Pub Date : 2025-09-17DOI: 10.1016/j.drup.2025.101310
Dongmei Sun , Letao Bo , Chao Jiang , Yanning Lan , Bohan Zhang , Chao Zhang , Zhe-Sheng Chen , Yuying Fan
Multidrug resistance (MDR) remains a primary obstacle to successful cancer chemotherapy, with the overexpression of ATP-binding cassette (ABC) transporters being a principal cause. These transporters actively efflux a wide range of anticancer drugs, reducing their intracellular efficacy. Consequently, targeting ABC transporters represents a critical strategy for overcoming therapeutic resistance. This comprehensive review details the molecular architecture and functional mechanisms of all seven human ABC transporter subfamilies (ABCA-ABCG), elucidating their distinct roles in both cancer progression and the development of MDR. We trace the evolution of therapeutic interventions, from first, second, and third-generation small molecule inhibitors to the potential of natural products. Furthermore, this review explores advanced and emerging strategies designed to circumvent or neutralize ABC transporter activity. These include genetic approaches such as RNA interference and CRISPR-Cas9 gene editing, immunotherapy-based tactics like monoclonal antibodies and antibody-drug conjugates (ADCs), and the application of sophisticated nanoparticle delivery systems designed to bypass efflux mechanisms. By providing a holistic overview of the entire ABC transporter family and the broad array of strategies being developed to counteract their function, this article aims to equip researchers with a full-scope perspective on the field, identifying current challenges and illuminating future directions for combating MDR in cancer.
{"title":"Beyond the boundary: The emerging roles of ATP-binding cassette transporters in multidrug resistance (MDR) and therapeutic targeting in cancer","authors":"Dongmei Sun , Letao Bo , Chao Jiang , Yanning Lan , Bohan Zhang , Chao Zhang , Zhe-Sheng Chen , Yuying Fan","doi":"10.1016/j.drup.2025.101310","DOIUrl":"10.1016/j.drup.2025.101310","url":null,"abstract":"<div><div>Multidrug resistance (MDR) remains a primary obstacle to successful cancer chemotherapy, with the overexpression of ATP-binding cassette (ABC) transporters being a principal cause. These transporters actively efflux a wide range of anticancer drugs, reducing their intracellular efficacy. Consequently, targeting ABC transporters represents a critical strategy for overcoming therapeutic resistance. This comprehensive review details the molecular architecture and functional mechanisms of all seven human ABC transporter subfamilies (ABCA-ABCG), elucidating their distinct roles in both cancer progression and the development of MDR. We trace the evolution of therapeutic interventions, from first, second, and third-generation small molecule inhibitors to the potential of natural products. Furthermore, this review explores advanced and emerging strategies designed to circumvent or neutralize ABC transporter activity. These include genetic approaches such as RNA interference and CRISPR-Cas9 gene editing, immunotherapy-based tactics like monoclonal antibodies and antibody-drug conjugates (ADCs), and the application of sophisticated nanoparticle delivery systems designed to bypass efflux mechanisms. By providing a holistic overview of the entire ABC transporter family and the broad array of strategies being developed to counteract their function, this article aims to equip researchers with a full-scope perspective on the field, identifying current challenges and illuminating future directions for combating MDR in cancer.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101310"},"PeriodicalIF":21.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145093862","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 : 2025-09-09DOI: 10.1016/j.drup.2025.101299
Caiyun Liu , Lin Meng , Lixin Wang , Bin Dong , Like Qu , Chuanke Zhao , Chengchao Shou
Background
Resistance to Bevacizumab (Bev) remains a major obstacle in colorectal cancer (CRC) treatment. Gamma-synuclein (SNCG), overexpressed in tumor vasculature and cancer cells, is investigated here for its role in Bev resistance and therapeutic potential.
Methods
Using isogenic CRC models with SNCG overexpression or knockout, we assessed SNCG's impact on Bev response in vitro and in vivo. The therapeutic efficacy of combining Bev with an anti-SNCG monoclonal antibody (42#) was evaluated in Bev-resistant models. Mechanistic studies, including ELISA, Western blot, surface plasmon resonance (SPR), and molecular docking, explored interactions between SNCG, VEGF, and VEGFR2.
Results
SNCG overexpression reduced Bev sensitivity by impairing the inhibition of migration, invasion, and spheroid formation, whereas SNCG knockout enhanced therapeutic response. Molecular docking revealed that SNCG binds VEGFR2 at an allosteric site, forming a stable ternary complex (SNCG-VEGF-VEGFR2) with enhanced hydrogen bonding, which sustained VEGFR2 phosphorylation and angiogenesis. In vivo, SNCG-overexpressing tumors showed reduced responsiveness to Bev (42.8 % inhibition vs. 64.3 % in controls, p < 0.05), while SNCG-deficient tumors exhibited a 3.2-fold increase in sensitivity. Combining Bev with 42# synergistically suppressed tumor growth (0.70 ± 0.36 g vs. 1.55 ± 0.41 g, p = 0.003), reduced metastatic burden (0.29 ± 0.23 g vs. 0.97 ± 0.42 g, p = 0.006), and extended median survival (86.8 vs. 69.8 days, p = 0.033) in Bev-resistant models.
