JOURNAL OF MEDICINAL CHEMISTRY
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2024
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IF 6.8
Ying-Da Zang,Hai-Jie Wu,Xin-Yi Chen,Zhi-Ling Ma,Chuang-Jun Li,Jie Ma,Xiao-Guang Chen,Li Sheng,Sen Zhang,Dong-Ming Zhang
Cisplatin is a widely used drug for the clinical treatment of tumors. However, nephrotoxicity limits its widespread use. A series of compounds including eight analogs (G3-G10) and 40 simplifiers (G11-G50) were synthesized based on the total synthesis of Psiguamer A and B, which were novel meroterpenoids with unusual skeletons from the leaves of Psidium guajava. Among these compounds, (d)-G8 showed the strongest protective effect on cisplatin-induced acute kidney injury (AKI) in vitro and vivo, and slightly enhanced the antitumor efficacy of cisplatin. A mechanistic study showed that (d)-G8 promoted the efflux of cisplatin via upregulating the copper transporting efflux proteins ATP7A and ATP7B. It enhanced autophagy through the activation of the adenosine monophosphate–activated protein kinase (AMPK) signaling pathway. (d)-G8 showed no acute toxicity or apparent pathological damage in the healthy mice at a single dose of 1 g/kg. This study provides a promising lead against cisplatin-induced AKI.
研究领域:
药理学
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药物化学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2024
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IF 10.5
Borui Zhao,Xuan Qin,Rui Fu,Maosen Yang,Xin Hu,Shaorong Zhao,Yange Cui,Qingxiang Guo,Wei Zhou
Chemoresistance to cisplatin remains a significant challenge affecting the prognosis of advanced oral squamous cell carcinoma (OSCC). However, the specific biomarkers and underlying mechanisms responsible for cisplatin resistance remain elusive. Through comprehensive bioinformatic analyses, we identified a potential biomarker, BCL2 associated athanogene-1 (BAG1), showing elevated expression in head and neck squamous cell carcinoma (HNSCC). Since OSCC represents the primary pathological type of HNSCC, we investigated BAG1 expression in human tumor tissues and cisplatin resistant OSCC cell lines, revealing that silencing BAG1 induced apoptosis in cisplatin-resistant cells both in vitro and in vivo . This effect led to impaired cell viability of cisplatin resistant OSCC cells and indicated a positive correlation between BAG1 expression and the G1/S transition during cell proliferation. Based on these insights, the administration of a CDK4/6 inhibitor in combination with cisplatin effectively overcame cisplatin resistance in OSCC through the CDK4/6-BAG1 axis. Additionally, to enable simultaneous drug delivery and enhance synergistic antitumor efficacy, we developed a novel supramolecular nanodrug LEE011-FFERGD/CDDP, which was validated in an OSCC orthotopic mouse model. In summary, our study highlights the potential of a combined administration of CDK4/6 inhibitor and cisplatin as a promising therapeutic regimen for treating advanced or cisplatin resistant OSCC.
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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DOI
PubMed
高影响因子
PHYTOTHERAPY RESEARCH
·
2024
·Vol. 38
·期 4
·2077-2093
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IF 6.1
Ziwei Yuan,Xuejia Yang,Zujian Hu,Yuanyuan Gao,Mengsi Wang,Lili Xie,Hengyue Zhu,Chaosheng Chen,Hong Lu,Yongheng Bai
Cisplatin-induced kidney injury (CKI) is a common complication of chemotherapy. Fraxetin, derived from Fraxinus bungeana A. DC . bark, has antioxidant, anti-inflammatory, and anti-fibrotic effects. This study aims to investigate fraxetin's effects on CKI and its underlying mechanism in vivo and in vitro. Tubular epithelial cells (TECs) and mice were exposed to cisplatin with and without fraxetin preconditioning assess fraxetin's role in CKI. TECs autophagy was observed using transmission electron microscopy. Apoptosis levels in animal tissues were measured using TUNEL staining. The protective mechanism of fraxetin was explored through pharmacological and genetic regulation of mTORC1. Molecular docking was used to identify potential binding sites between fraxetin and mTORC1. The results indicated that fraxetin pretreatment reduced cisplatin-induced kidney injury in a time- and concentration-dependent way. Fraxetin also decreased autophagy in TECs, as observed through electron microscopy. Tissue staining confirmed that fraxetin pretreatment significantly reduced cisplatin-induced apoptosis. Inhibition of mTORC1 using rapamycin or siRNA reversed the protective effects of fraxetin on apoptosis and autophagy in cisplatin-treated TECs, while activation of mTORC1 enhanced fraxetin's protective effect. Molecular docking analysis revealed that fraxetin can bind to HEAT-repeats binding site on mTORC1 protein. In summary, fraxetin pretreatment alleviates CKI by antagonizing autophagy and apoptosis via mTORC1 activation. This provides evidence for the potential therapeutic application of fraxetin in CKI.
