DRUG DEVELOPMENT RESEARCH
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2021
·Vol. 83
·期 1
·64-74
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IF 4.36
Yang Yang,Tao Cheng,Peng Xie,Lishan Wang,Hong Chen,Zhangjun Cheng,Jiahua Zhou
To explore the biological activity of transmembrane prostateandrogen induced RNA (PMEPA1) in human pancreatic cancer (hPAC) cells and its drug sensitivity to gemcitabine (GEM) and cisplatin (DDP). Gene Expression Profiling Interactive Analysis (GEPIA) and Cancer Cell Line Encyclopedia (CCLE) were consulted to indicate the expression of PMEPA1 in hPAC tissues and cells. Quantitative real-time PCR (RT-qPCR) and western blot were performed to verify the indication. RT-qPCR and western blot also detected the expressions of PTEN/PI3K/AKT before and after transfection of PMEPA1 siRNA plasmids. Cell counting Kit-8 (CCK-8) and EdU staining were performed to examine cell proliferation before and after transfection of phosphatase and tensin homologue delet2ed on chromosome ten (PTEN) siRNA plasmids. Transwell and wound healing detected the invasion and migration of hPAC cells. The expressions of MMP-2 and MMP-9 were detected by western blot. After GEM or DDP treatment, cell viability was observed by commercial kits and cell apoptosis by flow cytometry. GEPIA and CCLE predicted increased expression of PMEPA1 in hPAC tissues and cells, which was confirmed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blot. PMEPA1 was also shown to be associated with disease-free survival. Transfection of PMEPA1 siRNA plasmids affected the expressions of PTEN/PI3K/AKT. PMEPA1 interference inhibited the proliferation, invasion and migration of hPAC cells. Furthermore, PMEPA1 interference also enhanced the sensitivity of hPAC cells to GEM and DDP via PTEN interference. PMEPA1 interference inhibits the proliferation, invasion and migration of pancreatic cancer cells and enhances the sensitivity to GEM and cisplatin by activating PTEN/PI3K/AKT signaling.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2023
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IF 6.7
Changjun Zhang,Yi Lu,Jingqi Zhang,Anjie Zang,Jinhui Ren,Zhiyuan Zheng,Miaoliang Fan,Yuanyuan Xie
Recent advances in understanding the role of iron and ROS in cell death suggest new therapeutic avenues to treat organ damage including acute kidney injury (AKI). Inhibiting ferroptosis was expected to have great potential for the treatment of this disease. Ferroptosis is characterized by iron-dependent lipid peroxidation and currently, a majority of reported ferroptosis inhibitors belong to either radical-trapping antioxidants or iron chelators . However, clinically used iron chelators such as deferoxamine and deferiprone have limited efficacy against ferroptosis (generally with EC 50 > 100 μM), despite their proven safety. Herein, we present the rational design of novel ferroptosis inhibitors by incorporating the naturally occurring cinnamic acid scaffold and the 3-hydroxypyridin-4(1 H )-one iron-chelating pharmacophore . Through ABTS ˙ + radical-scavenging assay, oxygen radical absorbance capacity (ORAC) measurement, Fe 3+ affinity evaluation, and anti-erastin-induced HT22 cell ferroptosis assays, we identified compound 9c as the most prospective ferroptosis inhibitor (ABTS ˙ + , IC 50 = 4.35 ± 0.05 μM; ORCA = 23.79 ± 0.56 TE; pFe 3+ = 18.59; EC 50 = 14.89 ± 0.08 μM, respectively). Notably, 9c dose-dependently alleviated cell death in cisplatin-induced AKI model. Our results provide insight into the development of new ferroptosis inhibitors through rational incorporation of pharmacophores from existing ferroptosis inhibitors, and compound 9c could be a promising lead compound worth further investigation.
