Advanced Science
·
2024
·
IF 14.3
Weina Fan,Jian Huang,Fanglin Tian,Xin Hong,Kexin Zhu,Yuning Zhan,Xin Li,Xiangyu Wang,Xin Wang,Li Cai,Ying Xing
Alternative splicing (AS) generates protein diversity and is exploited by cancer cells to drive tumor progression and resistance to many cancer therapies, including chemotherapy. SNRPA is first identified as a spliceosome-related gene that potentially modulates resistance to platinum chemotherapy. Both the knockout or the knockdown of SNRPA via CRISPR/Cas9 and shRNA techniques can reverse the resistance of cisplatin-resistant lung adenocarcinoma (LUAD) cells to cisplatin. SNRPA overexpression enhanced the resistance of cisplatin-sensitive LUAD cells. Gene Ontology (GO) analysis reveals that SNRPA is associated with DNA damage repair. Depletion of SNRPA induced ERCC1 exon 8 skipping and reduced ERCC1–XPF complex formation, whereas SNRPA overexpression exerted the opposite effect. siRNAs targeting isoforms containing ERCC1 exon 8 [ERCC1-E8 (+)] reversed SNRPA-enhanced cisplatin resistance and DNA damage repair. Furthermore, the IGF2BP protein, an m 6 A reader, and the ELAVL1 protein, an RNA stabilizer recruited by IGF2BP1, are found to bind to the SNRPA mRNA. ELAVL1 promoted cisplatin resistance, DNA repair and ERCC1-E8 (+) expression in an SNRPA-dependent manner. In a mouse xenograft model, SNRPA- KO CRISPR enhanced the sensitivity of LUAD cells to cisplatin. Overall, this study illuminates the role of SNRPA in platinum-based drug resistance, thereby providing a novel avenue to potentially enhance chemosensitivity and improve the prognosis of patients with LUAD.
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JOURNAL OF CONTROLLED RELEASE
·
2025
·
IF 11.5
Zhi-Bin Zhou,Xue Bai,Zhi-Yong Zhou,Zi-Yue Lin,Bing Liao,Fei Gong,Mei-Qun Wang,Xu-Bo Chen,Yue-hui Liu,Hong-Ping Chen,Kai Xu
Hearing loss represents a common adverse effect following platinum-based chemotherapy regimens. The therapeutic management of inner ear diseases is significantly constrained by the blood-labyrinth barrier, which restricts the penetration of drug molecules into the endolymphatic, thereby limiting their therapeutic efficacy. Local drug delivery has emerged as a safe and effective method for the treatment of inner ear diseases. Nevertheless, the suboptimal retention duration of therapeutic agents within the middle ear substantially compromises drug delivery efficiency. To overcome this limitation, we designed and synthesized a methacrylate-gelatin microsphere (GH) conjugate polydopamine (PDA) layer (GH@PDA) with excellent adhesion ability. This engineered platform demonstrates rapid loading kinetics for bioactive molecules, enabling precise localized delivery of therapeutic payloads. Based on our findings that calcium overload and ROS accumulation are important mechanisms for cisplatin-induced hearing loss, we functionalized GH@PDA with both the nitric oxide (NO) precursor L-arginine and calmodulin-dependent kinase II inhibitor KN93 to construct the multifunctional composite GH@PDA@LK. In vivo imaging analyses revealed that the GH@PDA can prolong the retention of the middle ear and significantly increase the drug uptake concentration of the inner ear. Notably, intratympanic administration of GH@PDA@LK conferred robust protection against cisplatin-induced auditory threshold shifts and reduced outer hair cell loss in rat models. These findings collectively demonstrate that injectable GH@PDA microspheres constitute a clinically translatable platform for inner ear drug delivery. More importantly, our work establishes a novel mechanistically grounded therapeutic paradigm for preventing chemotherapy-induced ototoxicity through dual-pathway modulation of calcium signaling and oxidative stress.
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APOPTOSIS
·
2025
·
IF 8.1
Miao Jintian,Jiang Xinyan,Wang Siyun
Cisplatin resistance significantly hinders the efficacy of ovarian cancer treatment, presenting a major challenge in improving patient outcomes. This study identifies the m6A reader protein YTHDF1 as a key regulator of cisplatin resistance in ovarian cancer through its modulation of the FZD7/Wnt/β-catenin signaling pathway. Using cisplatin-resistant ovarian cancer cell lines (A2780/DDP and SKOV3/DDP), we observed elevated YTHDF1 expression, which positively correlated with tumor cell proliferation and migration. Silencing YTHDF1 reduced FZD7 expression, inhibited Wnt/β-catenin signaling, and restored cisplatin sensitivity both in vitro and in vivo. Mechanistic investigations revealed that YTHDF1 binds to m6A-modified FZD7 mRNA, enhancing its stability and translation. Functional studies in xenograft mouse models demonstrated that targeting YTHDF1 suppressed tumor growth and enhanced apoptosis in cisplatin-resistant ovarian cancer cells. These findings highlight the YTHDF1-FZD7 axis as a novel therapeutic target for overcoming cisplatin resistance, paving the way for improved treatment strategies in ovarian cancer.
