BIOMATERIALS
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2025
·
IF 12.9
Yu Wang,Hongrui Fan,Qinjun Chen,Haolin Song,Xuwen Li,Boyu Su,Tao Sun,Leilei Cheng,Chen Jiang
Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge to the efficacy of gemcitabine-based chemotherapy. Aberrant activation of intracellular pyrimidine metabolism is a key factor contributing to the reduced effectiveness of gemcitabine. Combining gemcitabine with metabolic regulators targeting critical pathways may alleviate gemcitabine resistance. In this study, we focus on the abnormal activation of dihydroorotate dehydrogenase (DHODH) in PDAC cells, a pivotal enzyme in the de novo pyrimidine synthesis pathway that diminishes cellular sensitivity to gemcitabine and catalyzes the reduction of ubiquinone to ubiquinol, playing an essential role in maintaining cellular redox homeostasis. To address these challenges, we developed GE11 peptide-modified polyphenol-iron chelate nanoparticles for co-delivery the long carbon chain-modified gemcitabine and the DHODH inhibitor leflunomide, with peptide modification enabling nanoparticles to target PDAC cells with high expression of epidermal growth factor receptor. The nanoparticles demonstrated the ability to induce mitocytosis and achieve deep tumor penetration in PDAC tissues. Upon drug release at the core lesion, the three components, modified gemcitabine, leflunomide and iron ions synergistically enhanced tumor cell killing by alleviating gemcitabine resistance and disrupting cellular redox homeostasis to induce multimodal cell death. In an in situ pancreatic cancer mouse model, this strategy exhibited superior anti-tumor efficacy compared to the standard AG chemotherapy regimen (nab-paclitaxel and gemcitabine), even at a 6.3-fold lower gemcitabine concentration. These findings underscore the potential of this approach as a highly effective therapeutic strategy for PDAC treatment.
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Materials Today Bio
·
2025
·
IF 10.2
Qixin Zhao,Shenglu Liu,Tao Bi,Ting Wang,Lei Chen,Juan Huang,Xuemei Yang,Xiyu Dai,Zengjin Liu,Qin Sun
Pancreatic malignancies rank among the most aggressive and fatal carcinomas in modern oncology, presenting significant therapeutic challenges due to their inherent chemoresistance. In the context of our experimental investigations, we have developed a mitochondria-targeted hydrogel formulation, termed SWMU690@PUE, which demonstrates the ability to modulate mitochondrial homeostasis effectively. The hydrogel construct was precisely designed via the spontaneous supramolecular assembly of puerarin (PUE) and SWMU690 components, facilitated under carefully controlled thermodynamic conditions. Comprehensive in vitro analyses of the SWMU690@PUE complex were conducted to rigorously evaluate its efficacy in regulating mitochondrial homeostasis. The experimental findings revealed that SWMU690@PUE exhibited pronounced selectivity for mitochondrial targeting, subsequently diminishing mitochondrial membrane potential—a pivotal parameter in cellular bioenergetics. Our study further demonstrated that SWMU690@PUE effectively mitigates the chemoresistance phenotype associated with mitochondrial dysfunction. This therapeutic potential was exemplified by its capacity to induce mitochondria-mediated apoptotic and ferroptotic cell death, critical oncocidal pathways, in pancreatic carcinoma cells across both in vitro and in vivo models. Additionally, SWMU690@PUE displayed significant antineoplastic activity, as evidenced by its robust inhibition of pancreatic cancer cell proliferation in both experimental frameworks. In conclusion, this study presents an innovative therapeutic approach specifically designed to overcome the persistent challenge of chemoresistance in the treatment of pancreatic neoplasms.