研究领域:
药理学
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肾病学
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细胞生物学
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分子生物学
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DOI
PubMed
高影响因子
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2024
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IF 2.5
Yuan Ning,Ping Chen,Zhengnan Shen,Xing Liu,Huan Gu
Cisplatin (CDDP) is commonly used as an anticancer drug in clinical practice, but severe nephrotoxicity restricts it from exerting anticancer effects. Natural drugs, such as resveratrol, can alleviate the side effects of cisplatin, but their low solubility and gastrointestinal effects prevent them from working. Herein, we developed nanoparticles for kidney injury consisting of a biocompatible material, zein, as a carrier. HA-Zein/Res NPs were fabricated using low-molecular-weight hyaluronic acid coatings. This preparation is non-cytotoxic to renal tubular epithelial cells and can be used with confidence. Low-molecular-weight hyaluronic acid has inflammation-targeting properties and CDDP damage causes renal inflammation. Owing to this property of the low-molecular-weight hyaluronic acid coating, in vivo imaging experiments in mice demonstrated that the HA-Zein/Res NPs enabled more nanoparticles to accumulate in the renal sites affected by inflammation. Efficient resveratrol delivery alleviated kidney injury, and experiments demonstrated that HA-Zein/Res NPs could treat kidney injury while reducing the serum creatinine and urea nitrogen levels in mice. Collectively, these results indicated that this nanomaterial is a promising agent for reducing the clinical nephrotoxicity of cisplatin.
研究领域:
药学
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生物医学工程
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毒理学
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DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL SCIENCES
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2021
·
IF 3.534
Dianlong Jia,Feifei Wang,Yujiao Yang,Ping Hu,Hao Song,Yue Lu,Rui Wang,Guangyong Li,Renmin Liu,Jun Li,Fengjiao Yuan
Epidermal growth factor receptor (EGFR) is an efficient target for cancer therapy. In this study, a high-affinity EGFR-antagonistic affibody (Z EGFR ) molecule coupled with cisplatin-loaded PEGylated liposomes (LS-DDP) was applied to actively target EGFR + A431 tumor cells in vitro and in vivo . The LS-DDP coupled with Z EGFR (AS-DDP) had an average size of 140.01 ± 0.84 nm, low polydispersity, a zeta potential of -13.40 ± 0.8 mV, an acceptable encapsulation efficiency of 17.30 ± 1.35%, and released cisplatin in a slow-controlled manner. In vitro , AS-DDP demonstrated a higher amount of platinum intracellular uptake by A431 cells than LS-DDP. The IC50 value of AS-DDP (9.02 ± 1.55 μg/ml) was much lower than that of LS-DDP (16.44 ± 0.87 μg/ml), indicating that the anti-tumor effects of AS-DDP were remarkable due to the modification of Z EGFR . In vivo , the concentration of AS-DDP in the tumor site increased more than 1.76-fold, while an increase in apoptotic cells at 48 h compared to the LS-DDP was also observed, illustrating that AS-DDP possessed excellent tumor-targeting efficiency. As a result, the targeted nano-liposomes achieved greater tumor suppression. Therefore, selective targeting of LS-DDP coupled with Z EGFR enhanced the anti-tumor effects and appeared to be a promising strategy for the treatment of EGFR + tumors.
