Pub Date : 2025-02-28DOI: 10.1016/j.drup.2025.101222
Hao Wu , Jiena Liu , Xing-Hua Zhang , Shengye Jin , Ping Li , Huidi Liu , Liuying Zhao , Jianyu Wang , Shilu Zhao , Hong-Da Tian , Jin-Ru Lai , Yi Hao , Gui-Rong Liu , Kaijian Hou , Meisi Yan , Shu-Lin Liu , Da Pang
Background
Patients with breast cancer (BC) who benefit from the PD-1/PD-L1 inhibitor (PDi) is limited, necessitating novel strategies to improve immunotherapy efficacy of BC. Here we aimed to investigate the inhibitory effects of flaxseed lignans (FL) on the biological behaviors of BC and evaluate the roles of FL in enhancing the anticancer effects of PDi.
Methods
HPLC was used to detect the content of enterolactone (ENL), the bacterial transformation product of FL. Transcript sequencing was performed and identified CD38 as a downstream target gene of ENL. CD38-overexpressing cells were constructed and cell proliferation, colony formation, wound healing and transwell assays were used to assess the function of ENL/CD38 axis on BC cells in vitro. Multiplexed immunohistochemistry (mIHC) and CyTOF were used to detect the changes of the tumor immune microenvironment (TIM). 16S rDNA sequencing was used to explore the changes of gut microbiota in mice. A series of in vivo experiments were conducted to investigate the anticancer effects and mechanisms of FL and PDi.
Results
FL was converted to ENL by gut microbiota and FL administration inhibited the progression of BC. ENL inhibited the malignant behaviors of BC by downregulating CD38, a key gene associated with immunosuppression and PD-1/PD-L1 blockade resistance. The mIHC assay revealed that FL administration enhanced CD3+, CD4+ and CD8+ cells and reduced F4/80+ cells in TIM. CyTOF confirmed the regulatory effects of FL and FL in combination with PDi (FLcPDi) on TIM. In addition, 16S rDNA analysis demonstrated that FLcPDi treatment significantly elevated the abundance of Akkermansia and, importantly, Akkermansia administration enhanced the response to PDi in mice treated with antibiotics.
Conclusions
The FL/ENL/CD38 axis inhibited BC progression. FL enhanced the anticancer effects of PDi by modulating gut microbiota and host immunity.
{"title":"The combination of flaxseed lignans and PD-1/ PD-L1 inhibitor inhibits breast cancer growth via modulating gut microbiome and host immunity","authors":"Hao Wu , Jiena Liu , Xing-Hua Zhang , Shengye Jin , Ping Li , Huidi Liu , Liuying Zhao , Jianyu Wang , Shilu Zhao , Hong-Da Tian , Jin-Ru Lai , Yi Hao , Gui-Rong Liu , Kaijian Hou , Meisi Yan , Shu-Lin Liu , Da Pang","doi":"10.1016/j.drup.2025.101222","DOIUrl":"10.1016/j.drup.2025.101222","url":null,"abstract":"<div><h3>Background</h3><div>Patients with breast cancer (BC) who benefit from the PD-1/PD-L1 inhibitor (PDi) is limited, necessitating novel strategies to improve immunotherapy efficacy of BC. Here we aimed to investigate the inhibitory effects of flaxseed lignans (FL) on the biological behaviors of BC and evaluate the roles of FL in enhancing the anticancer effects of PDi.</div></div><div><h3>Methods</h3><div>HPLC was used to detect the content of enterolactone (ENL), the bacterial transformation product of FL. Transcript sequencing was performed and identified CD38 as a downstream target gene of ENL. CD38-overexpressing cells were constructed and cell proliferation, colony formation, wound healing and transwell assays were used to assess the function of ENL/CD38 axis on BC cells <em>in vitro</em>. Multiplexed immunohistochemistry (mIHC) and CyTOF were used to detect the changes of the tumor immune microenvironment (TIM). 16S rDNA sequencing was used to explore the changes of gut microbiota in mice. A series of <em>in vivo</em> experiments were conducted to investigate the anticancer effects and mechanisms of FL and PDi.</div></div><div><h3>Results</h3><div>FL was converted to ENL by gut microbiota and FL administration inhibited the progression of BC. ENL inhibited the malignant behaviors of BC by downregulating CD38, a key gene associated with immunosuppression and PD-1/PD-L1 blockade resistance. The mIHC assay revealed that FL administration enhanced CD3<sup>+</sup>, CD4<sup>+</sup> and CD8<sup>+</sup> cells and reduced F4/80<sup>+</sup> cells in TIM. CyTOF confirmed the regulatory effects of FL and FL in combination with PDi (FLcPDi) on TIM. In addition, 16S rDNA analysis demonstrated that FLcPDi treatment significantly elevated the abundance of <em>Akkermansia</em> and, importantly, <em>Akkermansia</em> administration enhanced the response to PDi in mice treated with antibiotics.</div></div><div><h3>Conclusions</h3><div>The FL/ENL/CD38 axis inhibited BC progression. FL enhanced the anticancer effects of PDi by modulating gut microbiota and host immunity.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"80 ","pages":"Article 101222"},"PeriodicalIF":15.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-21DOI: 10.1016/j.drup.2025.101214
Jinmin Sun , Wenyu Zhao , Lei Zhang , Sicheng Wu , Senrui Xue , Haowei Cao , Biao Xu , Xinmiao Li , Nan Hu , Tao Jiang , Yixin Xu , Zhifei Wang , Chao Zhang , Jing Ren
Aims
Temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma (GBM) therapy; however, resistance to TMZ remains a major obstacle in GBM treatment. The aim of this study is to elucidate the mechanisms underlying TMZ resistance and explore how to enhance the sensitivity of GBM to TMZ.