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 20
·12624
·
IF 6.208
Shanming Zhang,Fen Zheng,Kaige Liu,Shengke Liu,Tonghu Xiao,Yabin Zhu,Long Xu
Mitochondrial DNA and nuclear DNA are essential genetic material which play an important role in maintaining normal metabolism, survival, and proliferation of cells. Constructing a mitochondria-targeting stimuli-responsive nano-drug delivery system releasing chemotherapeutic agents in a stepwise response manner and destroying mitochondrial DNA and nuclear DNA simultaneously is an effective way to improve the anti-tumor effect of chemotherapeutic agents. In this study, a new mitochondria-targeting pH/ROS dual-responsive block copolymer TPP-PEG2k-b-(BS-AA)n(P1), untargeted pH/ROS dual-responsive copolymer mPEG2k-b-(BS-AA)n(P2), pH single-responsive copolymer (mPEG2k-b-(AH-AA)n(P3), ROS single-responsive copolymer mPEG2k-b-(SA-TG)n(P4), and non-responsive copolymer mPEG-b-PCL (P5) were constructed. pH/ROS-responsive properties were characterized by proton nuclear magnetic resonance (1H NMR) and dynamic light scattering (DLS). Anticancer chemotherapeutic agent gemcitabine (GEM) or fluorescent substance Nile Red (NR) were loaded in the polymer micelles. Results of the mitochondrial colocalization experiment indicate that (5-carboxypentyl)(triphenyl)phosphonium bromide (TPP)-functionalized P1 micelles could be efficiently targeted and located in mitochondria. Results of the cellular uptake experiment showed that pH/ROS dual-responsive GEM-loaded P1 and P2 micelles have faster internalized and entry nucleus rates than single-responsive or non-responsive GEM-loaded micelles. The in vitro release experiment suggests pH/ROS dual-responsive GEM/P1 and GEM/P2 micelles have higher cumulative release than single-responsive GEM/P3 and GEM/P4 micelles. The in vitro cytotoxic experiment shows that the mitochondria-targeted dual-responsive GEM/P1 micelles had the lowest IC50 values, and the cytotoxic effect of dual-responsive GEM/P2 micelles was superior to the single-responsive and non-responsive drug-loaded micelles.Keywords:mitochondria-targeted;pH/ROS dual-responsive;acetal;thioether;TPP
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BIOCHEMICAL JOURNAL
·
2020
·Vol. 477
·期 10
·1923-1937
·
IF 4.097
Cai Aimin,Zheng Hailun,Chen Zhiwei,Lin Xinlu,Li Chen,yao Qing,Bhutia Yangzom D.,Ganapathy Vadivel,Chen Ruijie,Kou Longfa
Gemcitabine is the first-line chemotherapy for pancreatic cancer. To overcome the often-acquired gemcitabine resistance, other drugs are used in combination with gemcitabine. It is well-known that cancer cells reprogram cellular metabolism, coupled with the up-regulation of selective nutrient transporters to feed into the altered metabolic pathways. Our previous studies have demonstrated that the amino acid transporter SLC6A14 is markedly up-regulated in pancreatic cancer and that it is a viable therapeutic target. α-Methyltryptophan (α-MT) is a blocker of SLC6A14 and is effective against pancreatic cancer in vitro and in vivo. In the present study, we tested the hypothesis that α-MT could synergize with gemcitabine in the treatment of pancreatic cancer. We investigated the effects of combination of α-MT and gemcitabine on proliferation, migration, and apoptosis in a human pancreatic cancer cell line, and examined the underlying mechanisms using 1H-NMR-based metabolomic analysis. These studies examined the intracellular metabolite profile and the extracellular metabolite profile separately. Combination of α-MT with gemcitabine elicited marked changes in a wide variety of metabolic pathways, particularly amino acid metabolism with notable alterations in pathways involving tryptophan, branched-chain amino acids, ketone bodies, and membrane phospholipids. The metabolomic profiles of untreated control cells and cells treated with gemcitabine or α-MT were distinctly separable, and the combination regimen showed a certain extent of overlap with the individual α-MT and gemcitabine groups. This represents the first study detailing the metabolomic basis of the anticancer efficacy of gemcitabine, α-MT and their combination.