研究领域:
肿瘤学
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药学
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分子生物学
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药物递送系统
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癌症治疗
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2018
·
IF 3.862
Hongju Peng,Qi Huang,Hongcheng Yue,Yuan Li,Min Wu,Wei Liu,Guangpeng Zhang,Shaozhi Fu,Jianwen Zhang
Cisplatin-based chemo-radiotherapy (RT) is the most effective treatment in patients with loco-regionally advanced nasopharyngeal carcinoma (NPC). However, traditional chemotherapy drugs have low bioavailability and targeting ability, which reduce their antitumor effects. Therefore, we developed a chitosan/ cis -dichlorodiamineplatinum (CS/DDP) hydrogel-based drug delivery system for the in situ treatment of NPC in combination with RT, and investigated their synergistic antitumor efficacy and underlying mechanism of action. CS/DDP hydrogel remarkably prolonged the survival time (81 days) when combined with RT compared to the control group (P < 0.01). The main mechanism was likely the increase in cancer cell apoptosis (76.23 ± 1.13%, p < 0.01). Furthermore, the CS/DDP hydrogel in combination with RT also increased X-ray-induced DSBs and γ-H2AX foci, induced G2/M phase arrest, inhibited cell proliferation by blocking Ki-67, and decreased CD31+ micro-vessel density (MVD). These results underscore the therapeutic potential of the combination of CS/DDP hydrogel and RT for localized NPC.
研究领域:
肿瘤学
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药学
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放射肿瘤学
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DOI
PubMed
高影响因子
TRANSACTIONS OF NONFERROUS METALS SOCIETY OF CHINA
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2021
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IF 2.917
Jun-jie ZENG,Zhan-gui TANG,Jiao ZOU,Jin-gang YU
To improve five-year survival rate of oral squamous cell carcinoma (OSCC), the development of a novel composite material of black phosphorus nanosheets (BPNSs) and gold nanoparticles (AuNPs) for tumor treatment was carried out. The purpose of this study is to evaluate the cytostatic effects of BPNSs, AuNPs loaded with cisplatin (CDDP) on human tongue squamous cell carcinoma cells lines (SCC-9), and 7,12-dimethylbenz anthracene induced cheek squamous cell carcinoma was validated in golden hamsters animal models. The results showed that BPNSs could efficiently inhibit the metastasis and growth of OSCC compared with CDDP and AuNPs. And a combination composite of AuNPs–BPNSs loaded with CDDP could more effectively inhibit the metastasis and growth of OSCC, which might be due to the high drug-loading capacity, excellent photothermal properties and the combination of photodynamic and photothermal therapy of BPNSs and AuNPs, as well as the synergistic effects of AuNPs, BPNSs and CDDP.
研究领域:
纳米技术
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癌症研究
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光疗
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药学科学
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生物医学工程
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DOI
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
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IF 5.4
Meng-ya Zhang,Li-juan Ma,Ling Jiang,Li Gao,Xian Wang,Yue-bo Huang,Xiang-ming Qi,Yong-gui Wu,Xue-qi Liu
Ethnopharmacological relevance Paeonia lactiflora Pall has been used in Chinese Medicine for thousands of years, especially having anti-inflammatory, sedative, analgesic and other ethnic pharmacological effects. Moreover, Paeoniflorin is the main active ingredient of the Paeonia lactiflora Pall , and most are used in the treatment of inflammation-related autoimmune diseases. In recent years, studies have found that Paeoniflorin has a therapeutic effect on a variety of kidney diseases. Aim of the study Cisplatin (CIS) is limited in clinical use due to its serious side effects, such as renal toxicity, and there is no effective method for prevention. Paeoniflorin (Pae) is a natural polyphenol which has a protective effect against many kidney diseases. Therefore, our study is to explore the effect of Pae on CIS-induced AKI and the specific mechanism. Materials and methods Firstly, CIS induced acute renal injury model was constructed in vivo and in vitro , and Pae was continuously injected intraperitoneally three days in advance, and then Cr, BUN and renal tissue PAS staining were detected to comprehensively evaluate the protective effect of Pae on CIS-induced AKI. We then combined Network Pharmacology with RNA-seq to investigate potential targets and signaling pathways. Finally, affinity between Pae and core targets was detected by molecular docking, CESTA and SPR, and related