Wang,Xuejiao Gao,Yaling Huang,Jie Chen,Yong Chen,Lei Fan,Lizeng Gao
Emerging evidence demonstrates that intratumor bacteria promote tumor resistance to gemcitabine chemotherapy. The underlying mechanism is relate to intratumor bacteria expressing a specific cytidine deaminase (CDD) which metabolizes gemcitabine into its inactive form. Therefore, to overcome tumor resistance to gemcitabine, the CDD activity of intratumor bacteria must be restricted during chemotherapy. Herein, we developed an antitumor strategy by utilizing the dual functions of nitrogen-doped carbon nanospheres (N-CSs), i.e., as nanoinhibitors of CDD to overcome bacteria-mediated gemcitabine resistance and as nanozymes to integrate tumor catalytic therapy with chemotherapy. We found that the nitrogen-doped graphitized structure of the N-CSs could competitively bind to the active center of CDD and thus prevented gemcitabine metabolism. In addition, nitrogen doping endowed the N-CSs with peroxidase-like activity that generates •OH radicals for tumor catalytic therapy. Furthermore, in mouse cancer models with intratumor bacteria, the N-CSs successfully reversed bacterial CDD-induced gemcitabine resistance and restored tumor susceptibility to gemcitabine. The synergistic effects of catalytic therapy and chemotherapy for tumor treatment were achieved by using single N-CSs with dual nanozymatic and nanoinhibitory functions. This work provides a promising approach to overcome tumor drug-resistance induced by intratumor bacteria and synergize gemcitabine chemotherapy with nanozyme-mediated catalytic therapy for tumor treatment.
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BIOORGANIC & MEDICINAL CHEMISTRY
·
2021
·
IF 3.641
Zichen Xu,Bin Zhang,Zhixin Liao,Shaohua Gou
Hypoxia is one of the unique features of tumor physiology. Hypoxia inducible factor (HIF-1α), as a major transcription factor in response to hypoxia, has been considered as a promising tumor-specific target for anticancer therapy. The formation of a hypoxic microenvironment in tumors can decrease the curative effect of cytotoxic chemotherapeutic drugs. To promote the antitumor efficacy of chemotherapy by suppressing hypoxia, we designed and prepared a novel gemcitabine-based drug conjugate ( GEM -5 ) containing a HIF-1α inhibitor (YC-1). As expected, GEM -5 showed excellent antiproliferative activity (IC 50 = 0.03 μΜ under hypoxia) and remarkably induced the apoptosis of A2780 cells in vitro . Additionally, western blot analysis demonstrated that GEM -5 significantly down-regulated the expression of HIF-1α and up-regulated the expression of tumor suppressor p53. More importantly, GEM -5 effectively inhibited tumor growth in the A2780 xenograft mouse model and significantly ameliorated tumor hypoxia in vivo . This novel, simple, and effective strategy for overcoming tumor hypoxia and enhancing the antitumor effect of chemotherapeutic drugs has great potential in cancer therapy.
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高影响因子
JOURNAL OF PHARMACY AND PHARMACOLOGY
·
2021
·Vol. 74
·期 4
·596-604
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IF 3.765
Sun Liyun,Shang Huoli,Wu Yuzhen,Xin Xiujuan
ObjectivesThe combination of gemcitabine (Gem) and hypericin (HY) enhances the apoptosis of Capan-2 cells, providing a promising option for the treatment of pancreatic cancer. Our study further explored the cytotoxic mechanism of HY combined with chemotherapy drugs on pancreatic cancer.MethodsThe proliferation rate of the cells assayed with the MTT method. The ROS (reactive oxygen species) levels of each treatment were evaluated by DCFH-DA oxidisation methods. The activity of glutathione reductase and the levels of reduced glutathione (GSH) and oxidised glutathione (GSSG) were assessed using assay kits. The expression levels of apoptosis-related proteins were analysed by western blotting.Key findingsThe activity of glucose-6-phosphate dehydrogenase (G6PDH), a key enzyme of the pentose phosphate pathway, significantly decreased in Gem + HY groups, however, the ROS level enhanced accompanying with GSH depleting, mitochondrial membrane depolarisation and cytochrome C release. Gem + HY inhibits the expression of Bcl-2 but stimulates Bax level, triggering caspase activation and PARP cleavage and thus promoted apoptosis of Capan-2 cells.ConclusionsWe demonstrated that Gem combined HY-PDT could inhibit the proliferation of Capan-2 cells and induce cell apoptosis. HY-PDT combined with Gem had a great potential on pancreatic cancer treatment clinically.