研究领域:
药理学
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医学
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分子生物学
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ANALYTICAL LETTERS
·
2021
·
IF 2.329
Penghui Jin,Daoqing Ma,Yabiao Gao,Libin Wang,Zhihong Gao,Yating Zhang,Mingxin Liu,Jingying Xu,Jidong Wang
A highly sensitive and dual-directional fluorescent sensing system was developed to detect both cisplatin prodrug cross-linked hyaluronic acid (CPHA) hydrogel (quencher) and DNA (receptor) based on mercaptopropionic acid (MPA) capped CdTe quantum dots (QDs). Different from the previous work for this platinum compound, a multifunctional delivery system, CPHA hydrogel, which was used to address the challenges in drug resistance and severe side effects, was prepared and accurately detected based on the synthesis of the cisplatin prodrug and fluorescence quenching of CdTe QDs resulting from photo-induced electron transfer. When DNA was conjugated with Pt ions in a system composed of CdTe QDs and CPHA hydrogel, the fluorescence of the system was recovered for the determination of DNA. This reversible “turn off–on” strategy presented a high sensitivity and low detection for CPHA hydrogel from 10 to 50 nM with a detection limit of 1.50 nM and DNA from 0 to 75 nM with a detection limit of 0.60 nM. This approach provides a novel direction for further study of the Pt based drug-load with reduced side effects and improved therapy efficacy, effective screening of anticancer drugs, and accurate determination of DNA at low concentrations.
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PHARMACEUTICAL RESEARCH
·
2021
·Vol. 38
·期 12
·2091-2108
·
IF 4.2
Ding Ning,Zhao Zhiqing,Yin Na,Xu Ying,Yin Tian,Gou Jingxin,He Haibing,Wang Yanjiao,Zhang Yu,Tang Xing
Purpose The intention of the study was to co-delivery gemcitabine and cisplatin with totally different nature by prodrug and micelle strategy to improve its in vivo stability and antitumor effect. Methods A prodrug of gemcitabine (mPEG-PLG-GEM) was synthesized through the covalent conjugation between the primary amino group of gemcitabine and the carboxylic group of poly (L-glutamic acid)-g-methoxy poly (ethylene glycol) (mPEG-PLG). It was prepared into micelles by a solvent diffusion method, and then combined with cisplatin through chelation to prepare gemcitabine and cisplatin co-loaded mPEG-PLG micelles (mPEG-PLG-GEM@CDDP micelles) . Results Gemcitabine and cisplatin in each micelle group were released more slowly than in solutions. In addition, pharmacokinetics behaviors of them were improved after encapsulated in prodrug micelles. T 1/2z of gemcitabine and cisplatin encapsulated in micelles were prolonged to 6.357 h (mPEG-PLG-GEM), 10.490 h (mPEG-PLG@CDDP), 5.463 h and 12.540 h (mPEG-PLG-GEM@CDDP) compared with GEM@CDDP solutions (T 1/2z = 1.445 h and 7.740 h). The ratio of synergy between gemcitabine and cisplatin (3:1 ~ 1:1(n/n)) was guaranteed in the systemic circulation, thus improving its antitumor effect. The results of biochemical analysis showed that GEM@CDDP-Sol was more toxic to kidneys and marrow compared with mPEG-PLG-GEM@CDDP micelles. Conclusions By prodrug strategy, gemcitabine and cisplatin with totally different nature were prepared into micelles and obtained a better pharmacokinetic behavior. And the dual drug delivery system performed a better in vivo stability and antitumor effect compared with each single drug delivery system in the experiment. Graphical abstract
Scheme. Schematic of mPEG-PLG-GEM@CDDP micelles’ formation and action process.
