DRUG DEVELOPMENT RESEARCH
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2025
·Vol. 86
·期 2
·e70047
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IF 4.2
Kangmin Chen,Yanni Zhao,Tianyang Jin,Tingxin Xu,Conglun Zhu,Hui Shen,Xiaohong Xu,Yongsheng Jiang,Yi Wang,Shihang Xue
Triple-negative breast cancer (TNBC) is difficult to treat due to the lack of clear therapeutic targets. Paclitaxel (PTX) is commonly used to treat TNBC, but drug resistance limits its effectiveness. Myeloid differentiation protein 2 (MD2) and serum amyloid A1 (SAA1) are involved in various diseases, including infections, inflammatory diseases, and cancer. We investigated their role in PTX resistance to identify potential anti-TNBC drugs. In this study, we investigated the changes of SAA1 in TNBC tissues and its role in PTX-induced TNBC cells. Our study revealed SAA1 expressed in the human TNBC subtype and TNBC cells. PTX and CIS induce SAA1 in TNBC cells, and PTX induces inflammatory response via SAA1 in TNBC cells. MD2 blockade increased the sensitivity of TNBC cells to PTX, which was related to the expression of SAA1 during PTX-caused damage of TNBC cells. In further research, SAA1 binds to MD2, promotes the combination of TLR4/MD2 and TLR4/MyD88, activates the NF-κB signaling pathway, and creates the inflammatory microenvironment for cancer cells. Our study reports for the first time that the PTX/SAA1/MD2 axis exists in the PTX-resistance process, which could be a potential treatment target of PTX-resistance.
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Oncology
·
2025
·
IF 3.3
Keke Shang,Yang Chen,Jingjie Jin,Tong Wang,Gong Zhang
Genome instability, a hallmark of cancer, leads to endless mutations that eventually cause drug resistance against almost all chemotherapy drugs. This poses a significant obstacle to the success of cancer treatments. Here, we report that aurintricarboxylic acid (ATCA) effectively suppresses the malignant phenotypes, including proliferation, migration, invasion, and clone formation, of cancer cells of multiple cancers, including cisplatin-resistant lung cancer cells, paclitaxel-resistant lung cancer cells, and doxorubicin-resistant breast cancer cells. Interestingly, ATCA does not cause acute cytotoxicity. Proteome analysis of the whole proteome and nascent chains showed that ATCA reduced translation initiation and thus reduced the abundance of the highly abundant respiratory chain complex. This lowered the potential of the mitochondrial membrane and thus restricted the energy production. This principle could be hardly circumvented by cancer cells and thus may serve as a promising and universal candidate for a second-line therapeutic agent to control cancer progression after drug resistance.
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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产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-22
·
IF 12.6
Zhang Lian-Ying,Chen Xiao-Tong,Li Rong-Tian,Meng Wei,Huang Guo-Qin,Chen Yong-Jian,Ge Feng-Jun,Zhang Qun,Quan Yu-Jun,Zhang Cai-Tao,Liu Yi-Fei,Chen Ming,Chen Jin-Xiang
Breast cancer (BC) is a significant cause of cancer-related deaths among women worldwide. Hypoxia, a common feature of solid tumor, is associated with drug resistance and a poor prognosis in BC. In this study, we present a strategy to overcome hypoxia-induced chemotherapy tolerance in BC. Specifically, we synthesized a hollow gold (Au)-platinum (Pt) bimetallic nanoshell for the first time, which acted as a drug delivery system (DDS) for doxorubicin (DOX). The photothermal effect, induced by the surface plasmon resonance (SPR) from the Au-Pt shell under near infrared-II (NIR-II) laser irradiation, not only directly causes tumor cell death through photothermal therapy (PTT), but also significantly enhances the catalase-like activity between Pt nanoparticles and endogenous H 2 O 2 . This, subsequently, results in a heightened yield of O 2 , which further facilitates the release of DOX. This process alleviates tumor hypoxia and down-regulating hypoxia-inducible factor-1α (HIF-1α), multidrug resistance gene 1 (MDR1), and P-glycoprotein (P-gp), which can reverse drug resistance and achieve more effective DOX chemotherapy effects. Significantly, the increased availability of oxygen further re-polarizes immunosuppressive M2 macrophages into antitumor M1 macrophages. This study presents a novel strategy to tackle tumor proliferation and enhance tumor response to chemotherapy, offering hope for reversing in drug resistance in cancerous lesions. Graphical