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Discover Nano
·
2023
·Vol. 18
·期 1
·1-14
·
IF 0
Yang Fan,Fan Zehui,Zhang Lixia,He Yanjuan,Hu Run,Xiang Jinkun,Fu Shiyang,Wang Guowei,Wang Jianlong,Tao Xiaojun,Zhang Pan
Amphiphilic polymers (HA-ANI) were prepared by grafting hyaluronic acid (HA) and 6-(2-nitroimidazole)hexylamine (ANI) and then self-assemble in water to form nanoparticles (NPs) that could be loaded with paclitaxel (PTX) and gemcitabine (GEM) by dialysis. Infrared spectroscopy and 1 H-NMR indicated the successful synthesis of HA-ANI. Three different ratios of NPs were prepared by adjusting the ratios of hydrophilic and hydrophobic materials, and the particle size decreased as the ratio of hydrophilic materials increased. When HA:ANI = 2.0:1, the nanoparticles had the smallest size distribution, good stability and near spherical shape and had high drug loading and encapsulation rates. In vitro release experiments revealed that NADPH could accelerate the drug release from NPs. Cellular uptake rate reached 86.50% at 6 h. The toxic effect of dual drug-loaded nanoparticles (P/G NPs) on MDA-MB-231 cells at 48 h was stronger than that of the free drug. The AO/EB double-staining assay revealed that a large number of late apoptotic cells appeared in the P/G NPs group, and the degree of cell damage was significantly stronger than that of the free drug group. In the cell migration assay, the 24 h-cell migration rate of the P/G NPs group was 5.99%, which was much lower than that of the free group (13.87% and 17.00%). In conclusion, MDA-MB-231 cells could effectively take up P/G NPs, while the introduction of the nano-codelivery system could significantly enhance the toxicity of the drug to MDA-MB-231 cells as well as the migration inhibition effect.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2026
·
IF 2.5
Hai Huang,Liwei Guo,Hansong Sun,Yunhong Liu,Jun Zhang,Weijie Tang,Xiaodong Xia,Yu Wang,Ni Chen,Dong Lv,Jing Yang
Objective To investigate the mechanism of action of saikosaponin D (SSD) on bladder cancer (BCa) and evaluate its synergistic antitumor efficacy with the chemotherapeutic agent gemcitabine (GEM). Methods MTT, colony formation, Transwell, and scratch wound healing assays detected SSD's effects on the proliferation, invasion, and migration of RT112 and T24 cells. Specific inhibitors identified cell death mode. Western blotting, immunohistochemistry, and flow cytometry verified ferroptosis-related protein expression and oxidative stress. Network pharmacology predicted core pathways, validated by examining PI3K/AKT pathway activity. Animal models evaluated the synergistic effect of SSD and GEM. Results In vitro, SSD dose-dependently inhibited the BCa cells proliferation, invasion, and migration, and upregulating E-cadherin whilst downregulating N-cadherin, Vimentin, and Snail. The effects were blocked by the ferroptosis inhibitor Fer-1. Network pharmacology identified the PI3K/AKT pathway as a core target. Moreover, SSD regulated the GPX4/SLC7A11/ACSL4, suppressed PI3K/AKT phosphorylation, and triggered lipid peroxidation and reactive oxygen species accumulation, partially reversed by a PI3K-specific phosphopeptide agonist. In vivo, SSD inhibited tumor growth, and its combination with GEM showed superior efficacy. The combination therapy most effectively downregulated SLC7A11, GPX4, Vimentin, N-cadherin and Snail, while upregulating the ACSL4 and E-cadherin. Conclusion SSD inhibits the malignant phenotype of BCa by targeting PI3K/AKT to trigger ferroptosis. Its synergistic effect with GEM from the dual mechanisms of ferroptosis sensitization and epithelial-mesenchymal transition inhibition, providing an innovative combination strategy based on natural product active ingredients to overcome bladder cancer chemoresistance.