Conclusions
SNCG drives Bev resistance in CRC by forming a ternary complex with VEGF and VEGFR2, enhancing VEGFR2 signaling and angiogenesis. Dual targeting of VEGF and SNCG represents a promising therapeutic strategy to overcome Bev resistance, with the potential to improve outcomes in CRC patients.
贝伐单抗（Bevacizumab, Bev）耐药仍然是结直肠癌（CRC）治疗的主要障碍。在肿瘤血管和癌细胞中过度表达的γ -突触核蛋白（SNCG）在Bev耐药和治疗潜力中的作用进行了研究。方法采用SNCG过表达或敲除的等基因CRC模型，在体外和体内评估SNCG对Bev反应的影响。在Bev耐药模型中评估Bev联合抗sncg单克隆抗体（42#）的治疗效果。机制研究包括ELISA、Western blot、表面等离子体共振（SPR）和分子对接等，探讨了SNCG、VEGF和VEGFR2之间的相互作用。结果SNCG过表达降低了Bev的敏感性，损害了对迁移、侵袭和球体形成的抑制，而SNCG敲除增强了治疗反应。分子对接发现，SNCG在变构位点与VEGFR2结合，形成稳定的三元配合物（SNCG- vegf -VEGFR2），氢键增强，维持VEGFR2磷酸化和血管生成。在体内，sncg过表达的肿瘤对Bev的反应性降低（对照组抑制率为42.8 %，对照组为64.3 %,p <； 0.05），而sncg缺陷肿瘤的敏感性增加了3.2倍。贝福结合42 #协同抑制肿瘤生长( 0.70±0.36 g和1.55 ±0.41 g p = 0.003),降低转移负担( 0.29±0.23 g和0.97 ±0.42 g p = 0.006),和延长平均存活(86.8 vs 69.8天,p = 0.033)在Bev-resistant模型。结论sncg通过与VEGF和VEGFR2形成三元复合物，增强VEGFR2信号传导和血管生成，从而驱动结直肠癌的Bev耐药。VEGF和SNCG的双重靶向治疗是克服Bev耐药的一种有希望的治疗策略，有可能改善结直肠癌患者的预后。
{"title":"Gamma-synuclein drives bevacizumab resistance in colorectal cancer via VEGFR2 activation and angiogenesis","authors":"Caiyun Liu , Lin Meng , Lixin Wang , Bin Dong , Like Qu , Chuanke Zhao , Chengchao Shou","doi":"10.1016/j.drup.2025.101299","DOIUrl":"10.1016/j.drup.2025.101299","url":null,"abstract":"<div><h3>Background</h3><div>Resistance to Bevacizumab (Bev) remains a major obstacle in colorectal cancer (CRC) treatment. Gamma-synuclein (SNCG), overexpressed in tumor vasculature and cancer cells, is investigated here for its role in Bev resistance and therapeutic potential.</div></div><div><h3>Methods</h3><div>Using isogenic CRC models with SNCG overexpression or knockout, we assessed SNCG's impact on Bev response in vitro and in vivo. The therapeutic efficacy of combining Bev with an anti-SNCG monoclonal antibody (42#) was evaluated in Bev-resistant models. Mechanistic studies, including ELISA, Western blot, surface plasmon resonance (SPR), and molecular docking, explored interactions between SNCG, VEGF, and VEGFR2.</div></div><div><h3>Results</h3><div>SNCG overexpression reduced Bev sensitivity by impairing the inhibition of migration, invasion, and spheroid formation, whereas SNCG knockout enhanced therapeutic response. Molecular docking revealed that SNCG binds VEGFR2 at an allosteric site, forming a stable ternary complex (SNCG-VEGF-VEGFR2) with enhanced hydrogen bonding, which sustained VEGFR2 phosphorylation and angiogenesis. In vivo, SNCG-overexpressing tumors showed reduced responsiveness to Bev (42.8 % inhibition vs. 64.3 % in controls, <em>p</em> < 0.05), while SNCG-deficient tumors exhibited a 3.2-fold increase in sensitivity. Combining Bev with 42# synergistically suppressed tumor growth (0.70 ± 0.36 g vs. 1.55 ± 0.41 g, <em>p</em> = 0.003), reduced metastatic burden (0.29 ± 0.23 g vs. 0.97 ± 0.42 g, <em>p</em> = 0.006), and extended median survival (86.8 vs. 69.8 days, <em>p</em> = 0.033) in Bev-resistant models.</div></div><div><h3>Conclusions</h3><div>SNCG drives Bev resistance in CRC by forming a ternary complex with VEGF and VEGFR2, enhancing VEGFR2 signaling and angiogenesis. Dual targeting of VEGF and SNCG represents a promising therapeutic strategy to overcome Bev resistance, with the potential to improve outcomes in CRC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101299"},"PeriodicalIF":21.7,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145050623","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 : 2025-09-08DOI: 10.1016/j.drup.2025.101298
Zizheng Dong , Xiuzhen Fan , JoAnne J Babula , Shaobo Zhang , Jing-Yuan Liu , Jian-Ting Zhang
ABCG2 has been associated with multidrug resistance (MDR) and protection of cancer stem cells. ABCG2 knockout had no apparent adverse effect on mice. Thus, ABCG2 is an interesting and perhaps an ideal target for drug discovery to overcome MDR and eliminate cancer stem cells. Although many ABCG2 inhibitors have been identified, few have moved into clinical testing and none has been approved. Thus, there is an unmet need for novel ABCG2 inhibitors. