BREAST CANCER RESEARCH AND TREATMENT
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2025
·Vol. 57
·期 4
·1064
·
IF 3
Jie Hu,Qilong Liu,Bi Feng,Yanling Lu,Kai Chen
Purpose Esophageal cancer (EC) is a rapidly progressing malignancy characterized by a low survival rate and limited treatment success, largely due to late-stage detection, frequent recurrence, and a high propensity for metastasis, despite ongoing advances in therapeutic strategies. While oxaliplatin (L-OHP) is a potent chemotherapeutic agent that induces apoptosis in EC cells, its effectiveness is significantly hindered by the development of resistance. Materials and Methods The assessment of gene and protein expression was conducted through a combination of quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical staining. Cell viability was assessed using the cell counting kit-8 assay. The interactions among ALYREF, TBL1XR1, KMT2E, and APOC1 were investigated through RNA immunoprecipitation, chromatin immunoprecipitation (ChIP), ChIP-reChIP, RNA pulldown, and dual-luciferase assays. An in vivo mouse model of EC was established. Results Expression levels of both APOC1 and ALYREF were elevated in L-OHP–resistant EC tissues and cell lines, and their silencing enhanced sensitivity to L-OHP. TBL1XR1 and KMT2E synergistically upregulated APOC1 expression. Moreover, ALYREF recognized the 5-methylcytosine (m5C) sites on TBL1XR1 and KMT2E mRNAs, stabilizing these transcripts and promoting APOC1 expression. The regulatory role of these interactions was further validated in vivo . Conclusion This study demonstrated that ALYREF interacted with the m5C sites on TBL1XR1 and KMT2E mRNAs, enhancing their stability and leading to increased transcription of APOC1, which in turn contributed to L-OHP resistance in EC. These findings suggest that targeting APOC1 could be a promising strategy for overcoming L-OHP resistance in EC.
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高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
·
IF 5.6
Jiashuai Yan,Di Wu,Biwen Zhu,Xiaoqi Guan,Xue Zhang,Yibing Guo,Yuhua Lu
As a highly aggressive solid tumor, pancreatic ductal adenocarcinoma (PDAC) is featured by a conspicuous tumor microenvironment (TME) with abundant extracellular matrix (ECM) deposition, such as collagen and hyaluronic acid (HA). Accompanying with the pathological process, the dense matrix caused stiffen microenvironment, which leads to poor chemotherapy. Therefore, understanding the potential mechanism of mechanical microenvironment on PDAC chemoresistance is of great significance. To this end, 3D printed methacrylated gelatin (GelMA) and hyaluronic acid methacryloyly (HAMA) hydrogel model was fabricated to resemble the mechanical microenvironment of PDAC. The results presented that the PDAC cell lines (MIA-PaCa2 and PANC-1) embedded in the hydrogel were distinctively less sensitive to gemcitabine compared to tissue culture plate (TCP) group. Interestingly, immunofluorescence staining and qRT-PCR assay demonstrated that the NRF2 level was elevated, which further upregulated the downstream effectors, such as SLC7A11 and GPX4. Meanwhile, the GSH concentration and GPX4 activity of hydrogel group were increased, while the lipid peroxidation level was reduced, which indicated that the matrix stiffness microenvironment mediated ferroptosis phenotype. Furthermore, RNA interference experiment elaborated that shNRF2 group showcased significantly enhanced sensitivity to gemcitabine, which demonstrated that the biomimetic microenvironment modulated chemoresistance through ferroptosis. All in all, the 3D printed model may serve as a new platform for illustrating the underlying mechanism of the TME induced chemoresistance, and also proposed a novel therapeutic strategy for PDAC through NRF2 inhibition, which effectively promotes ferroptosis to overcome chemoresistance.