研究领域:
肿瘤学
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药理学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
NATURE MATERIALS
·
2025
·
IF 38.5
Liu Huayang,Song Zilin,Zhang Yu,Wu Bihan,Chen Dinghao,Zhou Ziao,Zhang Hongyue,Li Sangshuang,Feng Xinping,Huang Jing,Wang Huaimin
Bioinspired materials based on self-assembling peptides are promising for tackling various challenges in biomedical engineering. While contemporary data-driven approaches have led to the discovery of self-assembling peptides with various structures and properties, predicting the functionalities of these materials is still challenging. Here we describe the deep learning-guided de novo design of antimicrobial materials based on self-assembling peptides targeting bacterial membranes to address the emerging problem of bacterial drug resistance. Our approach integrates non-natural amino acids for enhanced peptide self-assembly and effectively predicts the functional activity of the self-assembling peptide materials with minimal experimental annotation. The designed self-assembling peptide leader displays excellent in vivo therapeutic efficacy against intestinal bacterial infection in mice. Moreover, it exhibits an enhanced biofilm eradication capability and does not induce acquired drug resistance. Mechanistic studies reveal that the designed peptide can self-assemble on bacterial membranes to form nanofibrous structures for killing multidrug-resistant bacteria. This work thus provides a strategy to discover functional peptide materials by customized design.
研究领域:
生物医学工程
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材料科学
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人工智能
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2024
·
IF 4.4
Lu Yixing,Qiao Weimei,Xue Yaqian,Hong Xiaoxin,Jin Yuhang,Li Jie,Peng Xianfeng,Zeng Dongping,Zeng Zhenling
Introduction: Riemerella anatipestifer (R. anatipestifer) is an important pathogen in waterfowl, leading to substantial economic losses. In recent years, there has been a notable escalation in the drug resistance rate of R. anatipestifer. Consequently, there is an imperative need to expedite the development of novel antibacterial medications to effectively manage the infection caused by R. anatipestifer.Methods: This study investigated the in vitro and in vivo antibacterial activities of a novel substituted benzene guanidine analog, namely, isopropoxy benzene guanidine (IBG), against R. anatipestifer by using the microdilution method, time-killing curve, and a pericarditis model. The possible mechanisms of these activities were explored.Results and Discussion: The minimal inhibitory concentration (MIC) range of IBG for R. anatipestifer was 0.5–2 μg/mL. Time-killing curves showed a concentration-dependent antibacterial effect. IBG alone or in combination with gentamicin significantly reduced the bacterial load of R. anatipestifer in the pericarditis model. Serial-passage mutagenicity assays showed a low probability for developing IBG resistance. Mechanistic studies suggested that IBG induced membrane damage by binding to phosphatidylglycerol and cardiolipin, leading to an imbalance in membrane potential and the transmembrane proton gradient, as well as the decreased of intracellular adenosine triphosphate. In summary, IBG is a potential antibacterial for controlling R. anatipestifer infections.
研究领域:
微生物学
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兽医学
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药理学
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产品关联
DOI
PubMed
高影响因子
PHARMAZIE
·
2018
·Vol. 73
·期 12
·729-732
·
IF 1.016
Wang YB.,Sun B.,Han B.