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTAC) and molecular-glues have been gaining traction with many in clinical trials, representing a new way targeting cytosolic proteins. However, TPD agents for membrane proteins are scarce. Recently, ABCG2 inhibitors with dynamic properties have been identified that they not only inhibit ABCG2 activity but also induce ABCG2 degradation. These dynamic inhibitors are unique and may represent a new class of TPD agents for membrane proteins and next generation inhibitors for development. Here, we investigated the mechanism of action of the dynamic inhibitor PZ-39 and its analogue PZ-39C8 and showed that they selectively bound to the extracellular loop between TM5-TM6 of ABCG2. This binding induces clathrin-dependent endocytosis of mature ABCG2 and hijacks nascent ABCG2, targeting them to lysosome via autophagy for degradation. PZ-39 also effectively induced ABCG2 loss and sensitized doxorubicin resistance in xenograft tumors. Thus, further investigation of dynamic ABCG2 inhibitors may lead to the next generation of therapeutics to overcome MDR in cancer chemotherapy and contribute to future design of TPD agents targeting membrane proteins.
{"title":"Overcoming multidrug resistance using small molecule dynamic inhibitors by hijacking nascent and inducing turnover of mature ABCG2 for degradation in lysosomes","authors":"Zizheng Dong , Xiuzhen Fan , JoAnne J Babula , Shaobo Zhang , Jing-Yuan Liu , Jian-Ting Zhang","doi":"10.1016/j.drup.2025.101298","DOIUrl":"10.1016/j.drup.2025.101298","url":null,"abstract":"<div><div>ABCG2 has been associated with multidrug resistance (MDR) and protection of cancer stem cells. ABCG2 knockout had no apparent adverse effect on mice. Thus, ABCG2 is an interesting and perhaps an ideal target for drug discovery to overcome MDR and eliminate cancer stem cells. Although many ABCG2 inhibitors have been identified, few have moved into clinical testing and none has been approved. Thus, there is an unmet need for novel ABCG2 inhibitors. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTAC) and molecular-glues have been gaining traction with many in clinical trials, representing a new way targeting cytosolic proteins. However, TPD agents for membrane proteins are scarce. Recently, ABCG2 inhibitors with dynamic properties have been identified that they not only inhibit ABCG2 activity but also induce ABCG2 degradation. These dynamic inhibitors are unique and may represent a new class of TPD agents for membrane proteins and next generation inhibitors for development. Here, we investigated the mechanism of action of the dynamic inhibitor PZ-39 and its analogue PZ-39C8 and showed that they selectively bound to the extracellular loop between TM5-TM6 of ABCG2. This binding induces clathrin-dependent endocytosis of mature ABCG2 and hijacks nascent ABCG2, targeting them to lysosome via autophagy for degradation. PZ-39 also effectively induced ABCG2 loss and sensitized doxorubicin resistance in xenograft tumors. Thus, further investigation of dynamic ABCG2 inhibitors may lead to the next generation of therapeutics to overcome MDR in cancer chemotherapy and contribute to future design of TPD agents targeting membrane proteins.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101298"},"PeriodicalIF":21.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145050622","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 : 2025-09-08DOI: 10.1016/j.drup.2025.101300
Caolu Liu , Zipeng Wu , Yingying Dai , Shuyi Hu , Lei Xia , Xiaoyou Li , Ruofan Yu , Tianyi Liu , Jingwen Li , Fei Yan , Lin Lu , Yue Shi , Yingying Jiang , Jinghua Zhu , Bo Shen , Guoren Zhou , Delin Liu , Guochun Cao , Xiaohua Wang , Cheng Chen
Objective
To evaluate the efficacy and safety of polymeric micellar paclitaxel (Pm-Pac), cisplatin, and tislelizumab as first-line therapy for advanced/metastatic esophageal squamous cell carcinoma (ESCC), addressing limitations of conventional paclitaxel regimens related to steroid-induced immunosuppression.
Methods
This phase II clinical trial enrolled 27 treatment-naïve patients with stage IV ESCC. The regimen consisted of Pm-Pac (230 mg/m²), cisplatin (70 mg/m²), and tislelizumab (200 mg) administered on day 1 of 21-day cycles. After two induction cycles, non-progressive patients received two additional cycles, followed by 12-month tislelizumab maintenance. Primary endpoint: objective response rate (ORR); secondary endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Exploratory analyses included blood counts, tumor markers, lymphocyte subsets, survival analysis, Kruskal-Wallis tests, clustering, and LASSO regression.