研究领域:
肿瘤学
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细胞生物学
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生物医学工程
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PubMed
高影响因子
Annals of Medicine and Surgery
·
2025
·
IF 1.6
Fu Qiang,Chen Peipei,Wang Zening,Liu Bo,Zhou Qingjiu,Anwar Ilhamjan,Wang Yongxin
Background: Acquired resistance to temozolomide is a major challenge for the effective treatment of glioblastoma (GBM). TRIML2, a member of the TRIM family, plays an important role in cancer genesis, progression, and treatment resistance. However, its mechanism of action in GBM resistance to temozolomide remains unclear. Methods: RNA bulk sequencing data from temozolomide-resistant U87 cells and wild-type U87 cells were downloaded from the NCBI public database (GEO: GSE193957) and analyzed. A temozolomide-resistant cell line (U87-TR) was induced with temozolomide, and the expression of TRIML2 in temozolomide-resistant and wild-type cell lines (U87-WT) was verified by cell activity assays, wound-healing assays, and western blotting. The alteration of resistance to temozolomide was assessed following the overexpression of TRIML2 in the resistant cell line by lentiviral transfection. The differences in TRIML2 expression between primary GBM and recurrent GBM after temozolomide chemotherapy were verified by immunofluorescence, immunohistochemistry, and western blotting. Results: The expression of TRIML2 was significantly lower in U87-TR cells than in U87-WT cells. After the TRIML2 overexpressed in U87-TR cells, their resistance to temozolomide was significantly decreased and became sensitive to temozolomide treatment. TRIML2 expression was significantly decreased in the temozolimide-resistant GBM tumors; in contrast, TRIML2 was relatively high expressed in the temozolimide-sensitive GBM tumors. Conclusions: TRIML2 inhibits temozolomide resistance in GBM and thus may serve as a novel therapeutic target for overcoming GBM resistance to temozolomide.
研究领域:
肿瘤学
·
分子生物学
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神经科学
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PubMed
高影响因子
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
·
2022
·Vol. 100
·期 7
·
IF 2.245
Yanzhen Han,Yan Zhou,Liyuan Zhou,Xiaoyan Jia,Xiangjun Yu,Xiaohong An,Zhe Shi
Chemotherapy is one of the most important strategies in the treatment of cancer; however, chemoresistance restricts the effect of chemotherapy. Growing reports suggest that chloride channel-3 (ClC-3) is involved in regulating the sensitivity of multiple chemotherapeutic agents in the chemotherapy of various tumours, while its role in the chemotherapy of cholangiocarcinoma (CCA) is still poorly understood. Herein, we observed that ClC-3 was highly expressed in CCA chemoresistant tissues and CCA cisplatin-resistant cells QBC939/DDP, and the sensitivities of QBC939 and QBC939/DDP cells to cisplatin were all increased after inhibition of ClC-3. Further mechanism exploration revealed that ClC-3 knockdown reduced the level of autophagy. Furthermore, in both QBC939 and QBC939/DDP cells, the autophagy agonist rapamycin eliminated the increased cisplatin sensitivity of ClC-3 knockdown without affecting ClC-3 expression. Collectively, all the findings demonstrate that ClC-3 knockdown increases cisplatin-induced cell death in CCA cells though inhibiting autophagy, regardless of the occurrence of cisplatin resistance. In addition, our results also suggest that targeted inhibition of ClC-3 may be a potential strategy for chemosensitization in CCA chemotherapy.
研究领域:
肿瘤学
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药理学
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细胞生物学
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PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2025
·
IF 13.2
Shuaiyin Zhang,Xinran Xie,Ming Liu,Zhixin Li,Yang Ye,Liang Peng,Kexing Lyu,Xiaomei Sun,Yuan Yuan,Zhijun Zhang,Weiping Wen,Zhaoxu Tu
Chemoresistance and the immunosuppressive tumor microenvironment (TME) severely constrain the current cancer therapy, which is a global clinical challenge. To address these issues, we engineered TPEC@CM, a biomimetic nanoplatform that synergizes chemotherapy with cuproptosis induction. This system employs homologous cancer cell membrane-coated Ti 3 C 2 nanosheets for targeted delivery, co-loaded with a cisplatin (DDP) prodrug succinato diamminedichloroplatinum (SDDP) and a copper ionophore complex (Elesclomol-Cu). The biomimetic coating ensures tumor-specific accumulation of the payloads while minimizing off-target toxicity. Upon reaching the tumor site, SDDP depletes intracellular glutathione (GSH), thereby reducing copper chelation and unleashing Pt (II)-mediated DNA damage and apoptosis. Concurrently, Elesclomol-Cu disrupts mitochondrial copper homeostasis, inducing cuproptosis via dihydrolipoamide S -acetyltransferase (DLAT) oligomerization and Fe S cluster protein degradation, ultimately collapsing mitochondrial integrity and metabolic activity. Crucially, the synergistic chemo-cuproptosis effect provokes immunogenic cell death (ICD), releasing damage-associated molecular patterns (DAMPs) that drive dendritic cell maturation and reprogram the immunosuppressive TME. RNA-seq analysis of DDP-resistant MC38 cells revealed heightened mitochondrial metabolic pathways, sensitizing the tumor cells to cuproptosis, resulting in reversed DDP resistance by TPEC@CM. Furthermore, TPEC@CM treatment with anti-programmed death-ligand 1 (anti-PD-L1) checkpoint blockade amplified anti-tumor efficacy, highlighting its potential for combinatorial tumor therapy. This study pioneers a dual-pathway strategy—combining chemotherapy and cuproptosis—to dismantle chemoresistance and amplify immune responses, presenting a clinically translatable paradigm for cancer therapy.