Malignant melanoma is a highly lethal disease, and advanced stages of melanoma have proven to be resistant to many chemotherapeutic drugs including temozolomide and paclitaxel. Cancer stem cells (CSCs) have been identified and isolated in different cancers including melanoma, and have
been proven playing important role in the drug resistance. Retinoic acid (RA) is a promising anticancer agent, which can induce differentiation of CSCs. The main purpose of the present study was to evaluate the possible RA-induced differentiation of melanoma CSCs and sensitization of melanoma
CSCs to paclitaxel. Our results show that CSCs of human melanoma A375 cells was more tolerant to paclitaxel than other non-CSCs melanoma cells. On the contrary, RA had stronger inhibitory effect on melanoma CSCs than on non-CSCs. At the same time, RA could arrest the cell cycle of CSCs and
reduce the expression of Sox-2, Oct-4 in CSCs of melanoma, thereby induced the differentiation of CSCs and increased its sensitivity to paclitaxel. With this study we concluded that RA increases the anticancer effect of paclitaxel by inducing differentiation of cancer stem cells in melanoma,
and the combined application of RA and paclitaxel may be more effective in the treatment of melanoma.
研究领域:
肿瘤学
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细胞生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF SOL-GEL SCIENCE AND TECHNOLOGY
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2024
·
IF 2.3
Yang Guoqiang,Hong Ye,Wang Yimei,Shi Xuechao,Hou Shuxian,Liu Xinxin,Wang Yuxuan,Ge Fei,Wang Jun
It is well known that bacterial infections pose a great threat to human health and life, and the situation has intensified because of the emergence of drug-resistant bacteria, especially in the medical field, the number of deaths due to super-bacteria infections that result from antibiotic misuse continues to increase every year. Researchers have been working hard and trying to find a suitable method to fight against bacterial infections, however, there is still no effective method to fight drug-resistant bacterial infections. In this study, an ultra-facile strategy was built to synthesize Copper Oxide Nanoclusters (CuO NCs), that exhibited broad-spectrum bactericidal activity against common pathogenic Gram-positive and Gram-negative bacteria. The synthesized CuO NCs exhibited a cluster structure with good stability and biocompatibility. The antibacterial mechanism revealed that the synthesized CuO NCs can cause bacterial death in multiple ways, including disrupting the bacterial cell membrane and ablating the biofilm, inducing the generation of ROS, and leading to nucleic acid leakage of bacteria. CuO NCs are simple to synthesize, have strong antibacterial activity, and are expected to open new avenues of antibacterial activity in the severe antibiotic environment due to the combination of antibacterial mechanisms that make it difficult for bacteria to develop drug resistance quickly. Graphical In this study, we designed and synthesized copper oxide nanoclusters (CuO NCs) with favorable biosafety and stability for combating bacterial infection problems. The material possesses several advantages that including: (1) CuO NCs are synthesized in a straightforward and expeditious method. (2) CuO NCs have been demonstrated to possess good biocompatibility. (3) The synthesized CuO NCs exhibit broad-spectrum antimicrobial activity against E. coli and S. aureus , as well as for their drug-resistant strains. (4) The synthesized CuO NCs are capable of effectively removing biofilms formed by bacteria and promoting ROS generation, which disrupts the bacterial cell membrane, induces nucleic acid leakage, and ultimately cause the death of bacteria. This study employing an efficient strategy to synthesize CuO NCs with excellent broad-spectrum anti-bacterial ability, offering a promising method for addressing the growing challenge of multi-drug resistant bacteria.
研究领域:
生物医学
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材料科学
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微生物学
✓ 已验证
产品关联
DOI
高影响因子
ACS Applied Bio Materials
·
2025
·
IF 4.7
Yusai Zhao,Xiaoqing Chen,Hengwei Zhang,Yifan Ge,Di Li
Multidrug resistance (MDR) presents a substantial challenge to the therapeutic efficacy of cancer chemotherapy. A common trait of drug-resistant cells is decreased cell membrane permeability, hindering the uptake of therapeutic agents. Additionally, these cells frequently overexpress drug efflux pumps that actively expel the drugs, leading to reduced intracellular accumulation. In this study, we introduce a high spatially resolved, domain-specific, mild heating strategy to counteract drug resistance using DNA nanodevices. This strategy aims to manipulate the membrane heterogeneity by increasing cell membrane permeability and decreasing the expression of drug efflux pumps. The DNA nanodevices (termed DNA nanoheaters) with specific domain affinity anchor distinct cell membrane domains (raft/nonraft) and elevate the local lipid environmental temperature upon near-infrared (NIR) laser exposure. This elevation in local lipid temperature modifies key biophysical membrane features of Doxorubicin-resistant tumor cells, resulting in a two-order magnitude decrease in IC50. Notably, our approach diverges from conventional methods that depend on the delivery of pharmacological reversal agents. Instead, we emphasize modulating the membrane properties of drug-resistant cells through mild physical stimuli, offering a potential reduction in systemic toxicity associated with chemotherapy.