Results
The regimen achieved an ORR of 62.96 % (95 % CI: 0.45–0.81) with complete response (CR) in 7.4 % and partial response (PR) in 55.6 % of patients. Median PFS was 10.2 months, with 1-year OS probability of 81.48 %. Treatment was well-tolerated without grade ≥ 3 treatment-related adverse events or deaths. Exploratory predictive analyses suggested potential correlations between outcomes and hyperkalemia, CD4 +CD25 + T cells, lung metastases, and distant lymph node metastases.
Conclusions
The Pm-Pac-based chemoimmunotherapy suggests encouraging efficacy and favorable safety in advanced ESCC, supporting its potential as a first-line steroid-free option. These findings highlight the role of nanotechnology in optimizing chemoimmunotherapy.
{"title":"Polymeric micellar paclitaxel, cisplatin, and tislelizumab as first-line therapy for advanced unresectable esophageal squamous cell carcinoma: A phase II study with resistance profiling in poor responders","authors":"Caolu Liu , Zipeng Wu , Yingying Dai , Shuyi Hu , Lei Xia , Xiaoyou Li , Ruofan Yu , Tianyi Liu , Jingwen Li , Fei Yan , Lin Lu , Yue Shi , Yingying Jiang , Jinghua Zhu , Bo Shen , Guoren Zhou , Delin Liu , Guochun Cao , Xiaohua Wang , Cheng Chen","doi":"10.1016/j.drup.2025.101300","DOIUrl":"10.1016/j.drup.2025.101300","url":null,"abstract":"<div><h3>Objective</h3><div>To evaluate the efficacy and safety of polymeric micellar paclitaxel (Pm-Pac), cisplatin, and tislelizumab as first-line therapy for advanced/metastatic esophageal squamous cell carcinoma (ESCC), addressing limitations of conventional paclitaxel regimens related to steroid-induced immunosuppression.</div></div><div><h3>Methods</h3><div>This phase II clinical trial enrolled 27 treatment-naïve patients with stage IV ESCC. The regimen consisted of Pm-Pac (230 mg/m²), cisplatin (70 mg/m²), and tislelizumab (200 mg) administered on day 1 of 21-day cycles. After two induction cycles, non-progressive patients received two additional cycles, followed by 12-month tislelizumab maintenance. Primary endpoint: objective response rate (ORR); secondary endpoints: progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Exploratory analyses included blood counts, tumor markers, lymphocyte subsets, survival analysis, Kruskal-Wallis tests, clustering, and LASSO regression.</div></div><div><h3>Results</h3><div>The regimen achieved an ORR of 62.96 % (95 % CI: 0.45–0.81) with complete response (CR) in 7.4 % and partial response (PR) in 55.6 % of patients. Median PFS was 10.2 months, with 1-year OS probability of 81.48 %. Treatment was well-tolerated without grade ≥ 3 treatment-related adverse events or deaths. Exploratory predictive analyses suggested potential correlations between outcomes and hyperkalemia, CD4 +CD25 + T cells, lung metastases, and distant lymph node metastases.</div></div><div><h3>Conclusions</h3><div>The Pm-Pac-based chemoimmunotherapy suggests encouraging efficacy and favorable safety in advanced ESCC, supporting its potential as a first-line steroid-free option. These findings highlight the role of nanotechnology in optimizing chemoimmunotherapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101300"},"PeriodicalIF":21.7,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082402","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 : 2025-09-03DOI: 10.1016/j.drup.2025.101295
Yuanqing Cai , Hongxin Hu , Yang Chen , Jiayu Li , Chaofan Zhang , Xuhui Yuan , Wenbo Li , Changyu Huang , Yiming Lin , Zeyu Zhang , Bin Yang , Zida Huang , Wenming Zhang , Xinyu Fang
Aims
In chronic osteomyelitis, the cortical bone serves as the primary site for long-term persistence of Staphylococcus aureus (S. aureus), the present study aimed to explore the mechanisms of immune evasion and antibiotic resistance remain incompletely understood.
Methods
Clinical methicillin-resistant S. aureus (MRSA) isolates, were collected and analyzed. Panton-Valentine leukocidin (PVL) expression levels were quantified via real-time PCR. The impact of PVL on pyroptosis was evaluated by infecting osteocytes and measuring caspase-1 activation and IL-1β release. Osteoclastogenesis and pathological bone formation were examined through TRAP staining and micro-CT. To assess therapeutic potential, pyroptosis was pharmacologically induced using disodium 4,4’-dimethoxy-5,6,5’,6’-dimethylene dioxybiphenyl-2,2’-disulfonate (DMB), followed by evaluation of antibiotic efficacy and bone remodeling in osteomyelitis model.
Results
We observed in clinical cases that the survival rate of MRSA small colony variants (SCVs) in cortical bone is higher than that of non-SCV strains, with SCVs demonstrating characteristic antibiotic resistance through reduced metabolic activity. The PCR results demonstrated that compared to wild-type, MRSA SCVs exhibited significantly reduced expression levels of PVL, this low-PVL-expression phenotype markedly suppresses the activation of the pyroptosis pathway following infection. Furthermore, we discovered that during the adaptation to the intra-cortical environment, the global regulatory factor Sae and the protease aureolysin mediate the active downregulation of PVL, which resulted in targeted inhibition of osteocyte pyroptosis. The suppression of osteocyte pyroptosis simultaneously diminishes the host immune response, MRSA colonization, and antibiotics resistance. Pharmacological induction of pyroptosis via DMB significantly enhanced antibiotic efficacy, as well as alleviated pathological bone formation in chronic osteomyelitis.
