Asian Journal of Pharmaceutical Sciences
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2021
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IF 6.598
Lu Yang,Jiaxi Xu,Zheng Xie,Faquan Song,Xin Wang,Rupei Tang
Carrier-free drug self-delivery systems consisting of amphiphilic drug-drug conjugate (ADDC) with well-defined structure and nanoscale features have drawn much attention in tumor drug delivery. Herein, we report a simple and effective strategy to prepare ADDC using derivatives of cisplatin (CP) and dasatinib (DAS), which further self-assembled to form reduction-responsive nanoparticles (CP-DDA NPs). DAS was modified with succinic anhydride and then connected with CP derivative by ester bonds. The size, micromorphology and in vitro drug release of CP-DDA NPs were characterized. The biocompatibility and bioactivity of these carrier-free nanoparticles were then investigated by HepG2 cells and H22-tumor bearing mice. In vitro and in vivo experiments proved that CP-DDA NPs had excellent anti-tumor activity and significantly reduced toxicities. This study provides a new strategy to design the carrier-free nanomedicine composed of CP and DAS for synergistic tumor treatment.
研究领域:
药学
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纳米技术
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肿瘤学
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PubMed
高影响因子
Journal of Zhejiang University-SCIENCE B
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2023
·Vol. 24
·期 3
·207-220
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IF 5.1
Yuan Meng,Wu Qian,Zhang Mingyang,Lai Minshan,Chen Wenbo,Yang Jianfeng,Jiang Li,Cao Ji
A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
研究领域:
肿瘤学
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药理学
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分子生物学
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癌症治疗
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PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2023
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IF 10.8
Xiaomei Liang,Yulu Yang,Chuanqing Huang,Zhibin Ye,Wujiang Lai,Jiamao Luo,Xiaoxuan Li,Xiao Yi,Jun-Bing Fan,Ying Wang,Yifeng Wang
Resistance to the chemotherapeutic agent cisplatin (DDP) is the primary reason for invalid chemotherapy of ovarian cancer. Given the complex mechanisms underlying chemo-resistance, the design of combination therapies based on blocking multiple mechanisms is a rationale to synergistically elevate therapeutic effect for effectively overcoming cancer chemo-resistance. Herein, we demonstrated a multifunctional nanoparticle ( [email protected] ), which could simultaneously co-deliver DDP and Olaparib (Ola, DNA damage repair inhibitor) using targeted ligand cRGD peptide modified with heparin (HR) as nanocarrier, enabling the concurrent tackling of multiple resistance mechanisms to effectively inhibit the growth and metastasis of DDP-resistant ovarian cancer. In combination strategy, heparin could suppress the function of multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) to promote the intracellular accumulation of DDP and Ola by specifically binding with heparanase (HPSE) to down-regulate PI3K/AKT/mTOR signaling pathway, and simultaneously served as a carrier combined with Ola to synergistically enhance the anti-proliferation ability of DDP for resistant ovarian cancer, thus achieving great therapeutic efficacy. Our [email protected] could provide a simple and multifunctional combination strategy to trigger an anticipated cascading effect, thus effectively overcoming the chemo-resistance of ovarian cancer.
研究领域:
药学科学
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癌症研究
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纳米技术
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药物递送系统
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PubMed
高影响因子
ONCOLOGY RESEARCH
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2025
·Vol. 34
·期 1
·26
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IF 4.1
Jianfa Wu,Huang Chen,Sihong Wang,Lei Peng,Xiaoying Hu,Zhou Liu
Objectives Ribosomal protein S6 kinase A2 (RPS6KA2) has been identified as a potential prognostic biomarker in several cancers, including breast cancer, glioblastoma, and prostate cancer. However, its functional significance in ovarian cancer is not well characterized. This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer, particularly in relation to cisplatin resistance. Methods The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR, immunofluorescence staining, immunohistochemistry, and western blotting. Prognostic associations were conducted using the Kaplan-Meier Plotter database. Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity. Ferroptosis-related parameters, including intracellular iron content, glutathione (GSH) levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential, were measured to determine ferroptotic changes. In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents. Results Using ovarian cancer cell lines and clinical tissue samples, we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts. Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance. Mechanistically, RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) signaling pathway, which in turn increased sensitivity to cisplatin. Additionally, RPS6KA2 facilitated ferroptosis, contributing to its tumor-suppressive function. miR-512-3p was identified as a negative regulator of RPS6KA2, driving cisplatin resistance through suppression of RPS6KA2 expression. In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models. Conclusion These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.