Methods
GBM organoids were generated from patient samples, and organoid-based TMZ sensitivity testing was performed. Transcriptome sequencing was conducted on GBM organoids, which identified Centromere protein U (CENPU) as a novel key gene mediating TMZ resistance. Histopathological assessments were carried out using immunohistochemistry (IHC) and Hematoxylin and Eosin (HE) staining. Single-cell sequencing data were utilized to determine the functional states of CENPU in GBM cells. Intracranial and subcutaneous glioma mouse models were constructed to evaluate the effect of CENPU on TMZ sensitivity. The underlying mechanisms were further investigated using immunofluorescence, lentivirus transduction, co-immunoprecipitation, mass spectrometry, alkaline comet assay et al.
Results
CENPU was found to be highly expressed in TMZ-resistant GBM organoids and enhanced the TMZ resistance of GBM cells by promoting DNA damage repair. Its abnormal expression correlates with poor clinical outcomes in glioma patients. In vivo studies demonstrated that downregulation of CENPU enhances the sensitivity of GBM to TMZ. Correspondingly, rescue of CENPU expression reversed this effect on TMZ sensitivity in GBM cells. Mechanistically, CENPU cooperates with TRIM5α to promote the ubiquitination and degradation of RPS3 by inducing its polyubiquitination at the K214 residue. This process subsequently activates the ERK1/2 pathway and promotes the expression of E2F1 and RAD51. Consequently, the degradation of RPS3 and upregulation of RAD51 in GBM cells enhance DNA damage repair, thereby contributing to TMZ resistance.
Conclusion
Our study identified CENPU as a novel key gene mediating TMZ resistance and elucidated its molecular mechanisms, providing a new target to overcome TMZ resistance in GBM.
{"title":"Centromere protein U mediates the ubiquitination and degradation of RPS3 to facilitate temozolomide resistance in glioblastoma","authors":"Jinmin Sun , Wenyu Zhao , Lei Zhang , Sicheng Wu , Senrui Xue , Haowei Cao , Biao Xu , Xinmiao Li , Nan Hu , Tao Jiang , Yixin Xu , Zhifei Wang , Chao Zhang , Jing Ren","doi":"10.1016/j.drup.2025.101214","DOIUrl":"10.1016/j.drup.2025.101214","url":null,"abstract":"<div><h3>Aims</h3><div>Temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma (GBM) therapy; however, resistance to TMZ remains a major obstacle in GBM treatment. The aim of this study is to elucidate the mechanisms underlying TMZ resistance and explore how to enhance the sensitivity of GBM to TMZ.</div></div><div><h3>Methods</h3><div>GBM organoids were generated from patient samples, and organoid-based TMZ sensitivity testing was performed. Transcriptome sequencing was conducted on GBM organoids, which identified Centromere protein U (CENPU) as a novel key gene mediating TMZ resistance. Histopathological assessments were carried out using immunohistochemistry (IHC) and Hematoxylin and Eosin (HE) staining. Single-cell sequencing data were utilized to determine the functional states of CENPU in GBM cells. Intracranial and subcutaneous glioma mouse models were constructed to evaluate the effect of CENPU on TMZ sensitivity. The underlying mechanisms were further investigated using immunofluorescence, lentivirus transduction, co-immunoprecipitation, mass spectrometry, alkaline comet assay et al.</div></div><div><h3>Results</h3><div>CENPU was found to be highly expressed in TMZ-resistant GBM organoids and enhanced the TMZ resistance of GBM cells by promoting DNA damage repair. Its abnormal expression correlates with poor clinical outcomes in glioma patients. <em>In vivo</em> studies demonstrated that downregulation of CENPU enhances the sensitivity of GBM to TMZ. Correspondingly, rescue of CENPU expression reversed this effect on TMZ sensitivity in GBM cells. Mechanistically, CENPU cooperates with TRIM5α to promote the ubiquitination and degradation of RPS3 by inducing its polyubiquitination at the K214 residue. This process subsequently activates the ERK1/2 pathway and promotes the expression of E2F1 and RAD51. Consequently, the degradation of RPS3 and upregulation of RAD51 in GBM cells enhance DNA damage repair, thereby contributing to TMZ resistance.</div></div><div><h3>Conclusion</h3><div>Our study identified CENPU as a novel key gene mediating TMZ resistance and elucidated its molecular mechanisms, providing a new target to overcome TMZ resistance in GBM.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"80 ","pages":"Article 101214"},"PeriodicalIF":15.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-15DOI: 10.1016/j.drup.2025.101213