Conclusions
MRSA modulates its own virulence factors to create a favorable space and environment for long-term survival within the cortical bone, and therapeutic strategies targeting osteocyte pyroptosis may represent a potential strategy of eradicating MRSA from cortical bone.
{"title":"Staphylococcus aureus manipulates osteocytes to cause persistent chronic osteomyelitis and antibiotic resistance via pyroptosis pathway suppression","authors":"Yuanqing Cai , Hongxin Hu , Yang Chen , Jiayu Li , Chaofan Zhang , Xuhui Yuan , Wenbo Li , Changyu Huang , Yiming Lin , Zeyu Zhang , Bin Yang , Zida Huang , Wenming Zhang , Xinyu Fang","doi":"10.1016/j.drup.2025.101295","DOIUrl":"10.1016/j.drup.2025.101295","url":null,"abstract":"<div><h3>Aims</h3><div>In chronic osteomyelitis, the cortical bone serves as the primary site for long-term persistence of <em>Staphylococcus aureus</em> (<em>S. aureus</em>), the present study aimed to explore the mechanisms of immune evasion and antibiotic resistance remain incompletely understood.</div></div><div><h3>Methods</h3><div>Clinical methicillin-resistant <em>S. aureus</em> (MRSA) isolates, were collected and analyzed. Panton-Valentine leukocidin (PVL) expression levels were quantified via real-time PCR. The impact of PVL on pyroptosis was evaluated by infecting osteocytes and measuring caspase-1 activation and IL-1β release. Osteoclastogenesis and pathological bone formation were examined through TRAP staining and micro-CT. To assess therapeutic potential, pyroptosis was pharmacologically induced using disodium 4,4’-dimethoxy-5,6,5’,6’-dimethylene dioxybiphenyl-2,2’-disulfonate (DMB), followed by evaluation of antibiotic efficacy and bone remodeling in osteomyelitis model.</div></div><div><h3>Results</h3><div>We observed in clinical cases that the survival rate of MRSA small colony variants (SCVs) in cortical bone is higher than that of non-SCV strains, with SCVs demonstrating characteristic antibiotic resistance through reduced metabolic activity. The PCR results demonstrated that compared to wild-type, MRSA SCVs exhibited significantly reduced expression levels of PVL, this low-PVL-expression phenotype markedly suppresses the activation of the pyroptosis pathway following infection. Furthermore, we discovered that during the adaptation to the intra-cortical environment, the global regulatory factor Sae and the protease aureolysin mediate the active downregulation of PVL, which resulted in targeted inhibition of osteocyte pyroptosis. The suppression of osteocyte pyroptosis simultaneously diminishes the host immune response, MRSA colonization, and antibiotics resistance. Pharmacological induction of pyroptosis via DMB significantly enhanced antibiotic efficacy, as well as alleviated pathological bone formation in chronic osteomyelitis.</div></div><div><h3>Conclusions</h3><div>MRSA modulates its own virulence factors to create a favorable space and environment for long-term survival within the cortical bone, and therapeutic strategies targeting osteocyte pyroptosis may represent a potential strategy of eradicating MRSA from cortical bone.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101295"},"PeriodicalIF":21.7,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145021104","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 : 2025-08-29DOI: 10.1016/j.drup.2025.101296
Sifen Wang , Chao Zhang , Sha Zhou , Shiliang Liu , Qiaoqiao Li , Xingyuan Cheng , Ruixi Wang , Baoqing Chen , Yue Li , Mian Xi
Resistance to chemoradiotherapy is a crucial factor limiting the efficacy of therapy and prognosis of esophageal cancer. It is necessary to elucidate the key genes and regulatory mechanisms responsible for therapeutic resistance in esophageal squamous cell carcinoma (ESCC). In this study, we found a relationship between ferroptosis and therapeutic sensitivity in ESCC and identified the ring finger protein 217 (RNF217) as a new regulator of ferroptosis associated with resistance to chemoradiotherapy in ESCC. Mechanistically, RNF217 interacts with kelch like ECH associated protein 1 (KEAP1) and promotes its ubiquitination and degradation, resulting in nuclear factor erythroid 2-related factor 2 (NRF2) evading KEAP1-mediated degradation and, consequently, enhanced NRF2 signaling and led to ferroptosis resistance. Furthermore, NRF2 facilitated the transcription of RNF217 by binding to antioxidant response elements in the RNF217 promoter upon irradiation. Overall, our findings indicate that the RNF217-KEAP1-NRF2 feedback loop is a previously unrecognized mechanism regulating resistance to chemoradiotherapy in ESCC and could be a target to overcome therapeutic resistance in ESCC.