研究领域:
肿瘤学
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分子生物学
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药理学
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细胞生物学
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癌症研究
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PubMed
高影响因子
TOXICOLOGY LETTERS
·
2021
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IF 4.374
Xing Ma,Xiaowei Yu,Jialing Min,Xin Chen,Ren Liu,Xueqing Cui,Jing Cheng,Mingyong Xie,Patrick Diel,Xiaojuan Hu
Genistein (GEN) has been demonstrated to interfere with antitumor effects of cisplatin (CIS) in vitro . To analyze whether these findings are also relevant in vivo , we examined the effects of combined GEN and CIS treatment in an ovariectomized nude mouse breast cancer xenograft model. Tumor growth and markers for antitumor activity were determined after three weeks of treatment. Furthermore, the concentrations of GEN metabolites were measured in serum, liver, and xenograft tumor tissues using liquid chromatography-tandem mass spectrometry (LC–MS/MS). Three weeks’ oral exposure to GEN at a dose of 5 mg kg −1 ·d -1 resulted in an average concentration of total GEN metabolite equivalent as high as 0.2729 nmol g −1 wet weight in xenograft tumor tissues. At this dosage, GEN significantly antagonized the antitumor effects of CIS. Mechanistically, GEN blocked both the inhibition of cell proliferation and induction of apoptosis triggered by CIS. Moreover, GEN concentrations in xenograft tumor tissues were found to be significantly higher than in serum and liver. In conclusion, our findings suggested that oral GEN exposure at a level comparable to dietary exposure in humans could interfere with CIS chemotherapy.
研究领域:
肿瘤学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
NEW JOURNAL OF CHEMISTRY
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2019
·Vol. 43
·期 47
·18685-18694
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IF 3.069
Rui-Xue Liu,Ying-Shu Wu,Yan-Cheng Liu,Ru-Yi Luo,Li-Dong Yang,Meng-Ting Tang,Zhen-Feng Chen,Hong Liang
Based on the characteristic anthrahydrazone pharmacophore, two new anthrahydrazone derivatives (9-PMAH and APMAH) were synthesized, which further afforded two corresponding cisplatin-like Pt(II) complexes (9-PMAH-Pt and APMAH-Pt). Their chemical structures were characterized by IR, ESI-MS, elemental analysis and X-ray single crystal diffraction method. Their in vitro cytotoxicity towards a series of human tumor cell lines and the normal liver cell line HL-7702 were screened and shown in IC50 values and compared with that of cisplatin. 9-PMAH-Pt showed higher cytotoxicity against MGC-803 and HepG-2 than the other tested compounds including cisplatin, while it showed lower toxicity on HL-7702 than cisplatin. The structure–activity relationship from the in vitro cytotoxicity study indicated that the substitution of –CHO on the opposite C10 of anthrahydrazone was unfavorable to higher cytotoxicity, which might be due to its steric hindrance considering the planar aromatic anthracene. Further studies demonstrated that 9-PMAH-Pt induced cell apoptosis in both MGC-803 and T-24 cells by arresting the cell cycle at the G2/M phase, which was totally different for cisplatin, suggesting the different antitumor efficacies of this platinum complex and cisplatin. On the molecular level, it was suggested that 9-PMAH-Pt could bind with DNA via an intercalative mode, likely competing with GelRed in similar intercalative binding sites. 9-PMAH-Pt also effectively inhibited the activity of TOPO I, acting as a TOPO I suppressor. The results of this work suggest a new type of platinum complex bearing anthrahydrazone ligands to form a new bifunctional antitumor candidate in comparison with the classic platinum drugs.
研究领域:
药物化学
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肿瘤学
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分子生物学
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DOI
高影响因子
Cells
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2026
·Vol. 15
·期 18
·1657
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IF 6
Ting Li,Wenting Yu,Huanzhi Wan,Xuan Yu,Xi Lian,Ziqi Zhou,Shimin Zong,Hongjun Xiao
Cisplatin–induced ototoxicity is a significant clinical issue linked to ferroptosis and mitophagy dysfunction. This study investigated how mitophagy regulates ferroptosis in cisplatin–induced hearing loss using cultured primary rat cochlear marginal cells in vitro and a C57BL/6J mouse model of cisplatin–induced ototoxicity in vivo. Cisplatin suppressed the PTEN–induced putative kinase 1 (PINK1) pathway, impaired mitophagy, and triggered ferroptosis characterized by iron overload, lipid peroxidation, increased acyl–CoA synthetase long–chain family member 4 (ACSL4), and decreased glutathione peroxidase 4. Pharmacological activation of mitophagy or PINK1 overexpression alleviated ferroptosis in vitro, while deferoxamine treatment reduced cisplatin–induced hearing loss and blood–labyrinth barrier damage in vivo. Mechanistically, restoration of mitophagy was associated with increased mitochondrial targeting and reduced cytosolic accumulation of ACSL4, potentially through mitophagic clearance, thereby suppressing ferroptosis. These findings support a model in which impaired PINK1–associated mitophagy contributes to cytosolic ACSL4 accumulation and ferroptotic injury. Modulating mitophagy and ACSL4 subcellular distribution may represent a potential strategy for mitigating cisplatin–induced ototoxicity.