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CHEMISTRY-A EUROPEAN JOURNAL
·
2025
·
IF 3.7
Fa Wang,Zhiyang Wang,Shuqi Huang,Jinrong Yang,Yu Chen,Hui Chao
Graphical A convenient strategy by synergistic delivering DNA and DNA photocleavage agents to tumor cells was developed for effective photodynamic immunotherapy under hypoxia. Plasmid DNAs intercalated with Ru(II) complexes were encapsulated in liposomes to create nano-photosensitizers. Upon light exposure, the ruthenium complex photo-cleavages DNA. The DNA fragments specifically stimulate the cGAS-STING pathway and induce immunogenic death. This study presents a convenient strategy for photodynamic immunotherapy against cisplatin-resistant tumor cells under hypoxia.
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高影响因子
MOLECULES
·
2025
·Vol. 30
·期 11
·2400
·
IF 4.6
Ming Yuan,Huai Wang,Mingjun Yu,Sen Yao,Risheng Yao
Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds,3mexhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound3mmarkedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that3mexhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that3mpossesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity.
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Translational Lung Cancer Research
·
2026
·Vol. 15
·期 9
·286
·
IF 3.4
Xinyu Wang,Dan Qin,Chunyu Yao,Xiang Ji,Chuankui Li,Tao Tao,Xinyu Chen,Qicai Li,Yifan Yang,Lixiang Li,Zuyi Wang,Xiaonan Zhang,Guowen Wang
Background The clinical application of traditional chemotherapy for treating patients with lung cancer is restricted by its poor targeting efficacy and severe systemic toxicity. In this study, we developed an acid-sensitive lipid-polymer nanocapsule (PTX/Pt@RGD) for the co-delivery of a redox-sensitive paclitaxel (PTX) prodrug and cisplatin (Pt), which can facilitate both tumor microenvironment-responsive drug release and active targeting. Methods The physicochemical properties of the nanocapsules were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The drug-loading efficiency and release profile were analyzed via high-performance liquid chromatography (HPLC). In vitro antitumor activity was evaluated with Cell Counting Kit-8 assay, Annexin V/propidium iodide (PI) double staining, and Transwell assay. The underlying mechanisms were explored via reactive oxygen species (ROS) detection to assess oxidative stress levels, JC-1 mitochondrial membrane potential assay to evaluate mitochondrial dysfunction, γ-H2AX immunofluorescence to quantify DNA double-strand breaks, and Western blot analysis to determine the expression of apoptosis-related proteins. Tumor-bearing mouse models were established to assess the in vivo targeting efficacy, therapeutic effect, and biosafety of PTX/Pt@RGD. Results PTX/Pt@RGD exhibited a regular spherical morphology with a particle size of 99.4 nm, a drug-loading efficiency of 2.60%, an encapsulation efficiency (EE) of 44.68%, and the ability for pH/redox dual-responsive drug release. In vitro , PTX/Pt@RGD induced apoptosis by promoting ROS generation, reducing mitochondrial membrane potential, causing DNA damage, and activating apoptotic proteins, resulting in a total apoptosis rate of 84.2% in the group treated with PTX/Pt@RGD. In vivo , arginine-glycine-aspartic acid (RGD) modification enhanced tumor-specific accumulation, effectively suppressing tumor growth and angiogenesis, and demonstrated a favorable safety profile. Conclusions PTX/Pt@RGD integrates active targeting with pH/redox dual-responsive release, achieving a high tumor-to-background ratio and efficacy comparable to that of the free PTX/cisplatin combination, together with reduced systemic toxicity and a favorable in vivo safety profile. Although the in vivo therapeutic benefit of RGD-mediated targeting warrants further investigation, our findings support the proactive evaluation of this combinatorial nanoplatform for lung cancer combination chemotherapy.