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JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2025
·
IF 4.9
Xiaoping Chen,Suya Zhang,Jun Wang,Junping Xu,Yubin Kou
Chemodynamic therapy (CDT) is an innovative oncological therapeutic approach that utilizes CDT agents to change hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (·OH), the toxic reactive oxygen species (ROS), through Fenton/Fenton-like processes, thereby triggering cell death. This therapy technique has been extensively studied due to its slight invasiveness and good tumor specificity, rendering it a prominent subject of investigation. In this study, to improve anticancer potential by GSH depletion and tumor-targeted-amplified chemo/chemodynamic therapy (CDT/CT), polydopamine (PD)/hyaluronic acid (HA)-coated Fe 2+ -doped zeolite imidazole frameworks-8 (FZ MOF) was developed and used to encapsulate the chemotherapy drug gemcitabine (GEM), via charge, hydrophobic interactions, and π-π stacking. In a GSH and acidic milieu, the obtained PD/HA-covered GEM-carrying FZ MOFs (PHGFZ MOFs) enhanced the release of GEM and Fe 2+ and demonstrated acidity-activated •OH generation. In addition to significantly increasing •OH accumulations by GSH consuming via PD in conjunction with the Fe 2+ /Fe 3+ to cause lipid peroxidation and mitochondrial damage, the PHGFZ MOFs internalized by BxPC-3 cells through effective CD44-facilitated endocytosis also achieved intracellular GEM release, which in turn triggered apoptosis and ferroptosis. Crucially, the PHGFZ MOFs demonstrated promising tumor-targeted treatment by effectively inhibiting pancreatic cancer cells and exhibiting excellent biosafety.
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MOLECULAR MEDICINE
·
2025
·Vol. 31
·期 1
·1-23
·
IF 6.4
Wang Qiuhong,Wei Dong,Li Chunman,Yang Xiawei,Su Kun,Wang Tao,Zou Renchao,Wang Lianmin,Cun Dongyun,Tang Bo,Wu Tao
Section
Background
Pancreatic cancer is highly lethal, and METTL3 plays a crucial role in the regulation of m6A. However, the therapeutic potential of METTL3 in pancreatic cancer is unclear.
Section
Methods
By means of functional gain and loss experiments, the relationship between METTL3 and gemcitabine resistance as well as ferroptosis was explored. The target genes of METTL3 were screened, and the influence of O-GlcNAcylation on the stability and ubiquitination modification of METTL3 was dissected.
Section
Results
We found that METTL3 is highly expressed in pancreatic cancer and regulates ferroptosis and gemcitabine resistance by promoting the degradation of HMGB1 in an m6A-YTHDF2-dependent manner. O-GlcNAcylation modulates the METTL3’s stability. The interaction between the deubiquitinase EIF3H and METTL3 is influenced by O-GlcNAcylation.
Section
Conclusion
METTL3 affects pancreatic cancer progression by promoting degradation of HMGB1. The O-GlcNAcylation of METTL3 not only stabilizes METTL3 but also augments EIF3H-mediated deubiquitination. These findings uncover potential mechanisms underlying gemcitabine resistance in pancreatic cancer and offer potential therapeutic strategies for the treatment of this disease.