Santiago Ramón-García , Rubén González del Río , María Pilar Arenaz-Callao , Helena I. Boshoff , Joaquín Rullas , Sara Anca , Mónica Cacho Izquierdo , Esther Porras de Francisco , Esther Pérez Herrán , Angel Santos-Villarejo , Alfonso Mendoza-Losana , Santiago Ferrer-Bazaga , Charles J. Thompson , David Barros Aguirre , Robert H. Bates
Tuberculosis (TB) is historically the world’s deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB. Recently, a growing body of evidence indicates that later-generation carbapenems in the presence of β-lactamase inhibitors could play a role in TB treatment. However, most of these drugs can only be administered intravenously in the clinic. We performed a screening of β-lactams against intracellular Mycobacterium tuberculosis (Mtb) and identified sanfetrinem cilexetil as a promising oral β-lactam candidate. Preclinical in vitro and in vivo studies demonstrated that: (i) media composition impacts the activity of sanfetrinem against Mtb, being more potent in the presence of physiologically relevant cholesterol as the only carbon source, compared to the standard broth media; (ii) sanfetrinem shows broad spectrum activity against Mtb clinical isolates, including MDR/XDR strains; (iii) sanfetrinem is rapidly bactericidal in vitro against Mtb despite being poorly stable in the assay media; (iv) there are strong in vitro synergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in an in vivo model of infection. These data, together with robust pre-clinical and clinical studies of broad-spectrum carbapenem antibiotics carried out in the 1990s by GSK, identified sanfetrinem as having potential for treating TB and catalyzed a repurposing proof-of-concept Phase 2a clinical study (NCT05388448) in South Africa.
{"title":"Sanfetrinem, an oral β-lactam antibiotic repurposed for the treatment of tuberculosis","authors":"Santiago Ramón-García , Rubén González del Río , María Pilar Arenaz-Callao , Helena I. Boshoff , Joaquín Rullas , Sara Anca , Mónica Cacho Izquierdo , Esther Porras de Francisco , Esther Pérez Herrán , Angel Santos-Villarejo , Alfonso Mendoza-Losana , Santiago Ferrer-Bazaga , Charles J. Thompson , David Barros Aguirre , Robert H. Bates","doi":"10.1016/j.drup.2025.101213","DOIUrl":"10.1016/j.drup.2025.101213","url":null,"abstract":"<div><div>Tuberculosis (TB) is historically the world’s deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB. Recently, a growing body of evidence indicates that later-generation carbapenems in the presence of β-lactamase inhibitors could play a role in TB treatment. However, most of these drugs can only be administered intravenously in the clinic. We performed a screening of β-lactams against intracellular <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) and identified sanfetrinem cilexetil as a promising oral β-lactam candidate. Preclinical <em>in vitro</em> and <em>in vivo</em> studies demonstrated that: (i) media composition impacts the activity of sanfetrinem against <em>Mtb</em>, being more potent in the presence of physiologically relevant cholesterol as the only carbon source, compared to the standard broth media; (ii) sanfetrinem shows broad spectrum activity against <em>Mtb</em> clinical isolates, including MDR/XDR strains; (iii) sanfetrinem is rapidly bactericidal <em>in vitro</em> against <em>Mtb</em> despite being poorly stable in the assay media; (iv) there are strong <em>in vitro</em> synergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in an <em>in vivo</em> model of infection. These data, together with robust pre-clinical and clinical studies of broad-spectrum carbapenem antibiotics carried out in the 1990s by GSK, identified sanfetrinem as having potential for treating TB and catalyzed a repurposing proof-of-concept Phase 2a clinical study (NCT05388448) in South Africa.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"80 ","pages":"Article 101213"},"PeriodicalIF":15.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-10DOI: 10.1016/j.drup.2025.101212
Guangqi Li , Yuting Jiang , Huan Tong , Jifeng Liu , Zedong Jiang , Yunuo Zhao , Keqin Tan , Yu Zhang , Xiaomeng Yin , Hong Yun , Yuxin He , Hu Liao , Jiangjiang Qin , Xuelei Ma
Aims
Triple-negative breast cancer (TNBC) has shown resistance to immunotherapy. Stimulating ProkR2-bearing sensory neurons of the sciatic nerve has been reported to regulate immune function by catecholamine release through the vagal-adrenal axis. We aimed to investigate the impact of sciatic nerve stimulation on anti-tumor immune responses and immunotherapy efficacy in TNBC.