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Bioengineered
·
2021
·
IF 3.269
Haixia Liu,Mei Song,Xiaoyan Sun,Xin Zhang,Huayan Miao,Yankui Wang
Cervical cancer (CC) is the fourth most common cancers among women worldwide. T-box transcription factor 1 (TBX1), a member of the T-box family, has anti-tumor effects in some types of cancer, but its role in CC is yet unknown. The aim of this study is to investigate the functions and underlying mechanisms of TBX1 in CC. Online database UALCAN showed that TBX1 was down-regulated in CC tissues compared with normal tissues and patients with lower TBX1 expression level had a poor prognosis. TBX1 overexpression significantly decreased the proliferation, migration, and invasion of Hela and SiHa cells. Conversely, cell apoptosis and chemosensitivity to cisplatin were promoted in TBX1-overexpressing CC cells. Moreover, up-regulation of TBX1 inhibited both AKT and MAPK signaling pathways. Furthermore, dual luciferase report assay indicated that TBX1 could directly bind to miR-6727-5p. In addition, TBX1 expression was inhibited by miR-6727-5p mimic and up-regulated by miR-6727-5p inhibitor. Knockdown of TBX1 reversed the inhibitory effect of the miR-6727-5p inhibitor on CC cells. This study demonstrates that TBX1, a target gene of miR-6727-5p, acts as a tumor suppressor in CC, indicating that TBX1 may be a new target for CC therapy.
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RSC Advances
·
2025
·Vol. 15
·期 29
·23966
·
IF 4.6
Yi Liu,Zheng Zhang,Huyang Du,Xiangjun Chen,Nan Hu,Tingting Yu,Meili Hou,Xiaolin Yu
Chemoresistance poses a critical challenge in cancer therapy across diverse tumor types, including non-small cell lung cancer (NSCLC), where chemotherapy-induced neuroendocrine differentiation (NED) of tumor cells plays a pivotal role in acquiring treatment resistance. This process significantly reduces chemotherapy efficacy, accelerates tumor progression, and ultimately worsens patient survival outcomes. The complex mechanisms underlying chemoresistance involve multiple factors, including enhanced DNA repair pathways, increased drug efflux capacity, and alterations in gene expression. Additionally, the tumor microenvironment, a dynamic ecosystem surrounding cancer cells, fosters a protective niche that exacerbates chemotherapy resistance. To address this challenge, we propose an innovative nanocomposite hydrogel system for the co-delivery of cisplatin and short hairpin RNA (shRNA) targeting protein arginine methyltransferase 5 (PRMT5), a key gene implicated in drug resistance. This system utilizes polyethyleneimine-modified mesoporous silica nanoparticles, which serve as nanocarriers, encapsulating cisplatin within the mesopores and coating the surface with methacryloylated hyaluronic acid (HA-MA). The design enables tumor microenvironment-responsive drug release, triggered by hyaluronidase enzymes abundant within the tumor, resulting in nanoparticle disassembly and the release of cisplatin. Simultaneously, the delivery of shRNA silences PRMT5 expression, enhancing chemosensitivity. By integrating targeted gene therapy with chemotherapy, this system offers a promising strategy for overcoming chemoresistance in NSCLC. Targeting both cancer cells and their microenvironment, this approach holds potential to transform the treatment of chemotherapy-resistant cancers, advancing more effective and personalized oncological therapies. An enzyme-responsive hydrogel to co-deliver cisplatin and shRNA, targeting NED-driven chemoresistance in NSCLC.