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高影响因子
Frontiers in Pharmacology
·
2025
·
IF 4.8
Xiaoli Deng,Chunjie Hu,Lin Li,Guixian Yang,Chikun Li,Wanxun Zhang,Guangyu Cheng
Background Lung cancer is a leading cause of cancer-related deaths, with cisplatin being a cornerstone of treatment. However, resistance to cisplatin presents a significant challenge. β-elemene, a natural compound, has demonstrated potential to reverse cisplatin resistance. LncRNA LINC00511 has been implicated in cisplatin resistance through its role in activating the PI3K/AKT/mTOR pathway, which supports tumor survival and proliferation. Purpose This study aims to investigate the mechanism by which β-elemene overcomes cisplatin resistance in lung cancer by regulating LINC00511. Methods Human lung adenocarcinoma cells (A549 and A549/DDP) were treated with β-elemene and cisplatin. Cell proliferation and apoptosis were assessed using CCK-8, EdU staining, and flow cytometry. LINC00511 expression was measured by qRT-PCR, and protein levels of PI3K, AKT, and mTOR were evaluated via Western blot. A xenograft model was used to confirm in vivo effects. Results β-elemene significantly enhanced cisplatin-induced apoptosis in A549/DDP cells, reduced LINC00511 expression, and inhibited the PI3K/AKT/mTOR pathway. LINC00511 knockdown further potentiated these effects, both in vitro and in vivo . Xenograft models confirmed the enhanced anti-tumor effects of the combination treatment. Conclusion β-elemene overcomes cisplatin resistance in lung cancer by downregulating LINC00511 and inhibiting the PI3K/AKT/mTOR pathway. These findings propose a promising therapeutic strategy for treating cisplatin-resistant lung cancer.
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JOURNAL OF MEDICINAL CHEMISTRY
·
2023
·
IF 7.3
Meng Wang,Guoxiu Cao,Junjie Zhou,Jinyuan Cai,Xianjie Ma,Zhikun Liu,Xiaochao Huang,Hengshan Wang
Developing multitarget platinum(IV) prodrugs is an important strategy to attenuate cisplatin (CDDP) resistance in tandem with reduced toxicity. Herein, six novel ligustrazine-derived chalcones-modified platinum(IV) complexes were synthesized and evaluated for their anti-proliferative activities. Among them, 16a displayed higher cytotoxicity toward the tested cancer cell lines and lower cytotoxicity toward the human normal cells than CDDP or the combined group. Mechanistic studies revealed that 16a efficiently induced DNA damage and initiated a mitochondria-dependent apoptosis pathway. Besides, 16a significantly triggered ferroptosis by down-regulating expression levels of nuclear factor erythroid 2-related factor 2, glutathione peroxidase 4, and solute carrier family 7 member 11. Further, 16a obtained superior in vivo anti-tumor efficiency than CDDP in CDDP-resistant pancreatic cancer xenograft models but showed no significant side effects. In summary, our study suggested that 16a acts via a different anti-cancer mechanistic pathway than CDDP and may therefore encompass a novel practical strategy for cancer treatment.
研究领域:
肿瘤学
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药理学
·
分子生物学
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ANTI-CANCER DRUGS
·
2023
·Vol. 34
·期 9
·1046
·
IF 2.3
Zhou Qidong,Wu Hao,Miao Fengze,Cao Yirui,Liang Lifei,Huang Jiahua,Qian Zhiyu
Cisplatin-based chemotherapy plays a vital role in the management of muscle-invasive bladder cancer (MIBC); however, off-tumor toxicity and resistance often lead to cancer recurrence and eventual treatment failure. The loss of function of the nucleotide excision repair gene excision repair cross-complementing rodent repair deficiency gene 2 ( ERCC2 ) in cancer cells correlates with sensitivity to cisplatin, while its overexpression causes cisplatin resistance. Small interfering RNA (siRNA) knockdown of ERCC2 combined with cisplatin treatment may improve therapeutic outcomes in patients with bladder cancer. Here, we aimed to develop macrophage-derived mimetic nanovesicles (MNVs) as a nanoplatform for the simultaneous delivery of cisplatin and ERCC2 siRNA for enhancing the efficacy of bladder cancer chemotherapy. The cellular uptake, gene down-regulation, tumor inhibition effects, and biosafety of the synthesized nanodrugs (MNV-Co) as a synergistic therapeutic strategy for MIBC were evaluated in vitro and in vivo . The results indicated high efficacy of MNV-Co against MIBC and low off-tumor toxicity. Furthermore, by down-regulating ERCC2 mRNA and protein levels, MNV-Co improved chemosensitivity, promoted cancer cell apoptosis, and effectively suppressed tumor growth. This study presents a potential approach for delivering cisplatin and ERCC2 siRNA concurrently to treat bladder cancer using a biomimetic nanosystem.