Methods
We implemented ProkR2-bearing neuron stimulation in a TNBC mouse model. Single-cell RNA sequencing, flow cytometry, and immunohistochemistry were employed to uncover alterations in the tumor immune microenvironment. Immune cell depletion and receptor inhibitors were used to verify the cellular and molecular mechanisms by which neurostimulation regulates anti-tumor immunity.
Results
Sciatic nerve stimulation inhibited 4T1 tumor growth by activating natural killer (NK) cells in the tumor microenvironment. The D1-like dopamine receptor-cAMP-PKA-CREB signaling pathway is essential for enhanced NK cell cytotoxicity and tumor inhibition induced by neurostimulation. Neurostimulation upregulated tumor PD-L1 expression through IFN-gamma pathway. Combining sciatic nerve stimulation with anti-PD-1 therapy resulted in superior tumor control compared to either approach alone and demonstrated good safety.
Conclusions
This research addresses a long-standing gap in understanding neuro-immune regulation in cancer treatment, presenting a promising strategy for overcoming immunoresistance in TNBC.
{"title":"Sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling and synergizes immunotherapy in triple-negative breast cancer","authors":"Guangqi Li , Yuting Jiang , Huan Tong , Jifeng Liu , Zedong Jiang , Yunuo Zhao , Keqin Tan , Yu Zhang , Xiaomeng Yin , Hong Yun , Yuxin He , Hu Liao , Jiangjiang Qin , Xuelei Ma","doi":"10.1016/j.drup.2025.101212","DOIUrl":"10.1016/j.drup.2025.101212","url":null,"abstract":"<div><h3>Aims</h3><div>Triple-negative breast cancer (TNBC) has shown resistance to immunotherapy. Stimulating ProkR2-bearing sensory neurons of the sciatic nerve has been reported to regulate immune function by catecholamine release through the vagal-adrenal axis. We aimed to investigate the impact of sciatic nerve stimulation on anti-tumor immune responses and immunotherapy efficacy in TNBC.</div></div><div><h3>Methods</h3><div>We implemented ProkR2-bearing neuron stimulation in a TNBC mouse model. Single-cell RNA sequencing, flow cytometry, and immunohistochemistry were employed to uncover alterations in the tumor immune microenvironment. Immune cell depletion and receptor inhibitors were used to verify the cellular and molecular mechanisms by which neurostimulation regulates anti-tumor immunity.</div></div><div><h3>Results</h3><div>Sciatic nerve stimulation inhibited 4T1 tumor growth by activating natural killer (NK) cells in the tumor microenvironment. The D1-like dopamine receptor-cAMP-PKA-CREB signaling pathway is essential for enhanced NK cell cytotoxicity and tumor inhibition induced by neurostimulation. Neurostimulation upregulated tumor PD-L1 expression through IFN-gamma pathway. Combining sciatic nerve stimulation with anti-PD-1 therapy resulted in superior tumor control compared to either approach alone and demonstrated good safety.</div></div><div><h3>Conclusions</h3><div>This research addresses a long-standing gap in understanding neuro-immune regulation in cancer treatment, presenting a promising strategy for overcoming immunoresistance in TNBC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101212"},"PeriodicalIF":15.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-06DOI: 10.1016/j.drup.2025.101211
Yan-yan Yan , Zhuo-fen Deng , Xing-tao Wu , Yu Lu , Zhuang-yan Zhu , Qing Wen , Wei Zhang , Hai-yan Zhang , Xin-zhu Chen , Yu-song Wu , Xue-bing He , Zi-ang Ma , Jin-shuo Li , Hong Bi , Jian-ye Zhang
This study aimed to identify molecular markers that mediate 5-fluorouracil (5-FU) resistance in colorectal cancer (CRC). Exosomes from 5-FU resistant CRC cells (HCT-15/FU) significantly enhanced the resistance to 5-FU and the malignant properties of HCT-15 cells. Double screening of miRNAs in CRC cell-exosomes and serum-exosomes from clinical CRC patients revealed that miR-224–5p was expressed at significantly lower levels in the 5-FU resistant type than in the 5-FU sensitive type. Moreover, the overall survival rates of 5-FU-resistant CRC patients were much lower than those of 5-FU-sensitive CRC patients. Furthermore, cellular miRNA sequencing (miR-Seq) and proteomic studies revealed that several miRNAs such as miR-224–5p, were significantly downregulated and that calcium-related proteins, including S100 calcium-binding protein A4 (S100A4), were upregulated in HCT-15/FU cells. An analysis of data from public databases revealed that patients with CRC with lower S100A4 expression had a better prognosis. In addition, miR-224–5p was shown to directly target S100A4. Functionally, in vitro and in vivo experiments verified that the downregulation of miR-224–5p promoted malignant properties and resistance to 5-FU in HCT-15 cells, whereas the upregulation of miR-224–5p in HCT-15/FU cells attenuated these effects. Notably, 5-FU combined with verapamil reversed 5-FU resistance in CRC by regulating the miR-224–5p/S100A4 pathway. Triptolide inhibited the malignant properties of HCT-15/FU cells by affecting the miR-224–5p/S100A4 axis. Overall, miR-224–5p is involved in CRC 5-FU resistance by regulating S100A4, and might serve as a molecular marker for the early prediction and intervention of 5-FU resistance in CRC patients in the clinic. Triptolide or 5-FU combined with a calcium antagonist could be used as a trial therapy for 5-FU resistant CRC patients.