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JOURNAL OF NANOPARTICLE RESEARCH
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2026
·Vol. 28
·期 9
·221
·
IF 3.5
Li Rongye,Zhu Congying,Song Xiaoping,Zhang Xiaodong,Hamdi Marwa,Chen Jiahong
Recent advances in polymeric nanocarriers have highlighted the potential of amphiphilic block copolymers for the simultaneous delivery of chemotherapeutic agents with different physicochemical properties. In this study, asymmetric poly(ethylene glycol)-b-polylactide-b-poly(ethylene glycol) (PEG- b -PLA- b -PEG) triblock copolymers were synthesized via ring-opening polymerization, end-group functionalization, and click coupling, and subsequently evaluated as biodegradable nanocarriers for the co-delivery of paclitaxel (PTX) and cisplatin (CDDP). The copolymers were characterized by 1 H nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC). Self-assembly in aqueous media yielded spherical micelles with uniform size distributions, as confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The micelles exhibited efficient encapsulation of PTX and CDDP with high drug-loading capacities and encapsulation efficiencies. Hydrolytic degradation studies conducted at 37 °C for 45 days revealed progressive cleavage of the ester bond, reduction in molecular weight, and gradual disintegration of the micellar structure. In vitro release studies of single- and dual-drug-loaded micelles demonstrated sustained release of both drugs over time. Analysis of the release data using the Korsmeyer–Peppas model provided insight into the release behavior and suggested contributions from both diffusion and polymer degradation processes. The biocompatibility of the unloaded triblock copolymer micelles was assessed through cytocompatibility, hemocompatibility, and zebrafish embryo assays, which indicated low intrinsic toxicity and minimal hemolytic activity. Collectively, these results demonstrate that PEG- b -PLA- b -PEG triblock copolymer micelles can be recognized as biodegradable carriers capable of dual-drug encapsulation and sustained release, providing a useful platform for further investigation of combination drug delivery systems. Graphical abstract Asymmetric PEG- b -PLA- b -PEG triblock copolymers were synthesized and self-assembled into uniform micelles capable of co-encapsulating Paclitaxel and Cisplatin. The micellar architecture provided controlled degradation and synchronized dual-drug release over 45 days. The combination of tunable structure, sustained release, and excellent biocompatibility highlights these triblock copolymer micelles as efficient nanocarriers for combinational cancer therapy
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Frontiers in Pharmacology
·
2025
·
IF 4.8
Wenxin Zhang,Hongbo Teng,Tianyi Zhao,Roberts I. Eglitis,Xv Wang,Zhengxuan Yu,Shurong Qu,Haijing Wang,Yaru Zhao,Bowen Fan,Shuangli Liu,Yan Zhao
Introduction: Cisplatin is extensively employed in the treatment of multiple solid malignant tumors. Nevertheless, side effects such as cisplatin-induced ototoxicity (CIO) pose obstacles to tumor therapy.The important natural product chiisanoside from Acanthopanax sessiliflorus has abundant activity against CIO.Methods: In this study, 26 chiisanoside derivatives were screened, and compound 19 demonstrated significant protective activity against CIO damage. A cisplatin—induced HEI—OC1 cell injury model and a mouse ototoxicity model were established. The regulatory effects were revealed through transcriptome sequencing, and the protein expression levels were analyzed by molecular docking, ELISA, Western blotting, and immunofluorescence.Results: It was found that compound 19 inhibited cell apoptosis, alleviated abnormal hearing and spiral ganglion damage. Transcriptome sequencing revealed its regulatory effects. Compound 19 treatment increased autophagy levels, thereby alleviating mitochondrial dysfunction and reducing the accumulation of reactive oxygen species (ROS).In-depth studies have found that the autophagy inhibitor 3-methyladenine (3-MA) weakens the regulatory effect of compound 19 on autophagy and inhibits the clearance of damaged cells, resulting in oxidative stress damage, apoptosis and necrosis. By knocking down LRP6, it was found that the protective effect of compound 19 was eliminated, the autophagy level was significantly reduced, oxidative stress and ROS production were induced, and apoptosis after cisplatin exposure was promoted. Finally, the inhibitor LiCl was used to suppress the expression of GSK3β. It was found that inhibiting GSK3β could protect cells from cisplatin-induced damage by activating autophagy.Discussion: These findings suggest that compound 19 is capable of preventing ototoxicity by activating autophagy via the LRP6/GSK3β axis and consequently inhibiting oxidative stress, offering a new approach for treating CIO and sensorineural hearing loss.