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DRUG RESISTANCE UPDATES
·
2026
·
IF 21.7
Lianli Ni,Hailong Li,Peipei Chen,Yun Yu,Chenjun Xie,Wenfeng Hong,Gaowei Fang,Baohong Wan,Yiwei Shen,Peng Zou,Wangyu Zhu,Zhiguo Liu,Xiaokun Li,Ri Cui
Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and the leading cause of cancer-related deaths globally. The RNA binding protein Quaking-5 (QKI-5) has been established as a tumor suppressor in NSCLC. Inducing ferroptosis is regarded as an effective therapeutic strategy for cancer treatment, and long non-coding RNA (lncRNA) plays a critical role in the regulation of ferroptosis. However, the relationship between QKI-5-regulated lncRNA and ferroptosis remains uncharacterized in NSCLC. In this study, we discovered that QKI-5 downregulates the oncogenic lncRNA linc01833, which inhibits ferroptosis and promotes NSCLC progression by activating SLC7A11/GPX4 signaling pathway. Mechanistically, QKI-5 negatively regulates the stability of linc01833, leading to increased linc01833 expression in NSCLC. Silencing linc01833 enhanced WW domain-containing E3 ubiquitin protein ligase 1 (WWP1)-mediated ubiquitination of SLC7A11, resulting in decreased SLC7A11 expression, while overexpression of linc01833 produced the opposite effect. Further analyses demonstrated that linc01833 diminished the anti-tumor effect of gemcitabine (GEM) in NSCLC both in vivo and in vitro . Additionally, knocking down linc01833 or SLC7A11 is able to inhibit GEM resistant NSCLC growth. Our findings suggest that targeting linc01833 to induce ferroptosis could enhance the cytotoxic effects of chemotherapeutic agents and may serve as an effective therapeutic strategy for some NSCLC patients.
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MOLECULAR MEDICINE
·
2021
·Vol. 27
·期 1
·1-16
·
IF 6.354
Cui Jing,Guo Yao,Wu Heshui,Xiong Jiongxin,Peng Tao
Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEM sen ) and GEM-resistant (GEM res ) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEM sen and GEM res cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEM res cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEM res cells than that in GEM sen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEM res tumors, Evr significantly decreased the volume of GEM res tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.
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CELLULAR ONCOLOGY
·
2023
·
IF 6.6
Wei Wanhui,Lu Yuanyuan,Hu Qian,Yin Jinwen,Wang Youwei,Zhang Heng,Zhao Qiu,Liu Lan
Purpose The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. Methods First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC–MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. Results Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. Conclusions In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.
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DRUG RESISTANCE UPDATES
·
2023
·
IF 24.3
Ran Qi,Yixuan Bai,Kun Li,Nanbin Liu,Yan Xu,Emre Dal,Yufeng Wang,Rui Lin,Hui Wang,Zhongyan Liu,Xinbo Li,Xiuyan Wang,Baomin Shi
Background Pancreatic cancer continues to be one of the world's most lethal cancers. Chemotherapy resistance in patients with advanced pancreatic cancer often accompany with dismal prognosis, highlighting the need to investigate mechanisms of drug resistance and develop therapies to overcome chemoresistance. Methods This research was filed with the Chinese Clinical Trial Registry (ChiCTR2200061320). In order to isolate primary normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) samples of pancreatic ductal adenocarcinoma (PDAC) and paracancerous pancreatic tissue from individuals diagnosed with PDAC were obtained. The exosomes were obtained using ultracentrifugation, and their characteristics were determined by Western blotting, nanoparticle tracking analysis, and transmission electron microscopy. CAF-derived miRNAs were analyzed by RT-qPCR and high-throughput sequencing. Gemcitabine (GEM) was employed to promote ferroptosis, and ferroptosis levels were determined by monitoring lipid reactive oxygen species (ROS), cell survival, and intracellular Fe 2+ concentrations. To assess in vivo tumor response to GEM therapy, a xenograft tumor mouse model was utilized. Results Exosomes derived from CAFs in PDAC did not exhibit innate GEM resistance. CAFs promoted chemoresistance in PDAC cells following GEM treatment by secreting exosomes, and maintaining signaling communication with cancer cells. Mechanistically, miR-3173–5p derived from CAF exosomes sponged ACSL4 and inhibited ferroptosis after uptake by cancer cells. Conclusion This work demonstrates a novel mode of acquired chemoresistance in PDAC and identifies the miR-3173–5p/ACSL4 pathway as a promising treatment target for GEM-resistant pancreatic cancer.
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