{"title":"Low miR-224–5p in exosomes confers colorectal cancer 5-FU resistance by upregulating S100A4","authors":"Yan-yan Yan , Zhuo-fen Deng , Xing-tao Wu , Yu Lu , Zhuang-yan Zhu , Qing Wen , Wei Zhang , Hai-yan Zhang , Xin-zhu Chen , Yu-song Wu , Xue-bing He , Zi-ang Ma , Jin-shuo Li , Hong Bi , Jian-ye Zhang","doi":"10.1016/j.drup.2025.101211","DOIUrl":"10.1016/j.drup.2025.101211","url":null,"abstract":"<div><div>This study aimed to identify molecular markers that mediate 5-fluorouracil (5-FU) resistance in colorectal cancer (CRC). Exosomes from 5-FU resistant CRC cells (HCT-15/FU) significantly enhanced the resistance to 5-FU and the malignant properties of HCT-15 cells. Double screening of miRNAs in CRC cell-exosomes and serum-exosomes from clinical CRC patients revealed that miR-224–5p was expressed at significantly lower levels in the 5-FU resistant type than in the 5-FU sensitive type. Moreover, the overall survival rates of 5-FU-resistant CRC patients were much lower than those of 5-FU-sensitive CRC patients. Furthermore, cellular miRNA sequencing (miR-Seq) and proteomic studies revealed that several miRNAs such as miR-224–5p, were significantly downregulated and that calcium-related proteins, including S100 calcium-binding protein A4 (S100A4), were upregulated in HCT-15/FU cells. An analysis of data from public databases revealed that patients with CRC with lower S100A4 expression had a better prognosis. In addition, miR-224–5p was shown to directly target S100A4. Functionally, <em>in vitro</em> and <em>in vivo</em> experiments verified that the downregulation of miR-224–5p promoted malignant properties and resistance to 5-FU in HCT-15 cells, whereas the upregulation of miR-224–5p in HCT-15/FU cells attenuated these effects. Notably, 5-FU combined with verapamil reversed 5-FU resistance in CRC by regulating the miR-224–5p/S100A4 pathway. Triptolide inhibited the malignant properties of HCT-15/FU cells by affecting the miR-224–5p/S100A4 axis. Overall, miR-224–5p is involved in CRC 5-FU resistance by regulating S100A4, and might serve as a molecular marker for the early prediction and intervention of 5-FU resistance in CRC patients in the clinic. Triptolide or 5-FU combined with a calcium antagonist could be used as a trial therapy for 5-FU resistant CRC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101211"},"PeriodicalIF":15.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cancer immunotherapy has revolutionized cancer treatment, but therapeutic ineffectiveness—driven by the tumor microenvironment and immune evasion mechanisms—continues to limit its clinical efficacy. This challenge underscores the need to explore innovative approaches, such as multimodal immunotherapy. Phytochemicals, bioactive compounds derived from plants, have emerged as promising candidates for overcoming these barriers due to their immunomodulatory and antitumor properties. This review explores the synergistic potential of phytochemicals in enhancing immunotherapy by modulating immune responses, reprogramming the tumor microenvironment, and reducing immunosuppressive factors. Integrating phytochemicals with conventional immunotherapy strategies represents a novel approach to mitigating resistance and enhancing therapeutic outcomes. For instance, nab-paclitaxel has shown the potential in overcoming resistance to immune checkpoint inhibitors, while QS-21 synergistically enhances the efficacy of tumor vaccines. Furthermore, we highlight recent advancements in leveraging nanotechnology to engineer phytochemicals for improved bioavailability and targeted delivery. These innovations hold great promise for optimizing the clinical application of phytochemicals. However, further large-scale clinical studies are crucial to fully integrate these compounds into immunotherapeutic regimens effectively.