研究领域:
癌症研究
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生物物理学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Brazilian Journal of Pharmaceutical Sciences
·
2022
·
IF 1.214
Zhang Rong,Huang Limin,Pan Di,Zhang Wen
Drug resistance is a crucial obstacle to achieve satisfactory chemotherapeutic effects. Numerous studies have shown that the PI3K/Akt signaling pathway plays a significant role in various processes of cellular events and tumor progression, while few studies have focused on the PI3K/Akt signaling pathway in drug resistance of endothelial cells. The present study aims to explore the relationship of PI3K/Akt signaling and cellular resistance to anticancer drugs in human microvessel endothelial cells (HMEC-1). We established stable sunitinib-resiatant human microvessel endothelial cells (HMEC-su) after long-term exposure to sunitinib (a small-molecule tyrosine kinase receptor inhibitor) for 12 months. HMEC-su showed significant alternations of cell morphology and exhibited a 2.32-fold higher IC50 of sunitinib than parental HMEC-1 cells. Expression of P-glycoprotein (P-gp) and breast cancer-resistance protein (ABCG2) which mediates drug efflux, increased significantly in HMEC-su lines compared with HMEC-1 cells by western blots assay. Our study further demonstrates that LY294002 (blocking the PI3K/Akt pathway) enhances the sensibility of HMEC-su to suntinib and inhibits the gene transcription and protein expression of P-gp, ABCG2 in HMEC-su cells. In conclusion, these results indicate that LY294002 could reverse P-gp and ABCG2 mediated-drug resistance to sunitinib in HMEC-su cells by inhibiting PI3K/Akt signaling.
研究领域:
肿瘤学
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药理学
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细胞生物学
✓ 已验证
DOI
高影响因子
Biomaterials Science
·
2019
·Vol. 7
·期 10
·4142-4152
·
IF 5.251
Jian-Bin Zhen,Mu-Han Zhao,Ying Ge,Ya Liu,Li-Wei Xu,Cheng Chen,Yong-Kuan Gong,Ke-Wu Yang
The emergence of drug-resistant bacteria poses a serious threat to public health. The traditional antibiotics have specific intracellular targets and disinfect via chemical ways, which easily lead to the development of drug resistance, therefore, cationic peptides as promising antibiotic agents have attracted extensive attention due to their unique properties. Herein, we report a class of amphiphilic peptide-based pectinate polymers with primary amino groups. The polymers spontaneously self-assembled into the positively charged nanoparticles, which were evaluated and confirmed by scanning electron microscopy (SEM) and dynamic light scattering (DLS). Biological assays revealed that the nanoparticles showed broad-spectrum antibacterial efficacy against both Gram-positive and Gram-negative bacteria, exhibiting a MIC of 16 μg mL−1 against six clinical bacteria, namely, E. faecalis, S. aureus, MRSA, VRE, P. aeruginosa, and K. pneumonia, and three bacterial strains E. coli and E. coli producing NDM-1 and ImiS, and showed a sterilization rate of 95.6% and 94.7% on S. aureus and E. coli, respectively. Importantly, the nanoparticles did not result in drug-resistance for both the normal and drug-resistant bacteria tested after 14 passages and showed low toxicity on the mouse fibroblast cells (L929). The fluorescence staining, electrical conductivity, SEM, and surface plasmon resonance (SPR) characterization suggested that the nanoparticles initially bound to the surface of the bacteria, then pierced into the membranes of the bacteria with their phenyl groups, and finally disrupted the membranes, resulting in ions leaking out and thus exhibiting broad-spectrum antibacterial efficacy. This bactericidal mechanism that the nanoparticles employed does not lead the bacteria susceptible to developing drug resistance. This study provides a promising pathway for the development of the efficient antibacterial materials.