研究领域:
肿瘤学
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生物医学工程
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免疫学
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材料科学
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DOI
高影响因子
MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Zhihao Wu,Tao Shi,Qi Shao,Dongmei Chen,Peisheng Gao,Jie Wang,Ting Xu,Qingqing Meng,Shaoshun Li
Early detection and precise treatment for breast cancer are crucial, given its high global incidence rate. Hence, the development of novel imaging targets is essential for diagnosing and monitoring resistance to chemotherapy, which is pivotal for achieving precise and personalized treatment for breast cancer patients. In our previous work, we successfully developed a near-infrared (NIR) probe 1 for CYP1B1-targeted imaging. In this study, we aimed to investigate the utility of the probe as a NIR fluorescence and photoacoustic dual-mode imaging probe for the detection and surveillance of breast cancer. Western blotting of cancer cell lines has confirmed that CYP1B1 is widely expressed in breast cancer and gynecological cancer. In vitro NIR fluorescence imaging capability of the probe for tracking CYP1B1-positive tumor cells was validated by using confocal microscopy. Further studies, including in vivo fluorescence and photoacoustic dual-model imaging and ex vivo biological distribution analysis on a triple-negative breast cancer xenograft mouse model, demonstrated that the probe selectively accumulated in tumor tissue within as early as 0.5 h postinjection. The results of the surgical resection experiment revealed that the tumor could be entirely removed under the guidance of NIR imaging, thereby indicating the probe’s efficacy in surgical navigation. CYP1B1 expression was found to be upregulated in adriamycin (ADR)-resistant breast cancer cells, MCF-7/ADR. Consequently, the sensitivity of CYP1B1 overexpressed cells, MCF-7/1B1, to ADR was significantly reduced, with an IC50 value of 0.586 ± 0.0934 μM, compared to the parental MCF-7 cells with an IC50 value of 0.183 ± 0.0444 μM. In vivo and ex vivo imaging assays conducted on MCF-7/ADR tumor-bearing mice demonstrated that the probe was specifically enriched in tumor sites, suggesting its potential for monitoring chemotherapy resistance in breast cancer. This study expands the scope of application for NIR probe 1, establishing its utility in breast cancer diagnosis through fluorescence-photoacoustic dual-model imaging, monitoring of chemotherapy resistance, and guidance for surgical resection. This strategy paves the way for novel approaches to precise and personalized treatment for breast cancer patients.
研究领域:
肿瘤学
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医学影像学
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药物动力学
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DOI
PubMed
高影响因子
ACS Biomaterials Science & Engineering
·
2025
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IF 5.5
Yue Chen,Dan Xue,Di Huang,Xinying Li,Yuyou Duan,Bin Chen
Matrix stiffness is a key factor in breast cancer progression, but its impact on cell function and response to treatment is not fully understood. Here, we developed a stiffness-tunable hydrogel-based three-dimensional system that recapitulates the extracellular matrix and physiological properties of human breast cancer in vitro. Adjusting the ratio of GelMA to PEGDA in the hydrogel formulation enabled the fine-tuning of matrix stiffness across a range of 7 to 52 kPa. Utilizing this three-dimensional (3D) hydrogel platform for a breast cancer cell culture has enabled precise functional evaluations. Variations in matrix stiffness resulted in significant changes in the morphology of breast cancer cells after 2 weeks of incubation. The analysis of transcriptomic sequencing revealed that the 3D microenvironment significantly changed the expression of a wide panel of transcriptomic profiles of breast cancer cells in various matrix stiffness. Gene Ontology analysis further suggested that specific biological functions could potentially be linked to the magnitude of the matrix stiffness. According to our findings, extracellular matrix rigidity modulates the sensitivity of breast cancer cells to paclitaxel and adriamycin. Notably, the expression of ABCB1 and YAP1 genes may be upregulated in the 3D culture environment, potentially contributing to the increased drug resistance observed in breast cancer cells. This work aims to establish facile adjustable hydrogels to deepen insights into matrix rigidity effects on breast cancer cells within 3D microenvironments, highlighting the critical role of extracellular matrix stiffness in modulating cell-matrix interactions.