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Journal of Ovarian Research
·
2024
·Vol. 17
·期 1
·1-17
·
IF 3.8
Sui Xue,Gao Bingqing,Zhang Liu,Wang Yanmin,Ma Junnan,Wu Xingchen,Zhou Chenyu,Liu Min,Zhang Lin
Background Cisplatin (DDP) is one of the most effective anticancer drugs, commonly used to treat advanced ovarian cancer (OC). However, DDP has significant limitations of platinum-based drugs, including chemical resistance and high-dose toxic side effects. Traditional Chinese medicines (TCMs) often presented in the form of formula, in which the herb pair was the basic unit. Scutellaria barbata D.Don and Hedyotis diffusa Willd (SB-HD) are famous TCMs herb pair that have been shown to help treat multiple types of cancers. However, the synergistic effects and mechanism of combination of SB-HD and DDP to enhance DDP chemosensitivity in OC are still unknown.Results In vitro, we found that the optimal proportion of SB-HD to inhibit the proliferation of OC cells was 2:1, SB-HD and DDP were shown to synergistically reduce the viability of OC cells, inhibit the colony formation, promote cell cycle arrest and apoptosis, as well as inhibit cell migration and invasion. In vivo, combination treatment significantly inhibited the growth of subcutaneous tumors in BALB/c nude mice and reduced the toxic side effects of DDP. Mechanistically, SB-HD and DDP combination treatment significantly promoted oxidative stress response, decreased MMP, inhibited ATP production, decreased ROS levels and increased SOD activity, increased the expression of NRF2, HO-1, ATG5 and LC3, decreased the expression of p62 and FTH1 both in OC cells and tumor tissue of mice. Inhibitor 3-MA (Methyladenine, autophagy inhibitor) and Fer-1 (Ferrostatin-1, iron ion inhibitor) can effectively reverse the expression changes of the key target proteins, but not ZnPP (Zinc protoporphyrin, HO-1 inhibitor). Through bioinformatics analysis, it was found that the abnormal expression level of NRF2 and FTH1 mRNA has a high prognostic value, at the same time, the other four key proteins respectively or interacting with NRF2 and FTH1, also play important roles in the occurrence and development of OC.Conclusion Our findings uncover a synergistic effect of SB-HD and DDP against OC through modulating oxidative stress via NRF2-FTH1 autophagic degradation pathway, which may provide an important theoretical foundation for the use of SB-HD and a new strategy for enhancing DDP chemosensitivity as well as reducing toxic side effects.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Jie Li,Xiaolong Lian,Baojian Li,Quhuan Ma,Lingling Yang,Guangmiao Gao,Tingmei Yin,Xiaoyan Fu,Yi Deng,Zhijun Yang,Xiujuan Yang
Ethnopharmacological relevance Cisplatin (CP), a widely used antineoplastic agent, is a leading cause of drug-induced liver injury (DILI) due to its hepatotoxic effects. Licorice (GC), an established remedy in traditional Chinese medicine (TCM), has shown promise in addressing liver diseases and DILI. Nonetheless, the specific active components and underlying mechanisms of GC in mitigating CP-induced liver injury remain inadequately investigated. Aim of the study This study examined the active components and efficacy of GC in addressing CP-induced hepatotoxicity, focusing on its mechanisms related to bile acid metabolism and gut microbiota regulation. Materials and methods Utilizing a CP-induced rat liver injury model, this study evaluated changes in liver coefficient, liver function indices, and pathological morphology while assessing the efficacy of GC for both prevention and treatment of CP-induced liver injury. Subsequently, UPLC-Q-TOF-MS qualitatively analyzed GC's blood-entering components, elucidating its pharmacodynamic material basis. Network pharmacology analysis identified potential pathways and targets of GC's blood components in relation to CP-induced liver injury. Furthermore, metabolomics and 16S rRNA sequencing were employed to clarify the pharmacodynamic mechanisms of GC in modulating bile acid metabolism and gut microbiota, offering insights into its preventive and therapeutic roles. Results The pharmacodynamic results revealed that GC significantly reduced liver function biomarkers and improved pathological changes in liver tissue. UPLC-Q-TOF-MS analysis identified 16 blood-entering components as potential pharmacodynamic agents of GC for preventing and treating CP-induced liver injury. Network pharmacology analysis suggested a link between GC's efficacy and the bile acid metabolic pathway. Furthermore, metabolomics analysis, immunoblotting, and 16S rRNA sequencing demonstrated that GC regulated bile acid metabolites in both liver and feces, enhanced FXR and BSEP expressions in the liver, and decreased CYP27A1 expression. Additionally, GC mitigated CP-induced intestinal dysbiosis by altering the abundance of gut microbiota. Conclusions UPLC-Q-TOF-MS performed a qualitative analysis of 16 blood-entering components linked to GC, providing a basis for further exploration of the pharmacodynamic material underpinning GC. The protective role of GC in CP-induced liver injury appears connected to enhanced bile acid metabolism and restoration of gut microbiota balance.