{"title":"Harnessing phytochemicals: Innovative strategies to enhance cancer immunotherapy","authors":"Qianru Zhu , Ruonan Zhang , Ziming Zhao , Tian Xie , Xinbing Sui","doi":"10.1016/j.drup.2025.101206","DOIUrl":"10.1016/j.drup.2025.101206","url":null,"abstract":"<div><div>Cancer immunotherapy has revolutionized cancer treatment, but therapeutic ineffectiveness—driven by the tumor microenvironment and immune evasion mechanisms—continues to limit its clinical efficacy. This challenge underscores the need to explore innovative approaches, such as multimodal immunotherapy. Phytochemicals, bioactive compounds derived from plants, have emerged as promising candidates for overcoming these barriers due to their immunomodulatory and antitumor properties. This review explores the synergistic potential of phytochemicals in enhancing immunotherapy by modulating immune responses, reprogramming the tumor microenvironment, and reducing immunosuppressive factors. Integrating phytochemicals with conventional immunotherapy strategies represents a novel approach to mitigating resistance and enhancing therapeutic outcomes. For instance, nab-paclitaxel has shown the potential in overcoming resistance to immune checkpoint inhibitors, while QS-21 synergistically enhances the efficacy of tumor vaccines. Furthermore, we highlight recent advancements in leveraging nanotechnology to engineer phytochemicals for improved bioavailability and targeted delivery. These innovations hold great promise for optimizing the clinical application of phytochemicals. However, further large-scale clinical studies are crucial to fully integrate these compounds into immunotherapeutic regimens effectively.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101206"},"PeriodicalIF":15.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143377648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Extracellular vesicles (EVs) are heterogeneous vesicles released by donor cells that can be taken up by recipient cells, thus inducing cellular phenotype changes. Since their discovery decades ago, roles of EVs in modulating initiation, growth, survival and metastasis of cancer have been revealed. Recent studies from multifaceted perspectives have further detailed the contribution of EVs to cancer drug resistance; however, the role of EV uptake in conferring drug resistance seems to be overlooked. In this comprehensive review, we update the EV subtypes and approaches for determining EV uptake. The biological basis of EV uptake is systematically summarized. Moreover, we focus on the diverse uptake mechanisms by which EVs carry out the intracellular delivery of functional molecules and drug resistance signaling. Furthermore, we highlight how EV uptake confers drug resistance and identify potential strategies for targeting EV uptake to overcome drug resistance. Finally, we discuss the research gap on the role of EV uptake in promoting drug resistance. This updated knowledge provides a new avenue to overcome cancer drug resistance by targeting EV uptake.
{"title":"The uptake of extracellular vesicles: Research progress in cancer drug resistance and beyond","authors":"Luomeng Qian , Pangzhou Chen , Shiwu Zhang , Zhenglu Wang , Yuan Guo , Vasili Koutouratsas , Joshua S. Fleishman , Chuanqiang Huang , Sihe Zhang","doi":"10.1016/j.drup.2025.101209","DOIUrl":"10.1016/j.drup.2025.101209","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) are heterogeneous vesicles released by donor cells that can be taken up by recipient cells, thus inducing cellular phenotype changes. Since their discovery decades ago, roles of EVs in modulating initiation, growth, survival and metastasis of cancer have been revealed. Recent studies from multifaceted perspectives have further detailed the contribution of EVs to cancer drug resistance; however, the role of EV uptake in conferring drug resistance seems to be overlooked. In this comprehensive review, we update the EV subtypes and approaches for determining EV uptake. The biological basis of EV uptake is systematically summarized. Moreover, we focus on the diverse uptake mechanisms by which EVs carry out the intracellular delivery of functional molecules and drug resistance signaling. Furthermore, we highlight how EV uptake confers drug resistance and identify potential strategies for targeting EV uptake to overcome drug resistance. Finally, we discuss the research gap on the role of EV uptake in promoting drug resistance. This updated knowledge provides a new avenue to overcome cancer drug resistance by targeting EV uptake.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101209"},"PeriodicalIF":15.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.drup.2025.101208
Min Sun , Le He , Ran Chen , Mingchen Lv , Zhe-Sheng Chen , Zhen Fan , Yuxiao Zhou , Jinlong Qin , Jianzhong Du
Chemotherapy is widely used clinically, however, its efficacy is often compromised by the development of drug resistance, which arises from prolonged administration of drugs or other stimuli. One of the driven causes of drug resistance in tumors or bacterial infections is metabolic reprogramming, which alters mitochondrial metabolism, disrupts metabolic pathways and causes ion imbalance. Bioactive peptide materials, due to their biocompatibility, diverse bioactivities, customizable sequences, and ease of modification, have shown promise in overcoming drug resistance. This review provides an in-depth analysis of metabolic reprogramming and associated microenvironmental changes that contribute to drug resistance in common tumors and bacterial infections, suggesting potential therapeutic targets. Additionally, we explore peptide-based materials for regulating metabolism and their potential synergic effect with other therapies, highlighting the mechanisms by which these peptides reverse drug resistance. Finally, we discuss future perspectives and the clinical challenges in peptide-based treatments, aiming to offer insights for overcoming drug-resistant diseases.