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DRUG DELIVERY
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2018
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IF 3.095
Wei Wu,Yong Dai,Han Liu,Ruoyu Cheng,Qing Ni,Tingjun Ye,Wenguo Cui
Osteosarcoma is among the most common malignant bone tumors in human skeletal system. The conventional treatment of osteosarcoma mainly consists of combining neoadjuvant chemotherapy with surgical approach. However, it is crucial to design an artificial implant that possesses excellent biomechanical properties and is capable of sustaining local release of chemotherapeutics. In this study, we envision that the highly efficient combination of gemcitabine (GEM) hydrochloride loaded liposomes with gelatin methacryloyl (GelMA) of in situ photocrosslinkable hydrogel will lead to a multifunctional implant with unique antitumor, mechanical, and biodegradable properties. A sustained controlled release was observed; more specifically, the release of GEM in vitro lasted for 4 days long. Furthermore, its capability in killing MG63 cells was further explored by using the lixivium of GEM-Lip@Gel and GEM-GelMA hydrogel in vitro (composite hydrogel by GEM loaded liposomes blending with GelMA, short for GEM-Lip@Gel), which agreed with the drug release outcome. In addition, these hydrogel showed excellent ability in inhibiting osteosarcoma in vivo by Balb/c mice bearing MG63 cells. Therefore, GEM-loaded lipo-hydrogel certainly has presented itself as a promising strategy for the development of implant in the field of osteosarcoma treatment.
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JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2017
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IF 4.233
Haijie Han,Jinhui Wang,Tingting Chen,Lichen Yin,Qiao Jin,Jian Ji
Development of gemcitabine (GEM) nanocarriers as theranostic agents for pancreatic cancer chemotherapy has received extensive attention in recent years. A novel enzyme-sensitive albumin-based GEM delivery nanoplatform was developed in this research by simple conjugation of GEM to human serum albumin (HSA) via cathepsin B cleavable peptide GFLG and then complexing with near-infrared (NIR) dye IR780, forming a HSA-GEM/IR780 complex. The successful preparation of HSA-GEM/IR780 complex was confirmed by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS), UV–vis–NIR absorption spectra and fluorescent emission spectra . The in vivo performance of HSA-GEM/IR780 complex was carried out on BxPC-3 pancreatic tumor xenografted mice. As revealed by in vivo NIR imaging, HSA-GEM/IR780 exhibited enhanced accumulation and long-term retention in tumor tissues compared to free IR780. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2′,2′-difluorodeoxyuridine (dFdU) can be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2020
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IF 2.734
Ning Ding,Yaxi Wang,Xiaolin Wang,Wei Chu,Tian Yin,Jingxin Gou,Haibing He,Yu Zhang,Yanjiao Wang,Xing Tang
Gemcitabine , as a nucleoside analog , has been used as first-line chemotherapy drug for many years. However, the treatment dose of gemcitabine in the clinic has been usually extremely high due to its rapid metabolism. The aim of this study was to achieve successful chemotherapy at low doses by a PEGylated liposomal delivery system. The liposomes were prepared with Lipoid S-100, Cholesterol and DSPE-PEG2000 (at a molar ratio of 9:2:0.07) by the film dispersion-extrusion-ammonium sulfate gradient method. The entrapment efficiency (EE, %) and drug loading (DL, %) of the liposomes (117.8 ± 16.85 nm) were 68.83% and 2.52%, respectively. The in vitro release study and plasma stability experiments showed the gemcitabine liposomes (GEM-Lip) was more stable than gemcitabine solutions (GEM-Sol) at pH 7.4 and in the plasma. AUC and C max of GEM-Lip were shown to be 6.20 and 16.44-fold higher than that of the solutions. The pharmacodynamics (PD) experiment in Kunming mice bearing a H22 cancer cell model showed that the tumor inhibition rate (TIR) of GEM-Lip was 6.25-fold as that of GEM-Sol when administrated intravenously. Our findings demonstrated that the preparation of GEM-Lip could effectively enhance the pharmacokinetic properties , the plasma stability and antitumor effect of gemcitabine.