indicators were detected in vitro and in vivo . Results In this study, we first found that Pae significantly alleviated CIS-AKI in vivo and in vitro . Through network pharmacological analysis, molecular docking, CESTA and SPR experiments, we found that the target of Pae was Heat Shock Protein 90 Alpha Family Class A Member 1 (Hsp90AA1) which performs a crucial function in the stability of many client proteins including Akt. RNA-seq found that the KEGG enriched pathway was PI3K-Akt pathway with the most associated with the protective effect of Pae which is consistent with Network Pharmacology. GO analysis showed that the main biological processes of Pae against CIS-AKI include cellular regulation of inflammation and apoptosis. Immunoprecipitation further showed that pretreatment with Pae promoted the Hsp90AA1-Akt protein-protein Interactions (PPIs). Thereby, Pae accelerates the Hsp90AA1-Akt complex formation and leads to a significant activate in Akt, which in turn reduces apoptosis and inflammation. In addition, when Hsp90AA1 was knocked down, the protective effect of Pae did not continue. Conclusion In summary, our study suggests that Pae attenuates cell apoptosis and inflammation in CIS-AKI by promoting Hsp90AA1-Akt PPIs. These data provide a scientific basis for the clinical search for drugs to prevent CIS–AKI.
研究领域:
药理学
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肾病学
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分子生物学
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民族药理学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2020
·Vol. 18
·期 1
·1-15
·
IF 6.518
Fu Ji-jun,Li Chu-wen,Liu Yang,Chen Ming-yue,Zhang Qiang,Yu Xi-yong,Wu Bo,Li Jie-xia,Du Ling-ran,Dang Yuan-ye,Wu Dan,Wei Min-yan,Lin Zhi-qiang,Lei Xue-ping
Backgrounds Surgical resection and adjunct chemotherapy or radio-therapy has been applied for the therapy of superficial malignant tumor in clinics. Whereas, there are still some problems limit its clinical use, such as severe pains and side effect. Thus, it is urgent need to develop effective, minimally invasive and low toxicity therapy stagey for superficial malignant tumor. Topical drug administration such as microneedle patches shows the advantages of reduced systemic toxicity and nimble application and, as a result, a great potential to treat superficial tumors. Methods In this study, microneedle (MN) patches were fabricated to deliver photosensitizer IR820 and chemotherapy agent cisplatin (CDDP) for synergistic chemo-photodynamic therapy against breast cancer. Results The MN could be completely inserted into the skin and the compounds carrying tips could be embedded within the target issue for locoregional cancer treatment. The photodynamic therapeutic effects can be precisely controlled and switched on and off on demand simply by adjusting laser. The used base material vinylpyrrolidone—vinyl acetate copolymer (PVPVA) is soluble in both ethanol and water, facilitating the load of both water-soluble and water-insoluble drugs. Conclusions Thus, the developed MN patch offers an effective, user-friendly, controllable and low-toxicity option for patients requiring long-term and repeated cancer treatments.
研究领域:
肿瘤学
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药学
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生物医学工程
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产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
·
2015
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IF 3.85
Shan Zong,Xue Wang,Yongping Yang,Wenbin Wu,Hongjun Li,Yue Ma,Wenhai Lin,Tingting Sun,Yubin Huang,Zhigang Xie,Ying Yue,Shi Liu,Xiabin Jing
Polymer-based local drug delivery system may be suitable for the treatment of cervix cancer. A pilot study was carried out to examine the efficacy of cisplatin-loaded poly(ethylene oxide)/polylactide composite electrospun nanofibers as a local chemotherapy system against cervical cancer in mice via vaginal implantation. The nanofibers were proven to have good mucoadhesive property by in vitro mucoadhesion test and in vivo vaginal retention evaluation. An orthotopic cervical/vaginal cancer model was established by injecting murine cervical cancer U14 cells into the vaginal submucosa nearby the cervix. By inserting the nanofibers mat into the vagina of mice, the cisplatin released from the fiber-mat showed a much more accumulation in the vagina/cervix region than in the peripheral organs such as kidneys, liver, or blood, in contrary to the case of intravenous (i.v) injection. The in vivo trials showed that a better balance between anti-tumor efficacy and systemic safety was achieved in nanofibers group than that in i.v injection group at the equal drug dose. Therefore, electrospun nanofibers present a promising approach to the local drug delivery via vagina against cervical cancer.