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高影响因子
Science Advances
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2026
·Vol. 12
·期 12
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IF 13.9
Yiyi Zhang,Huimin Wang,Hua Guo,Xiaorong Gou,Xinxin Hao,Jiayi Li,Hong Deng,Weiqi Zhang
Cisplatin’s (Cis’s) antitumor efficacy is limited by dose-dependent toxicity due to nonspecific tissue distribution. While targeted Cis delivery and combination therapies boost therapeutic efficacy, developing multifunctional yet simplified formulations remains challenging. Inspired by the Cis’s interaction with DNA, here, we transformed Cis into a reversible photothermal agent through the platinum-phosphate (Pt-phos) interaction within a hyaluronan (HA) nanogel (named as HA/PtP) to afford synergistic photothermal therapy (PTT) and chemotherapy. The HA/PtP nanogel exhibits near infrared absorption and 32.08% photothermal conversion efficiency, and degrades to release Cis through the reversible Pt-phos interaction under acidic conditions. Leveraging HA’s intrinsic CD44 targeting, HA/PtP nanogel simultaneously enables highly efficient PTT and targeted chemotherapy in 4T1 breast tumor xenografts. Moreover, HA/PtP-based PTT successfully mimics hyperthermic intraperitoneal chemotherapy (HIPEC) but with alleviated Cis toxicity in MC38 metastatic mouse model. This HA/PtP nanogel represents a rationally designed Cis nanomedicine integrating the PTT with self-targeting and facile preparation.
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高影响因子
npj Precision Oncology
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2025
·Vol. 9
·期 1
·1-21
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IF 8
Li Xiaoli,Wang Jiashuo,Guo Jiaxing,Zhang Ming
Cisplatin resistance is a major challenge in laryngeal cancer treatment. Tumor necrosis factor-alpha-induced protein 2 (TNFAIP2) has been implicated in chemoresistance, though its role in laryngeal cancer remains unclear. We identified TNFAIP2 as a key gene associated with cisplatin resistance and developed a second near-infrared (NIR-II) light-responsive CRISPR-Cas9 nanosystem (APC@RBCs) to target it. In cisplatin-resistant Tu177/CDDP cells, light-activated knockout of TNFAIP2 significantly increased cisplatin sensitivity (IC50 reduced from 12.55 to 4.37 µg/mL). Mechanistic studies revealed that TNFAIP2 modulates cisplatin resistance via the NRF2 pathway, affecting oxidative stress response and epithelial-mesenchymal transition. TNFAIP2 deletion also suppressed cancer cell migration and invasion. Our results establish TNFAIP2 as a critical mediator of chemoresistance and demonstrate the potential of APC@RBCs as a precise, non-invasive gene therapy platform. This strategy offers a promising approach to overcoming cisplatin resistance and improving treatment outcomes in laryngeal cancer patients.
研究领域:
肿瘤学
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分子生物学
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药理学
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纳米技术
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基因工程
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产品关联
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Wei Zhu,Sai Zhu,Shan Jiang,Jiuyu Yin,Yonggui Wu,Xiaomei Luo
Background Cisplatin (CIS), a widely administered chemotherapeutic agent, is associated with acute kidney injury (AKI). Lansoprazole (LPZ), commonly prescribed to mitigate chemotherapy-induced gastrointestinal complications, may further elevate AKI risk. Paeoniflorin (Pae), a bioactive compound derived from traditional Chinese medicine, demonstrates renal protective properties in AKI, yet its mechanism against CIS and LPZ induced AKI remains undefined. Methods A composite AKI model was established in vivo and in vitro using CIS and LPZ. The protective effect of Pae on the injury of renal tissue or renal tubular cells in mice was observed, followed by Pae pretreatment. The target of Pae was found through network pharmacology, and the binding ability of the target was verified by CETSA experiment and molecular docking. Finally, the target gene was knocked out or over expressed to verified whether Pae regulates necroptosis through this target. Results It was found that renal injury could be exacerbated by LPZ in the CIS induced AKI. Pae could alleviate CIS and LPZ induced AKI. The target gene of Pae was TNFAIP3, which played an important role in necroptosis. The TNFAIP3 could bind well to Pae in molecular docking and CETSA experiment. The necroptosis and inflammatory responses in AKI induced by CIS and LPZ could be also inhibited by Pae in vivo and in vitro. Overexpression of TNFAIP3 played the same cellular protective role as Pae preconditioning. In contrast, Pae could not continue to play a protective role after TNFAIP3 was knocked down. Conclusion The traditional Chinese medicine Pae holds promise as a potential therapeutic agent for AKI, with TNFAIP3 representing an effective therapeutic target in this pathology.