{"title":"RNF217-KEAP1-NRF2 feedback loop confers therapeutic resistance by inhibiting ferroptosis in esophageal squamous cell carcinoma","authors":"Sifen Wang , Chao Zhang , Sha Zhou , Shiliang Liu , Qiaoqiao Li , Xingyuan Cheng , Ruixi Wang , Baoqing Chen , Yue Li , Mian Xi","doi":"10.1016/j.drup.2025.101296","DOIUrl":"10.1016/j.drup.2025.101296","url":null,"abstract":"<div><div>Resistance to chemoradiotherapy is a crucial factor limiting the efficacy of therapy and prognosis of esophageal cancer. It is necessary to elucidate the key genes and regulatory mechanisms responsible for therapeutic resistance in esophageal squamous cell carcinoma (ESCC). In this study, we found a relationship between ferroptosis and therapeutic sensitivity in ESCC and identified the ring finger protein 217 (RNF217) as a new regulator of ferroptosis associated with resistance to chemoradiotherapy in ESCC. Mechanistically, RNF217 interacts with kelch like ECH associated protein 1 (KEAP1) and promotes its ubiquitination and degradation, resulting in nuclear factor erythroid 2-related factor 2 (NRF2) evading KEAP1-mediated degradation and, consequently, enhanced NRF2 signaling and led to ferroptosis resistance. Furthermore, NRF2 facilitated the transcription of RNF217 by binding to antioxidant response elements in the RNF217 promoter upon irradiation. Overall, our findings indicate that the RNF217-KEAP1-NRF2 feedback loop is a previously unrecognized mechanism regulating resistance to chemoradiotherapy in ESCC and could be a target to overcome therapeutic resistance in ESCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101296"},"PeriodicalIF":21.7,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988606","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 : 2025-08-20DOI: 10.1016/j.drup.2025.101294
Ling Li , Yangyang Feng , Jingbo Zhou , Fangyuan Shao , Yuzhong Peng , Sitian Zang , Josh Haipeng Lei , Heng Sun , Dongyang Tang , Shiqi Lin , Jinghong Chen , Hanghang Li , Xiangpeng Chu , Yunfeng Qiao , Xinyu Guo , Kakun Wu , Xiaoling Xu , Chu-Xia Deng
Multidrug resistance (MDR) is associated with increased proteasome activity, which facilitates the clearance of damaged proteins and reduced mitochondrial activity, which contributes to quiescence. However, the mechanistic link between protein damage, mitochondrial dysfunction, and proteasome activity remains elusive. Here, we demonstrate that chemical drugs bind to newly synthesized mitochondrial proteins, which are largely unfolded and are coimported into the mitochondrion before appearing in the lysosome and/or nucleus. This triggers a mitochondrion-lysosome–mediated chain reaction, including the integrity stress response (ISR) and the mitochondrial unfolded protein response (UPRmt), followed by increased lysosome biogenesis and PINK1–Parkin independent but ROS–BNIP3–mediated mitophagy. We further observed that proteasomes are the main controller of the mitochondrion-lysosome reaction by monitoring proteostasis, suppressing mitochondrial protein import and promoting mitophagy under both normal and drug-treated conditions. The combination of chemical drugs and the proteasome inhibitor bortezomib (BTZ) triggered excessive mitochondrial import of damaged proteins, overwhelming mitochondrial capacity, causing mitochondrial membrane damage, profound mitochondrial ROS production, lysosome membrane permeabilization, impaired mitophagy, and proteostasis stress-induced cell death.
{"title":"Proteasomes suppress anticancer drug-induced cytotoxicity by inhibiting mitochondrial protein import and promoting ROS-BNIP3-mediated mitophagy","authors":"Ling Li , Yangyang Feng , Jingbo Zhou , Fangyuan Shao , Yuzhong Peng , Sitian Zang , Josh Haipeng Lei , Heng Sun , Dongyang Tang , Shiqi Lin , Jinghong Chen , Hanghang Li , Xiangpeng Chu , Yunfeng Qiao , Xinyu Guo , Kakun Wu , Xiaoling Xu , Chu-Xia Deng","doi":"10.1016/j.drup.2025.101294","DOIUrl":"10.1016/j.drup.2025.101294","url":null,"abstract":"<div><div>Multidrug resistance (MDR) is associated with increased proteasome activity, which facilitates the clearance of damaged proteins and reduced mitochondrial activity, which contributes to quiescence. However, the mechanistic link between protein damage, mitochondrial dysfunction, and proteasome activity remains elusive. Here, we demonstrate that chemical drugs bind to newly synthesized mitochondrial proteins, which are largely unfolded and are coimported into the mitochondrion before appearing in the lysosome and/or nucleus. This triggers a mitochondrion-lysosome–mediated chain reaction, including the integrity stress response (ISR) and the mitochondrial unfolded protein response (UPR<sup>mt</sup>), followed by increased lysosome biogenesis and PINK1–Parkin independent but ROS–BNIP3–mediated mitophagy. We further observed that proteasomes are the main controller of the mitochondrion-lysosome reaction by monitoring proteostasis, suppressing mitochondrial protein import and promoting mitophagy under both normal and drug-treated conditions. The combination of chemical drugs and the proteasome inhibitor bortezomib (BTZ) triggered excessive mitochondrial import of damaged proteins, overwhelming mitochondrial capacity, causing mitochondrial membrane damage, profound mitochondrial ROS production, lysosome membrane permeabilization, impaired mitophagy, and proteostasis stress-induced cell death.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101294"},"PeriodicalIF":21.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898421","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 : 2025-08-18DOI: 10.1016/j.drup.2025.101293