研究领域:
药学
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肿瘤学
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生物医学工程
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2021
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IF 5.875
Zixu Liu,Wei Chu,Qianhe Sun,Linxuan Zhao,Xinyi Tan,Yu Zhang,Tian Yin,Haibing He,Jingxin Gou,Xing Tang
Combination, synergistic chemotherapy with gemcitabine (GEM) and cisplatin (CDDP) is a common strategy, and has been recommended for tumor treatment due to its promoted therapeutic effect and reduced systemic toxicity. However, this process involves the intravenous infusion of GEM prior to that of CDDP, which is inconvenient for patients and staff. Here, a novel hybrid nano-carrier system comprised of micelles encapsulated within PEGylated liposomes is proposed, in order to combine the unique strengths of each component. CDDP was bonded with PLG-PEG, and then the formed CDDP@PLG-PEG micelles and GEM were co-loaded inside PEGylated liposomes. The hybrid liposomes with the optimized GEM/CDDP ratio (1:0.6) showed a roughly spherical morphology, appropriate drug loading, and sustained release behavior. In vitro, the hybrid liposomes had 1.72-fold increased cellular uptake, and 57.42%-fold decreased IC 50 value. In vivo , pharmacokinetic studies showed increased t 1/2 values (125.64%- and 128.57%-folds for GEM and CDDP), decreased clearance (41.90%- and 2.37%-folds), and promoted AUC (262.76%- and 4577.24%-folds). Finally, an in vivo antitumor study showed effective activity in regards to lung tumor size and weight, which were 40.48%- and 33.11%-folds that of GEM/CDDP solution. In summary, we demonstrated the development of an effective micelle-containing PEGylated hybrid liposomes for combined GEM/CDDP delivery.
研究领域:
药剂学
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肿瘤学
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生物医学工程
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
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IF 7.7
Zhenjiang Zheng,Mengfei Li,Jianchen Yang,Xintao Zhou,Yonghua Chen,Epiphane K. Silli,Jiali Tang,Songlin Gong,Yuan Yuan,Yihao Zong,Jianping Kong,Pu Chen,Lingxi Yu,Shujun Luo,Ying Wang,Chunlu Tan
Fucoidan-coated pH sensitive liposomes were designed for targeted delivery of gemcitabine (FU-GEM PSL) to treat pancreatic cancer (PC). FU-GEM PSL had a particle size of 175.3 ± 4.9 nm, zeta potential of −19.0 ± 3.7 mV, encapsulation efficiency (EE) of 74.05 ± 0.17 %, and drug loading (DL) of 21.27 ± 0.05 %. Cell experiments in vitro showed that FU-GEM PSL could increase the release of GEM and drug concentration, and could inhibit tumor cell proliferation by affecting the cell cycle. FU-GEM PSL entered cells through macropinocytosis and caveolin-mediated endocytosis to exert effects. Meanwhile, the expression of P-selectin was detected in human tissues, demonstrating the feasibility of targeting FU. Moreover, combined with animal experiments in vivo, FU-GEM PSL could inhibit the development of PC. Furthermore, anti-tumor experiments in vivo carried on BALB/c mice indicated that FU-GEM PSL had tumor suppression abilities and safety. Therefore, FU-GEM PSL is a promising formulation for PC therapy.
研究领域:
药理学
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肿瘤学
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纳米技术
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药物递送系统
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2026
·
IF 5.2
Xinyi Zhang,Jingxin Gou,Yanjiao Wang,Xing Tang,Haibing He
The combination of the antiangiogenic agent nintedanib (BIBF) with the antimetabolite gemcitabine (GEM) represents a mechanistically rational yet clinically challenging strategy for breast cancer therapy. However, its clinical translation has been hindered by mismatched pharmacokinetics and the absence of a delivery system capable of coordinating their temporal release profiles. In this study, we developed a polymer-based nanoplatform designed to achieve sequential drug release: rapid initial release of BIBF to modulate the tumor microenvironment, followed by sustained release of GEM to exert cytotoxic effects. The gemcitabine prodrug (mPEG-PLG- GEM) was synthesized via covalent conjugation and subsequently used to prepare dual-loaded nanomicelles (mPEG-PLG-GEM@BIBF) through thin-film hydration. This system exhibited a well-defined sequential release profile in vitro, with BIBF released faster than the GEM prodrug. An optimal synergistic molar ratio (GEM:BIBF = 3:1) was identified. The nanomicelles (∼134.5 nm) enhanced the plasma stability and prolonged the systemic