{"title":"Rational design of peptides to overcome drug resistance by metabolic regulation","authors":"Min Sun , Le He , Ran Chen , Mingchen Lv , Zhe-Sheng Chen , Zhen Fan , Yuxiao Zhou , Jinlong Qin , Jianzhong Du","doi":"10.1016/j.drup.2025.101208","DOIUrl":"10.1016/j.drup.2025.101208","url":null,"abstract":"<div><div>Chemotherapy is widely used clinically, however, its efficacy is often compromised by the development of drug resistance, which arises from prolonged administration of drugs or other stimuli. One of the driven causes of drug resistance in tumors or bacterial infections is metabolic reprogramming, which alters mitochondrial metabolism, disrupts metabolic pathways and causes ion imbalance. Bioactive peptide materials, due to their biocompatibility, diverse bioactivities, customizable sequences, and ease of modification, have shown promise in overcoming drug resistance. This review provides an in-depth analysis of metabolic reprogramming and associated microenvironmental changes that contribute to drug resistance in common tumors and bacterial infections, suggesting potential therapeutic targets. Additionally, we explore peptide-based materials for regulating metabolism and their potential synergic effect with other therapies, highlighting the mechanisms by which these peptides reverse drug resistance. Finally, we discuss future perspectives and the clinical challenges in peptide-based treatments, aiming to offer insights for overcoming drug-resistant diseases.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101208"},"PeriodicalIF":15.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143217854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-29DOI: 10.1016/j.drup.2025.101210
Hyun-Jong Eun , Seok-Won Jang , Ju-Hyun Park , Jooyeon Lee , Ki-Young Lee , Eun-Jin Lee , Bong-Jin Lee
Aims
The ability to eliminate bacterial persister cells is still a medical challenge that has yet to be overcome. These cells represent a unique subpopulation within bacterial communities and are characterized by a reduced susceptibility to antibiotics with growth retardation. In this study, we investigated the molecular basis of persister formation in Salmonella Typhimurium 14028 s under aminoglycoside stress.
Methods
We analyzed the crystal structure of the STM14_5441–STM14_5442 complex, which belongs to the type II toxin-antitoxin system, and identified key ribosome-binding residues in STM14_5441. Changes in the antibiotic susceptibility of Salmonella caused by the loss of the ribosome-binding property of STM14_5441 were assessed. We conducted intracellular ATP assays under aminoglycoside stress and RNA-seq analysis following STM14_5441 induction.
Results
Our studies demonstrated the critical role of STM14_5441 in the formation of persister cells in Salmonella, particularly those under aminoglycoside stress. We observed that a loss of ribosome binding in STM14_5441 resulted in increased antibiotic susceptibility. Additionally, intracellular ATP assays revealed increased ATP levels in STM14_5441 induced group, and RNA-seq analysis identified several genes that play a role in this phenomenon.
Conclusions
The present data suggest that persister forms under aminoglycoside stress through the following mechanisms: i) inhibition of membrane hyperpolarization by impeding F1Fo ATP synthase activity and ii) enhanced poststress recovery by ATP storage and increased protein synthesis capacity. Based on this suggestion, we reannotated the STM14_5441-STM14_5442 TA pair as the ResTA (RNA cleavage-induced energy storage toxin-antitoxin) system. Furthermore, new insights into the function of TA systems may lay the groundwork for developing novel strategies to target bacterial persister cells, thereby preventing the accelerated emergence of antibiotic resistance in bacterial populations.
{"title":"Structural and functional analyses of STM14_5441-STM14_5442: A potential mechanism for persister formation against aminoglycosides","authors":"Hyun-Jong Eun , Seok-Won Jang , Ju-Hyun Park , Jooyeon Lee , Ki-Young Lee , Eun-Jin Lee , Bong-Jin Lee","doi":"10.1016/j.drup.2025.101210","DOIUrl":"10.1016/j.drup.2025.101210","url":null,"abstract":"<div><h3>Aims</h3><div>The ability to eliminate bacterial persister cells is still a medical challenge that has yet to be overcome. These cells represent a unique subpopulation within bacterial communities and are characterized by a reduced susceptibility to antibiotics with growth retardation. In this study, we investigated the molecular basis of persister formation in <em>Salmonella</em> Typhimurium 14028 s under aminoglycoside stress.</div></div><div><h3>Methods</h3><div>We analyzed the crystal structure of the STM14_5441–STM14_5442 complex, which belongs to the type II toxin-antitoxin system, and identified key ribosome-binding residues in STM14_5441. Changes in the antibiotic susceptibility of <em>Salmonella</em> caused by the loss of the ribosome-binding property of STM14_5441 were assessed. We conducted intracellular ATP assays under aminoglycoside stress and RNA-seq analysis following STM14_5441 induction.</div></div><div><h3>Results</h3><div>Our studies demonstrated the critical role of STM14_5441 in the formation of persister cells in <em>Salmonella</em>, particularly those under aminoglycoside stress. We observed that a loss of ribosome binding in STM14_5441 resulted in increased antibiotic susceptibility. Additionally, intracellular ATP assays revealed increased ATP levels in STM14_5441 induced group, and RNA-seq analysis identified several genes that play a role in this phenomenon.</div></div><div><h3>Conclusions</h3><div>The present data suggest that persister forms under aminoglycoside stress through the following mechanisms: i) inhibition of membrane hyperpolarization by impeding F<sub>1</sub>Fo ATP synthase activity and ii) enhanced poststress recovery by ATP storage and increased protein synthesis capacity. Based on this suggestion, we reannotated the STM14_5441-STM14_5442 TA pair as the ResTA (RNA cleavage-induced energy storage toxin-antitoxin) system. Furthermore, new insights into the function of TA systems may lay the groundwork for developing novel strategies to target bacterial persister cells, thereby preventing the accelerated emergence of antibiotic resistance in bacterial populations.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101210"},"PeriodicalIF":15.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143142882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.drup.2025.101207
Yong Ju , Joshua Watson , Jasmine J. Wang , Ying-Tzu Yen , Lilit Gevorkian , Zijing Chen , Kai Han Tu , Brenda Salumbides , Aaron Phung , Chen Zhao , Hyoyong Kim , You-Ren Ji , Ryan Y. Zhang , Junseok Lee , Jun Gong , Kevin Scher , Sungyong You , Jie-Fu Chen , Hsian-Rong Tseng , Yazhen Zhu , Edwin M. Posadas
Background
B7-H3 is a promising target for cancer therapy, notably in prostate cancer (PCa), particularly in metastatic, castration-resistant PCa (mCRPC). With the development of B7-H3-targeted therapies, there is a need for a rapid, reliable, and cost-effective method to detect and monitor B7-H3 expression. Leveraging their abundance and stability, we developed a liquid biopsy assay using extracellular vesicles (EVs) for this purpose.