Xiaofei Fan , Jiahao Liu , Shudong Xie , Hongpei Tan , Ze Mi , Pengpeng Zhang , Xiaoqian Ma , Qi Liang , Min Yang , Yingzi Ming , Pengfei Rong
Radiotherapy efficacy in cancer treatment is frequently compromised by tumor radioresistance, limited immune activation, and off-target toxicity. To address these challenges, we developed a multifunctional nanosystem (FPPF@HC), combining FePt-PEG-FA nanoparticles encapsulated in an HSA-CaP hybrid shell. This platform prolongs systemic circulation, effectively targets tumors via the enhanced permeability and retention effect, and facilitates active folate receptor-mediated uptake. In the acidic tumor microenvironment, the nanoparticles release FePt cores, triggering ferroptosis through Fe²⁺-mediated Fenton reactions, oxidative stress, lipid peroxidation, and subsequent tumor cell death. Concurrently, ferroptosis-induced immunogenic cell death enhances dendritic cell maturation and CD8⁺ effector T cell infiltration, remodeling the tumor immune microenvironment. In vitro and in vivo studies demonstrated significantly improved tumor suppression, radiosensitivity, and immune activation compared with radiotherapy alone. Comprehensive biosafety evaluations indicated minimal systemic toxicity. This nanosystem offers a promising strategy for overcoming radioresistance and improving clinical outcomes in cancer therapy.
{"title":"HSA-templated synergistic platform boosts radiotherapy via enhanced radiosensitization and ferroptosis induction","authors":"Xiaofei Fan , Jiahao Liu , Shudong Xie , Hongpei Tan , Ze Mi , Pengpeng Zhang , Xiaoqian Ma , Qi Liang , Min Yang , Yingzi Ming , Pengfei Rong","doi":"10.1016/j.drup.2025.101293","DOIUrl":"10.1016/j.drup.2025.101293","url":null,"abstract":"<div><div>Radiotherapy efficacy in cancer treatment is frequently compromised by tumor radioresistance, limited immune activation, and off-target toxicity. To address these challenges, we developed a multifunctional nanosystem (FPPF@HC), combining FePt-PEG-FA nanoparticles encapsulated in an HSA-CaP hybrid shell. This platform prolongs systemic circulation, effectively targets tumors via the enhanced permeability and retention effect, and facilitates active folate receptor-mediated uptake. In the acidic tumor microenvironment, the nanoparticles release FePt cores, triggering ferroptosis through Fe²⁺-mediated Fenton reactions, oxidative stress, lipid peroxidation, and subsequent tumor cell death. Concurrently, ferroptosis-induced immunogenic cell death enhances dendritic cell maturation and CD8⁺ effector T cell infiltration, remodeling the tumor immune microenvironment. In vitro and in vivo studies demonstrated significantly improved tumor suppression, radiosensitivity, and immune activation compared with radiotherapy alone. Comprehensive biosafety evaluations indicated minimal systemic toxicity. This nanosystem offers a promising strategy for overcoming radioresistance and improving clinical outcomes in cancer therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101293"},"PeriodicalIF":21.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144898422","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 : 2025-08-16DOI: 10.1016/j.drup.2025.101292
Chun Zhang , Yinhao Chen , Shuncang Zhu , Zuwei Wang , Hongyi Lin , Jinpeng Lu , Haoxiang Zhang , Yueyi Weng , Xiaoxiao Huang , Ge Li , Yongding Wu , Zhiyuan Li , Jianfei Hu , Chengke Xie , Jianlin Lai , Yifeng Tian , Chengyu Liao , Shi Chen
Aim
The persistently high mortality rate of pancreatic ductal adenocarcinoma (PDAC) is largely attributed to the acquired resistance to chemotherapy, particularly gemcitabine. This study aims to elucidate the underlying molecular mechanisms of gemcitabine resistance in PDAC, uncover additional pro-tumorigenic factors contributing to drug resistance, and develop more effective and safer targeted therapeutic strategies against this phenomenon.
Methods
Circular RNA (circRNA) sequencing was employed to identify differentially expressed circRNAs between chemo-sensitive and resistant tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) was utilized to uncover the RNA-binding proteins (RBPs) associated with circular RNA of alpha-1, 3-glucosyltransferase 8 (cALG8). Molecular biology techniques were applied to explore the biological functions and regulatory mechanisms of cALG8 in the context of gemcitabine resistance in PDAC. Single-cell sequencing was performed to reveal changes in the composition of tumor immune microenvironment of pancreatic cancer. Patient-Derived Organoid (PDO) and Patient-Derived Xenograft (PDX) were employed to further validate the molecular mechanisms. Finally, antisense oligonucleotides (ASOs) targeting cALG8 were developed for in vivo use, and their translational therapeutic potential was evaluated in mouse models.