研究领域:
肿瘤学
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药学
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纳米技术
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分子生物学
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高影响因子
APOPTOSIS
·
2023
·
IF 7.2
Pei Lipeng,Zhao Feng,Zhang Yi
Epithelial ovarian cancer (EOC) is the leading cause of cancer death all over the world. USP43 functions as a tumor promoter in various malignant cancers. Nevertheless, the biological roles and mechanisms of USP43 in EOC remain unknown. In this study, USP43 was highly expressed in EOC tissues and cells, and high expression of USP43 were associated with a poor prognosis of EOC. USP43 overexpression promoted EOC cell proliferation, enhanced the ability of migration and invasion, decreased cisplatin sensitivity and inhibited apoptosis. Knockdown of USP43 in vitro effectively retarded above malignant progression of EOC. In vivo xenograft tumors, silencing USP43 slowed tumor growth and enhanced cisplatin sensitivity. Mechanistically, USP43 inhibited HDAC2 degradation and enhanced HDAC2 protein stability through its deubiquitylation function. USP43 diminished the sensitivity of EOC cells to cisplatin through activation of the Wnt/β-catenin signaling pathway mediated by HDAC2. Taken together, the data in this study revealed the functions of USP43 in proliferation, migration, invasion, chemoresistance of EOC cells, and the mechanism of HDAC2-mediated Wnt/β-catenin signaling pathway. Thus, USP43 might serve as a potential target for the control of ovarian cancer progression.
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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癌症研究
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Discover Nano
·
2026
·Vol. 21
·期 1
·415
·
IF 6.7
Long Lin,Zhang Yexi,Xiao Jun,Zang Jianhua
Purpose To fabricate hesperetin-loaded fucoidan-selenium (Hes/Fu-Se) nanoparticles (NPs) for alleviating cisplatin-induced acute kidney injury (AKI), overcoming hesperetin’s low solubility and bioavailability and boosting antioxidant and anti-inflammatory efficacy. Methods Hes/Fu-Se NPs were prepared by encapsulating hesperetin within fucoidan, and then functionalized selenium (Se) NPs. Nanoparticle physicochemical properties and antioxidant activity (FRAP, ABTS) were characterized. Cisplatin-stimulated HK-2 cells were used for in vitro detection of cell viability, apoptosis, ROS accumulation, mitochondrial function and cGAS-STING signaling. A cisplatin-induced AKI mouse model was adopted to test renal biochemical indexes, renal histopathology and renal injury-related protein expression. Results Synthesized Hes/Fu-Se NPs exhibited uniform particle size, superior aqueous solubility and potent antioxidant activity. In vitro, the NPs restored HK-2 cell viability, mitigated apoptosis and ROS overproduction, and inhibited DNA damage and cGAS-STING cascade activation. In vivo, Hes/Fu-Se markedly reduced serum BUN and CRE, alleviated renal histological lesions and inflammatory infiltration, and downregulated the expression of cGAS, STING, γH2AX and TNF-α in kidney tissues. Conclusions Hes/Fu-Se NPs relieve cisplatin-triggered AKI via amplified antioxidation, DNA damage restoration and cGAS-STING pathway suppression. This nanoformulation provides a promising nephroprotective strategy against chemotherapy-related renal toxicity for clinical translation. Graphical abstract
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MOLECULAR NUTRITION & FOOD RESEARCH
·
2026
·Vol. 70
·期 16
·e70582
·
IF 4.5
Xianjie Li,Zhaoming Liu,Yi Chen,Jieping Luo,Zi Xie,Yirui Yang,Ziqi Zhou,Lin Fu,Xiaoya Yang,Caixia Wu
Cisplatin-induced acute kidney injury (AKI) is a dose-limiting chemotherapy complication laking effective clinical interventions. This study investigated the protective mechanisms of proanthocyanidins (PACs), a promising food-derived polyphenol, against cisplatin-induced systemic toxicity in C57BL/6 mice. Multi-omics integration combining 16S rRNA sequencing and renal transcriptomics, was employed to identify microbial-metabolic signaling nodes. Notably, 7-day PAC pretreatment (25 or 50 mg/kg/day) significantly alleviated renal dysfunction, normalized serum creatinine, blood urea nitrogen, reinforced renal antioxidant defenses, and suppressed kidney inflammation. Transcriptomic profiling revealed that cisplatin-induced renal damage was associated with the dysregulation of the cAMP signaling pathway, which was effectively reversed by PACs. Furthermore, 16S rRNA sequencing revealed that PACs restructured the gut microbiota by suppressing the pathogenic taxa ( Alistipes and CAG_485 ) and enriching beneficial taxa ( Muribaculaceae ). Integrated network analysis further linked these microbial shifts to the stabilization of renal cAMP signaling and redox homeostasis, suggesting a coordinated gut-kidney crosstalk. In conclusion, PACs function as a multifaceted food-derived adjuvant that potentially attenuates cisplatin-induced AKI, providing a molecular framework for gut-targeted nutritional intervention in chemotherapy-induced systemic toxicity.
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