研究领域:
生物材料学
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微生物学
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药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Oncology Letters
·
2017
·Vol. 15
·期 1
·879-884
·
IF 1.39
Qian Liu,Bo Xu,Wanshan Zhou
The correlation between PAK5 (P21-activated kinase 5) and Ezrin gene expression and chemotherapy resistance of osteosarcoma patients was investigated. The cisplatin (CDDP)-resistance model of osteosarcoma cells SOSP-9607/CDDP was established to detect the cell growth curve. Methyl thiazolyl tetrazolium (MTT) assay was used to detect the drug resistance of cells to chemotherapy drugs. Transwell assay was used to detect the invasive capacity of cells. Semi-quantitative PCR (qPCR) was used to detect the mRNA expression levels in the drug resistance-related genes PAK5 and Ezrin. Western blot analysis was used to detect the protein expression levels in PAK5 and Ezrin. Tumor tissues were taken from the osteosarcoma patients with chemotherapy resistance to detect the expression levels of PAK5 and Ezrin via immunohistochemical detection, and the correlation between PAK5 and Ezrin expressions was studied. The results of MTT assay showed that the growth rate of SOSP-9607 was similar to that of SOSP-9607/CDDP, and the difference was not statistically significant (P>0.05). The sensitivity of SOSP-9607 to CDDP was significantly higher than that of SOSP-9607/CDDP, and the difference was statistically significant (P<0.01). Transwell assay showed that the migration capacity of SOSP‑9607/CDDP was significantly better than that of SOSP-9607 (P<0.01), indicating that the drug resistance cell lines of osteosarcoma were constructed successfully. Semi-qPCR and western blot analysis showed that the protein expression levels in PAK5 and Ezrin in SOSP-9607/CDDP were significantly higher than those in SOSP-9607 (P<0.01). The results of immunohistochemistry showed that the expression quantities of PAK5 and Ezrin in osteosarcoma tissues were significantly higher than those in para-tumor tissues (P<0.01). Pearson's correlation analysis showed that expression of PAK5 and Ezrin was positively correlated (r=0.197, P=0.023). The osteosarcoma resistance is closely related to the expression levels of PAK5 and Ezrin genes. Thus, PAK5 and Ezrin genes may affect the tolerance of osteosarcoma patients to chemotherapy drugs during treatment via the synergistic effect.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
BMC CANCER
·
2022
·Vol. 22
·期 1
·1-9
·
IF 4.638
Chen Zibo,Yuan Tao,Yan Fangjie,Ye Song,Xie Qin,Zhang Bo,Lin Nengmin,He Qiaojun,Yang Bo,Zhu Hong
Background Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Sorafenib is the first-line treatment for advanced HCC, but the anti-cancer effects remain to be improved as indicated by its low response rates and failure to prolong the progression-free survival (PFS). Thus, it is urgent to explore approaches to improve the clinical outcome.Materials and methodsThe effect of Sorafenib in HCC was analyzed by SRB (sulforhodamine B) assay in normoxia and hypoxia, respectively. The different dose combination effect of CT707 and sorafenib was analyzed by SRB assay in hypoxia. Flow cytometry assay was used to detect the cell apoptosis rate with CT707 and sorafenib treatment in hypoxia. Western blotting was used to detect the expression levels of apoptosis -related proteins and the mechanism of CT707 overcome the resistance of sorafenib in hypoxia.Results Our study showed that the characteristic intratumor hypoxia of advanced HCC is one of the major factors which mediated the drug resistance towards sorafenib in HCC. And CT-707, a novel multi-kinase inhibitor, could sensitize the hypoxic HCC cells towards sorafenib. Further studies showed that CT-707 abolished the nuclear translocation of Yes Associate-Protein (YAP), which has been demonstrated as one of mechanism of hypoxia-mediated sorafenib-resistance in HCC.Conclusion sOverall, this study not only favors the development of this novel multi-kinase inhibitor CT-707 as a therapeutic agent against HCC, but also provides a potential strategy to overcome the hypoxia-mediated resistance to sorafenib in HCC patients.
研究领域:
肿瘤学
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药理学
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分子生物学
✓ 已验证
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）