circulation of both drugs (half-lives of GEM increased from 1.38 h to 5.90 h; BIBF from 4.35 h to 8.90 h). Biodistribution studies showed increased tumor accumulation, with the intratumoral GEM:BIBF ratio maintained within the synergistic range around the target ratio of 3:1. In a 4T1 murine breast cancer model, mPEG-PLG-GEM@BIBF achieved a superior tumor inhibition rate of 77.84%, significantly outperforming the free drug combination (50.63%) and GEM monotherapy (33.54%), while also demonstrating a reduced systemic toxicity profile. This work presents a co-delivery nanoplatform designed to coordinate the release and tumor exposure of BIBF and GEM. The improved therapeutic effect is likely associated with the coordinated pharmacokinetics, enhanced tumor accumulation, and BIBF-faster-than-GEM release profile of the nanomicelles. Although direct evidence of vascular normalization and intracellular GEM activation was not obtained in this study, the results support a promising sequential co-delivery strategy for improving GEM/BIBF combination chemotherapy in breast cancer. Download: Download high-res image (206KB) Download: Download full-size image
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2023
·
IF 5
Zhenjiang Zheng,Dingchuan Peng,Mengfei Li,Xuehan Lu,Songlin Gong,Yuan Yuan,Epiphane K. Silli,Jiali Tang,Qiaoyun Zhao,HaoYun Xu,Yufei Lan,Chunlu Tan,Ying Wang
Due to the malignant proliferation and severe tumor fibrosis of pancreatic cancer (PC), the efficacy of chemotherapy has been largely limited. Peptidyl-prolyl cis -trans isomerase NIMA-interacting 1 (Pin1) promotes tumor progression by promoting collagen synthesis and tumor cell proliferation . In this study, we developed nano-liposomes (FU-GEM/Pin1 siRNA@LIP) that act simultaneously on pancreatic tumor cells. FU-GEM/Pin1 siRNA@LIP were designed with suitable particle size and potential, and effectively loaded with Pin1 siRNA and fucoidan (FU) while demonstrating good release stability and biocompatibility . Our study showed that FU-GEM/Pin1 siRNA@LIP effectively inhibited the proliferation of Panc01 and Panc02 tumor cells and significantly enhanced the uptake of these two types of cells in vitro . FU-GEM/Pin1 siRNA@LIP might cause tumor damage, promote apoptosis and reduce collagen formation in vivo . Molecular and histological studies demonstrated that FU-GEM/Pin1 siRNA@LIP regulated the expression of CDH11 and α-SMA, and also reducing collagen synthesis of peripheral matrix. In summary, our experiments highlight that FU-GEM/Pin1 siRNA@LIP is an effective combination delivery system. It can inhibit tumor cell proliferation in vitro , promote tumor cell apoptosis and reduce collagen synthesis in vivo . This system could provide a promising therapeutic option for PC.
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JOURNAL OF CELLULAR BIOCHEMISTRY
·
2018
·Vol. 120
·期 3
·4463-4471
·
IF 2.959
Xingda Wu,Zhe Liu,Kejia Guo,Gang Ma,Shaowei Song
Objective This work aimed to study the activating transcription factor 2 or AMP-dependent transcription factor-2 (ATF-2) inhibition mediated gemcitabine sensitivity in human pancreatic cancer cells. Methods The protein and messenger RNA expressions of ATF-2 in 42 pancreatic cancer tissues and adjacent nontumorous tissues were detected. Kaplan-Meier survival analysis was performed based on the expression level of ATF-2 protein in tumor tissues. Then the pancreatic cancer cells were transduced with ATF-2-expressing lentivirus and small interfering RNAs (siRNAs) to investigate the effect of ATF-2 on pancreatic cancer cell invasion, epithelium to mesenchyme transition, apoptosis, and gemcitabine sensitivity. Results The expression of phosphorylated (p)-ATF-2 protein was upregulated in pancreatic cancer tissues compared with adjacent nontumorous tissues. Patients with relative higher p-ATF-2 level showed significantly lower survival time. Then we found that the transfection ATF-2 siRNA into BxPC3 cells inhibited cell proliferation, invasion, and epithelium to mesenchyme transition, but enhanced cell apoptosis. These changes could be enhanced by the additional administration of gemcitabine. In addition, we confirmed that the overexpression of ATF-2 in Panc-1 cells promoted cell invasion and epithelium to mesenchyme transition. Conclusion We concluded that inhibition-promoted ATF-2 expression was responsible for epithelium to mesenchyme transition and invasion of pancreatic cancer cells, while the inhibition of ATF-2 confers to gemcitabine sensitivity in human pancreatic cancer cells in vitro.
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