研究领域:
药理学
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分子生物学
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肾脏病学
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转化医学
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肿瘤学
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PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-21
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IF 10.6
Fei Yao,Cao Danping,Li Yanna,Wang Zhixiong,Dong Runyu,Zhu Menglin,Gao Peng,Wang Xiaoming,Cai Juan,Zuo Xueliang
Introduction Cisplatin-based chemotherapy is one of the fundamental therapeutic modalities for gastric cancer (GC). Chemoresistance to cisplatin is a great clinical challenge, and its underlying mechanisms remain poorly understood. Circular RNAs (circRNAs) are involved in the pathophysiology of multiple human malignancies. Methods High-throughput sequencing was performed to determine the differentially expressed profile of circRNA in GC tissues and cisplatin-resistant GC cells. Quantitative real-time polymerase chain reaction and Fluorescence in situ hybridization was utilized to confirm the dysregulation of circ_0008315 in GC tissues. To evaluate the prognostic significance of circ_0008315 in GC, we used Kaplan-Meier plot. The self-renewal ability of drug-resistant GC cell was verified through tumor sphere formation assay. GC organoids were constructed to simulate the tumor microenvironment and verified the function of circ_0008315 in cisplatin resistance of gastric cancer. In vivo evaluation was conducted using patient-derived xenograft models. Dual-luciferase reporter gene, RNA immunoprecipitation and miRNA pull-down assays were employed to investigate the molecular mechanisms of circ_0008315 in GC. Results We revealed that a novel circRNA hsa_circ_0008315 was upregulated in GC and cisplatin-resistant GC cells. Elevated circ_0008315 was also observed in cisplatin-resistant GC organoid model. High circ_0008315 expression predicted unfavorable survival outcome in GC patients. Downregulation of circ_0008315 expression inhibited proliferation, mobility, and epithelial-mesenchymal transition of GC cells in vitro and in vivo. Reducing circ_0008315 expression in cisplatin-resistant GC organoid model reversed cisplatin resistance. Mechanistically, circ_0008315 modulated the stem cell properties of GC through the miR-3666/CPEB4 signaling pathway, thereby promoting cisplatin resistance and GC malignant progression. Furthermore, we developed PLGA-PEG nanoparticles targeting circ_0008315, and the nanoparticles could effectively inhibit GC proliferation and cisplatin resistance. Conclusion Circ_0008315 exacerbates GC progression and cisplatin resistance, and can be used as a prognostic predictor. Circ_0008315 may function as a promising nanotherapeutic target for GC treatment. Graphical Abstract
研究领域:
肿瘤学
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分子生物学
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药理学
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纳米技术
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产品关联
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2025
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IF 5.6
Sichen Li,Difei Zhang,Yi Li,Jingjing Zhou,Jinghua Chen,Yan Zhang
Cisplatin (CDDP) as a first-line chemotherapy drug has long suffered drawbacks of severe side effects and poor pharmacokinetics. Thus, various nano-carriers of complex architectures and multi-step modifications have been developed to overcome these challenges, but a simple delivery system with integrated multi-functions is still in demand. Herein, we synthesized a new type of glyco-based triple hydrophilic block copolymers for the delivery of CDDP and thereof cancer therapy. The incorporated glucuronic acid part is complexed with CDDP with high entrapment efficiency, while providing pH-responsive release in the acidic tumor microenvironment. The galactose segment is implanted for liver-targeting effect, which can also significantly lower the side effects of CDDP. As a result, the CDDP-loaded nanoparticle PGG2/Pt showed selectively faster endocytosis rates into HepG2 cells in vitro, with the calculated IC 50 value even comparable to that of free CDDP. The in vivo experiments on a HepG2-bearing mouse model, PGG2/Pt showed excellent anti-tumor activity and enhanced drug accumulation on tumor, together with much lowered nephrotoxicity, hepatotoxicity, and splenic toxicity. This work provides a new strategy for CDDP delivery with higher loading efficiency as well as biosafety.
研究领域:
药剂学
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肿瘤学
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生物材料学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）