Methods
B7-H3+ EVs were isolated using a B7-H3 antibody-mediated, click chemistry-based enrichment method. Antibodies were conjugated to methyltetrazine-grafted microbeads. EVs were isolated from 100 µL of plasma from metastatic, castration-sensitive PCa (mCSPC) (n = 43) and mCRPC (n = 103) patients and quantified using RT-qPCR of ACTB. Measurements were compared with the patient's disease status over time.
Results
The assay detected higher B7-H3+ EVs in mCRPC than mCSPC and increased when mCSPC transitioned to mCRPC. Elevated B7-H3+ EVs were associated with lower overall survival (Hazard ratio (HR) 2.19, p = 0.01). In patients with serial plasma samples, B7-H3+ EV levels reflected treatment response and disease progression.
Conclusions
This B7-H3+ EV assay represents a significant advancement in utilizing tumor-derived EVs for a non-invasive, quantitative, and consistent real-time measurement of B7-H3. This assay warrants further development as a companion diagnostic for B7-H3 targeted therapies in PCa and other conditions.
{"title":"B7-H3-liquid biopsy for the characterization and monitoring of the dynamic biology of prostate cancer","authors":"Yong Ju , Joshua Watson , Jasmine J. Wang , Ying-Tzu Yen , Lilit Gevorkian , Zijing Chen , Kai Han Tu , Brenda Salumbides , Aaron Phung , Chen Zhao , Hyoyong Kim , You-Ren Ji , Ryan Y. Zhang , Junseok Lee , Jun Gong , Kevin Scher , Sungyong You , Jie-Fu Chen , Hsian-Rong Tseng , Yazhen Zhu , Edwin M. Posadas","doi":"10.1016/j.drup.2025.101207","DOIUrl":"10.1016/j.drup.2025.101207","url":null,"abstract":"<div><h3>Background</h3><div>B7-H3 is a promising target for cancer therapy, notably in prostate cancer (PCa), particularly in metastatic, castration-resistant PCa (mCRPC). With the development of B7-H3-targeted therapies, there is a need for a rapid, reliable, and cost-effective method to detect and monitor B7-H3 expression. Leveraging their abundance and stability, we developed a liquid biopsy assay using extracellular vesicles (EVs) for this purpose.</div></div><div><h3>Methods</h3><div>B7-H3<sup>+</sup> EVs were isolated using a B7-H3 antibody-mediated, click chemistry-based enrichment method. Antibodies were conjugated to methyltetrazine-grafted microbeads. EVs were isolated from 100 µL of plasma from metastatic, castration-sensitive PCa (mCSPC) (n = 43) and mCRPC (n = 103) patients and quantified using RT-qPCR of <em>ACTB</em>. Measurements were compared with the patient's disease status over time.</div></div><div><h3>Results</h3><div>The assay detected higher B7-H3<sup>+</sup> EVs in mCRPC than mCSPC and increased when mCSPC transitioned to mCRPC. Elevated B7-H3<sup>+</sup> EVs were associated with lower overall survival (Hazard ratio (HR) 2.19, <em>p</em> = 0.01). In patients with serial plasma samples, B7-H3<sup>+</sup> EV levels reflected treatment response and disease progression.</div></div><div><h3>Conclusions</h3><div>This B7-H3<sup>+</sup> EV assay represents a significant advancement in utilizing tumor-derived EVs for a non-invasive, quantitative, and consistent real-time measurement of B7-H3. This assay warrants further development as a companion diagnostic for B7-H3 targeted therapies in PCa and other conditions.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101207"},"PeriodicalIF":15.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143217855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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