研究领域:
生物医学工程
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肿瘤学
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细胞生物学
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高影响因子
JOURNAL OF NATURAL PRODUCTS
·
2025
·
IF 3.6
Mi Zhou,Yanlan Yang,Shoulun He,Qiannan Xu,Chunchun Du,Wenjing Tian,Haifeng Chen
Phosphorylation of checkpoint kinase 1 at Ser-345 (p-CHK1(S345)) mediates the replication stress response in cancer cells, leading to chemotherapy resistance. Therefore, finding inhibitors of p-CHK1(S345) is currently a promising strategy to prevent acquired drug resistance. In this study, 14 ingenane diterpenoids (1–14), involving two undescribed compounds possessing an unprecedented exocyclic double bond Δ6(20), were identified from Euphorbia peplus. The inhibitory effects of the isolated compounds on p-CHK1(S345) and their structure–activity relationship (SAR) were investigated. Compounds 7 and 8 presented the strongest inhibitory effects, abrogated cell cycle arrest, and caused the accumulation of DNA damage, improving the sensitivity of cancer cells to chemotherapeutic drugs. An in vivo assay confirmed the enhancement of 8 on the anticancer effect of topotecan via blocking of p-CHK1(S345). Mechanistically, 8 increased CHK1 ubiquitination to inhibit p-CHK1(S345) via activation of protein kinase C (PKC). PKC activation was first found to enhance CHK1 ubiquitination to block p-CHK1(S345). Above all, this finding not only indicates that compound 8 could be developed as a novel CHK1 inhibitor but also reveals a previously unrecognized role of PKC in regulating cancer chemotherapy sensitivity.
研究领域:
肿瘤学
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药理学
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植物化学
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DOI
PubMed
高影响因子
Heliyon
·
2022
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IF 3.776
Xiaotao Qian,Yongxin Zhao,Tengyue Zhang,Pingsheng Fan
The aim of this study is to investigate the reversal effect of verapamil (VER) on chemoresistance to irinotecan (CPT-11) in human colon cancer cells and relevant mechanisms. Cell counting kit-8 (CCK-8) test and colony-forming unit (CFU) experiment results show that VER strengthens the sensitivity of human colon cancer cell line HT29 to CPT-11 but has a small effect on SW480 cells. High-throughput transcriptome sequencing, RT-PCR, and Western blot results show that the inhibition of metastasis-associated in colon cancer-1 (MACC1) expression by VER is the key factor for reversal effect on chemoresistance to CPT-11. Transfection experiments further show that VER can reverse the resistance of human colon cancer cells to SN-38, the active metabolite of CPT-11, when MACC1 is overexpressed. The nude mouse transplantation tumor experiment provides an in vivo proof that VER can strengthen sensitivity to CPT-11 in drug-resistant human colon cancer cells, and the effect might be related to the inhibited expression of MACC1. In summary, VER might strengthen the reversal effect of VER on chemoresistance to CPT-11 in human colon cancer cells and facilitate the apoptosis of human colon cancer cells by downregulating MACC1 expression.
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
DRUG DEVELOPMENT RESEARCH
·
2021
·Vol. 83
·期 2
·328-338
·
IF 4.36
Min Wu,Mengmeng Jin,Xiaohui Cao,Kun Qian,Lei Zhao
Adenosine deaminases acting on RNA 1 (ADAR1) has been identified to play key roles in non-small cell lung cancer (NSCLC) progression, and can modulate the sensitivity of cancer cells to anticancer drugs. The current study aimed to investigate the effect of ADAR1 on the sensitivity of NSCLC cells to anlotinib. We established anlotinib-resistant NSCLC (NSCLC/AR) cells, including NCI-H1975/AR and A549/AR cells. Results showed that ADAR1 was significantly upregulated in NSCLC/AR cells. Genetic-knockdown of ADAR1 increased the sensitivity of NSCLC/AR cells to anlotinib by inducing cell proliferation suppression, cell cycle arrest, and apoptosis. Furthermore, knockdown of ADAR1 decreased the level of C-X3-C motif chemokine ligand 1 (CX3CL1) in NCI-H1975/AR and A549/AR cells after anlotinib treatment. Introduction of exogenous CX3CL1 significantly reversed the positive effect of ADAR1 deficiency on NSCLC/AR cell sensitivity, exhibited by the increase of cell viability and decrease of apoptosis. Further in-vivo study demonstrated that knockdown of ADAR1 inhibited NCI-H1975/AR cell tumorigenesis by reducing CX3CL1 expression. Collectively, ADAR1 deficiency increased the sensitivity of NSCLC/AR cells to anlotinib by downregulating CX3CL1, which might provide a potential strategy for NSCLC/AR therapy.