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Biomaterials Science
·
2019
·Vol. 7
·期 12
·5270-5282
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IF 5.251
Yuxin Wang,Diya Xie,Jiongru Pan,Chengwan Xia,Lei Fan,Yumei Pu,Qian Zhang,Yan hong Ni,Jianquan Wang,Qingang Hu
To ensure site–specific drug delivery/release in tumor cells and cancer-associated fibroblasts (CAFs) and reduce the systemic toxicity of chemotherapy, a novel drug delivery system called human serum albumin-indocyanine green-cisplatin nanoparticles (HSA-ICG-DDP NPs) was developed in our study. We characterized this system in vitro and in vivo and showed synergistic effects with photodynamic therapy (PDT), photothermal therapy (PTT) and chemotherapy; thereby it can significantly improve therapeutic efficacy compared with cancer monotherapy. High expression of secreted protein acidic and rich in cysteine (SPARC) in oral squamous cell cancer (OSCC) and CAFs was also confirmed in our study. Our study also found that the cellular uptake of HSA-ICG-DDP NPs in tumor cells and CAFs can be enhanced by SPARC-mediated endocytosis. Cisplatin (DDP) release from the NPs in the tumor site can be precisely triggered by the cleavage of the coordination bond of ICG-DDP via a near infrared (NIR)-induced photothermal effect of ICG. Treatment with HSA-ICG-DDP NPs induced generation of reactive oxygen species (ROS) and cytotoxicity in SPARC-highly expressed tumor and CAFs. On in vivo treatment, HSA-ICG-DDP NPs were accumulated within the tumor tissue, where they exhibited stronger antitumor effects, compared to treatment with ICG, HSA-ICG and DDP. Therefore, this novel NIR-triggered drug release system displays potential for the improvement of OSCC treatment through its synergistic effects of PTT/PDT and chemotherapy.
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Drug Design Development and Therapy
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2018
·
IF 2.935
Feng Yang,Aimei Li,Han Liu,Hairong Zhang
Purpose Gastric cancer is one of the most common human epithelial malignancies, and using nanoparticles (NPs) in the diagnosis and treatment of cancer has been extensively studied. The aim of this study was to develop hyaluronic acid (HA) containing lipid NPs coloaded with cisplatin (CDDP) and sorafenib (SRF) for the treatment of gastric cancer.Materials and methods HA and CDDP containing lipid prodrug was synthesized using polyethylene glycol (PEG) as a linker (HA-PEG-CDDP). HA-PEG-CDDP and SRF were entrapped into the lipid NPs by nanoprecipitation method (H-CS-NPs). The physicochemical and biochemical properties such as size, zeta potential, and drug release pattern were studied. In vitro viability was also evaluated with MKN28 and SGC7901 human gastric cancer cells. In vivo testing including biodistribution and accumulation in tumor tissue was applied in gastric tumor-bearing mice to confirm the inhibition of gastric cancer.Results H-CS-NP has a particle size of 173.2±5.9 nm, with a zeta potential of −21.5±3.2 mV. At day 21 of in vivo treatment, H-CS-NPs inhibited the tumor volume from 1,532.5±41.3 mm3 to 259.6±16.3 mm3 with no obvious body weight loss. In contrast, mice treated with free drugs had body weight loss from 20 to 15 g at the end of study.Conclusion The results indicate that H-CS-NPs enhanced the antitumor effect of drugs and reduced the systemic toxicity effects. It could be used as a promising nanomedicine for gastric cancer combination therapy.
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