研究领域:
肿瘤学
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药剂学
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生物材料学
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产品关联
DOI
PubMed
高影响因子
Experimental and Therapeutic Medicine
·
2019
·Vol. 19
·期 1
·375-383
·
IF 1.448
Xiaowei Shen,Jiaqi Lei,Lei Du
The limited efficacy of chemotherapy with Taxol (TAX) and cisplatin (DDP) in triple‑negative breast cancer (TNBC) has prompted the investigation of combined therapies. Previous studies demonstrated that microRNA (miR)‑31‑5p is involved in various biological processes. In the present study, it was hypothesized that the overexpression of miR‑31‑5p may enhance the efficacy of chemotherapy. The expression levels of miR‑31‑5p in the TNBC cell lines MDA‑MB‑231 and MDA‑MB‑468 were measured using reverse transcription‑quantitative PCR following transfection with miR‑31‑5p mimic or inhibitor. A Cell Counting Kit‑8 and flow cytometry assays suggested that the overexpression of miR‑31‑5p inhibited cell proliferation and promoted apoptosis, and these effects were reversed by transfecting a miR‑31‑5p inhibitor into MDA‑MB‑231 and MDA‑MB‑468 cells. Furthermore, the overexpression of miR‑31‑5p increased the sensitivity of cells to chemotherapy, which exhibited an increase in apoptosis and in the expression level of Bax, and a decrease in the expression level of Bcl‑2. Chemotherapy resistance induced by miR‑31‑5p inhibitor could be reversed by inhibiting the AKT signaling pathway in MDA‑MB‑231 and MDA‑MB‑468 cells. In conclusion, the present preclinical results indicated that targeting miR‑31‑5p may enhance the efficacy of TAX‑ and DDP‑mediated chemotherapy in TNBC.
研究领域:
肿瘤学
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分子生物学
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癌症治疗
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产品关联
DOI
PubMed
高影响因子
PLoS One
·
2011
·Vol. 6
·期 9
·e25433
·
IF 4.411
Lihua Cheng,Chengmeng Jin,Wen Lv,Qiuping Ding,Xu Han
Background
Cisplatin is a potent anticancer drug, but its clinical application has been limited due to its undesirable physicochemical characteristics and severe side effects. Better drug formulations for cisplatin are highly desired.
Methodology/Principal Findings
Herein, we have developed a nanoparticle formulation for cisplatin with high encapsulation efficiency and reduced toxicity by using cisplatin-crosslinked carboxymethyl cellulose (CMC) core nanoparticles made from poly(lactide-co-glycolide)-monomethoxy-poly(polyethylene glycol) copolymers (PLGA-mPEG). The nanoparticles have an average diameter of approximately 80 nm measured by transmission electron microscope (TEM). The encapsulation efficiency of cisplatin in the nanoparticles is up to 72%. Meanwhile, we have also observed a controlled release of cisplatin in a sustained manner and dose-dependent treatment efficacy of cisplatin-loaded nanoparticles against IGROV1-CP cells. Moreover, the median lethal dose (LD 50 ) of the cisplatin-loaded nanoparticles was more than 100 mg/kg by intravenous administration, which was much higher than that of free cisplatin.
Conclusion
This developed cisplatin-loaded nanoparticle is a promising formulation for the delivery of cisplatin, which will be an effective therapeutic regimen of ovarian cancer without severe side effects and cumulative toxicity.
研究领域:
药剂学
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肿瘤学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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