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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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yanan Chen,Zhonghao Jiang,Zhuo Yan,Jierong Liu,Yilin Lai,Li Li,Xiao Lin,Jiantao Lin
Sorafenib (SF) is a first-line drug for the treatment of hepatocellular carcinoma (HCC) in clinical practice. However, acquired drug resistance tremendously limits the clinical efficacy of sorafenib in treating HCC, which has attracted great attention. PDL1 plays a crucial role in the drug resistance of HCC. Here, a codelivery system based on poly-SS-lysine modified chitosan (TAT-C-SS-P) was established and was applied to deliver sorafenib and PDL1-siRNA for synergetic HCC therapy. The successful synthesis of TAT-C-SS-P was confirmed by 1 H NMR. Additionally, sorafenib and PDL1-siRNA were successfully transported into the cells as the decreased expression of VEGF and PD-L1 by administrated with TAT-C-SS-P@SF@ PDL1-siRNA. Simultaneously, the expression of pro-apoptosis proteins cyt-c and Bax was prominently augmented, whereas the expression of anti-apoptosis protein Bcl-2 was decreased. The reduced expression of PDL1 resulted in the downregulation of P-GP and MRP1, which contributed to more sorafenib aggregation in tumor cells. Moreover, TAT-C-SS-P@PDL1-siRNA@SF efficiently promotes apoptosis of HepG2-SI cells, as the apoptosis rate rised to 73 %. A sorafenib-insensitive model was established to evaluate in vivo antitumor effect of TAT-C-SS-P@PDL1-siRNA@SF. TAT-C-SS-P@PDL1-siRNA@SF showed a tumor inhibition rate of 90.2 ± 3.5 % and no significant decrease in body weight. Taken together, our study provided compelling evidence that TAT-C-SS-P@PDL1-siRNA@SF has great potential application in the treatment of HCC clinically.
研究领域:
肿瘤学
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药理学
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分子生物学
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PubMed
高影响因子
BIOMATERIALS
·
2016
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IF 8.387
Zhi-Ting Cao,Zhi-Yao Chen,Chun-Yang Sun,Hong-Jun Li,Hong-Xia Wang,Qin-Qin Cheng,Zu-Qi Zuo,Ji-Long Wang,Yang-Zhong Liu,Yu-Cai Wang,Jun Wang
Chemotherapy resistance has become a major challenge in the clinical treatment of lung cancer which is the leading cancer type for the estimated deaths. Recent studies have shown that nanoparticles as drug carriers can raise intracellular drug concentration by achieving effectively cellular uptake and rapid drug release, and therefore reverse the acquired chemoresistance of tumors. In this context, nanoparticles-based chemotherapy represents a promising strategy for treating malignancies with chemoresistance. In the present study, we developed cationic lipid assisted nanoparticles (CLAN) to deliver polylactide-cisplatin prodrugs to drug resistant lung cancer cells. The nanoparticles were formulated through self-assembly of a biodegradable poly(ethylene glycol)- block -poly(lactide) (PEG-PLA), a hydrophobic polylactide-cisplatin prodrug, and a cationic lipid. The cationic nanoparticles were proven to significantly improve cell uptake of cisplatin , leading to an increased DNA-Pt adduct and significantly promoted DNA damage in vitro . Moreover, our study reveals that cationic nanoparticles, although are slightly inferior in blood circulation and tumor accumulation, are more effective in blood vessel extravasation. The CLANs ultimately enhances the cellular drug availability and leads to the reversal of cisplatin resistance.
研究领域:
肿瘤学
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药剂学
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纳米技术
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）