Results
This study identified that cALG8, which is associated with alternative splicing, is highly expressed in gemcitabine-resistant PDAC cells. cALG8 regulates the alternative splicing complex, thereby promoting chemoresistance and immunosuppression in PDAC. Mechanistically, high level of cALG8 functions as a protein scaffold through its 34–85 nt and 109–160 nt regions, creating spatial conditions for CDC-like kinase 1 (CLK1) to phosphorylate serine/arginine-rich splicing factor 7 (SRSF7) at site 231S. This process facilitates the formation of the SRSF7-dependent ataxia-telangiectasia mutated (ATM) kinase variant, ATM203, enhancing the translational efficiency of ATM, and consequently promoting DNA damage repair and immune microenvironment remodeling in PDAC cells to counteract the effects of chemotherapeutic drugs. A cALG8-targeting ASO that disrupts the CLK1-SRSF7 interaction, when combined with gemcitabine and anti-programmed cell death protein (PD)-1 antibody, significantly reduced tumor burden in PDX model, validating its therapeutic translational value.
Conclusion
We demonstrated that the cALG8/CLK1/SRSF7 axis promotes ATM expression by enhancing the splicing of ATM203, thereby facilitating gemcitabine resistance and formation of an immunosuppressive microenvironment in PDAC. This insight aids in the development of drugs targeting chemotherapy resistance induced by DNA damage repair mechanisms in PDAC.
{"title":"Targeting CLK1/SRSF7 axis-dependent alternative splicing sensitizes pancreatic ductal adenocarcinoma to chemotherapy and immunotherapy","authors":"Chun Zhang , Yinhao Chen , Shuncang Zhu , Zuwei Wang , Hongyi Lin , Jinpeng Lu , Haoxiang Zhang , Yueyi Weng , Xiaoxiao Huang , Ge Li , Yongding Wu , Zhiyuan Li , Jianfei Hu , Chengke Xie , Jianlin Lai , Yifeng Tian , Chengyu Liao , Shi Chen","doi":"10.1016/j.drup.2025.101292","DOIUrl":"10.1016/j.drup.2025.101292","url":null,"abstract":"<div><h3>Aim</h3><div>The persistently high mortality rate of pancreatic ductal adenocarcinoma (PDAC) is largely attributed to the acquired resistance to chemotherapy, particularly gemcitabine. This study aims to elucidate the underlying molecular mechanisms of gemcitabine resistance in PDAC, uncover additional pro-tumorigenic factors contributing to drug resistance, and develop more effective and safer targeted therapeutic strategies against this phenomenon.</div></div><div><h3>Methods</h3><div>Circular RNA (circRNA) sequencing was employed to identify differentially expressed circRNAs between chemo-sensitive and resistant tumors. Liquid Chromatography-Mass Spectrometry (LC-MS) was utilized to uncover the RNA-binding proteins (RBPs) associated with circular RNA of alpha-1, 3-glucosyltransferase 8 (cALG8). Molecular biology techniques were applied to explore the biological functions and regulatory mechanisms of cALG8 in the context of gemcitabine resistance in PDAC. Single-cell sequencing was performed to reveal changes in the composition of tumor immune microenvironment of pancreatic cancer. Patient-Derived Organoid (PDO) and Patient-Derived Xenograft (PDX) were employed to further validate the molecular mechanisms. Finally, antisense oligonucleotides (ASOs) targeting cALG8 were developed for in vivo use, and their translational therapeutic potential was evaluated in mouse models.</div></div><div><h3>Results</h3><div>This study identified that cALG8, which is associated with alternative splicing, is highly expressed in gemcitabine-resistant PDAC cells. cALG8 regulates the alternative splicing complex, thereby promoting chemoresistance and immunosuppression in PDAC. Mechanistically, high level of cALG8 functions as a protein scaffold through its 34–85 nt and 109–160 nt regions, creating spatial conditions for CDC-like kinase 1 (CLK1) to phosphorylate serine/arginine-rich splicing factor 7 (SRSF7) at site 231S. This process facilitates the formation of the SRSF7-dependent ataxia-telangiectasia mutated (ATM) kinase variant, ATM203, enhancing the translational efficiency of ATM, and consequently promoting DNA damage repair and immune microenvironment remodeling in PDAC cells to counteract the effects of chemotherapeutic drugs. A cALG8-targeting ASO that disrupts the CLK1-SRSF7 interaction, when combined with gemcitabine and anti-programmed cell death protein (PD)-1 antibody, significantly reduced tumor burden in PDX model, validating its therapeutic translational value.</div></div><div><h3>Conclusion</h3><div>We demonstrated that the cALG8/CLK1/SRSF7 axis promotes ATM expression by enhancing the splicing of ATM203, thereby facilitating gemcitabine resistance and formation of an immunosuppressive microenvironment in PDAC. This insight aids in the development of drugs targeting chemotherapy resistance induced by DNA damage repair mechanisms in PDAC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101292"},"PeriodicalIF":21.7,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144866426","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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