Oncology Letters
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2020
·Vol. 20
·期 6
·1-1
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IF 2.311
Hao Zhu,Yuhuan Shi,Xiuxiu Jiao,Gang Yang,Rong Wang,Yongfang Yuan
Cisplatin resistance is an obstacle for the effective treatment of non‑small cell lung cancer (NSCLC). The combined use of two or more chemotherapeutic agents displays advantages for the clinical treatment of drug‑resistant lung cancer. The present study aimed to assess the synergy of the dual PI3K/Akt/mTOR signaling pathway inhibitor NVP‑BEZ235 and cisplatin, a chemotherapeutic agent, on proliferation, apoptosis, cell cycle arrest and protein expression in cisplatin‑resistant NSCLC A549/diamminedichloroplatinum resistance (DDP) cells. Cell proliferation was determined by performing Cell Counting Kit 8 and colony formation assays. Combination index (CI) was used to assess the combinatorial effects of NVP‑BEZ235 and cisplatin. Cellular apoptosis and cell cycle arrest were detected via flow cytometry. Western blotting was performed to evaluate protein expression levels relative to β‑actin. Cisplatin and NVP‑BEZ235 displayed the strongest synergy (CI50=0.23) at the mass ratio of 10:1. The half inhibitory concentrations of cisplatin and NVP‑BEZ235 at 10:1 were 1.53 and 0.15 µg/ml, respectively. Compared with the control group, the combination of cisplatin and NVP‑BEZ235 induced cell apoptosis and inhibited colony formation. Furthermore, compared with the control group, phosphorylation of Akt and p70S6 Kinase was significantly inhibited and cell cycle was arrested at G0G1 phase in the combination treatment group. The expression levels of drug efflux proteins, such as multidrug resistance‑associated protein 1 and ATP‑binding cassette sub‑family G member 2, were significantly decreased when A549/DDP cells were treated with a combination of cisplatin and NVP‑BEZ235 compared with the control group. Collectively, the present study indicated that the combined treatment of cisplatin and NVP‑BEZ235 displayed synergistic antitumor effects on drug‑resistant A549/DDP cells, by which the antiproliferative effects may occur via inhibition of the PI3K/Akt/mTOR signaling pathway and downregulation of drug efflux.
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Molecular Medicine Reports
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2020
·Vol. 22
·期 6
·5053-5068
·
IF 2.1
Guofang Guan,Xiao He,Jingjing Chen,Li Bin,Xuxia Tang
Sensorineural hearing loss is prevalent in patients receiving cisplatin therapy. Tetramethylpyrazine (Tet) and tanshinone IIA (Tan IIA) have protective roles against hearing impairment or ototoxicity. The present study aimed to investigate the molecular mechanisms underlying cisplatin‑induced ototoxicity and the protective effect of Tet and Tan IIA against it. House Ear Institute‑Organ of Corti 1 auditory cells were treated with titrating doses of Tan IIA, Tet, and cisplatin. In a cell viability assay, cisplatin, Tan IIA and Tet had IC50 values of 42.89 µM, 151.80 and 1.04x103 mg/l, respectively. Tan IIA augmented cisplatin‑induced cytotoxicity. However, Tet concentrations <75 mg/l attenuated cisplatin‑induced cytotoxicity and apoptosis. Moreover, RNA sequencing analysis was carried out on auditory cells treated for 30 h with 30 µM cisplatin alone for 48 h or combined with 37.5 mg/l Tet for 30 h. Differentially expressed genes (DEGs) induced in these conditions were identified and examined using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis. Cisplatin increased the expression of genes related to the p53 and FoxO pathways, such as Fas, p21/CDKN1A, and Bcl‑2 binding component 3, but decreased the expression of insulin‑like growth factor 1 (IGF1), as well as genes in the histone (Hist)1 and Hist2 clusters. Treatment with Tet downregulated FOXO3 and Bcl‑2 binding component 3, and increased the expression of IGF1. Moreover, Tet upregulated genes associated with Wnt signaling, but not p53‑related genes. Thus, the otoprotective properties of Tet might be mediated by activation of Wnt and IGF1 signaling, and inhibition of FoxO signaling.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Jue Liu,Yue-Xuan Liu,Yu-Song Song,Chen-Kai Liu,Fei-Xue Yu,Gao Liu,Tian-Rui Xu,Jun Sang
Ethnopharmacological relevance Paris polyphylla Smith var. yunnanensis (Franch.) Hand.-Mazz., known as “Chonglou” in traditional Chinese medicine, is clinically used in cancer therapy, with saponins identified as the key antitumor constituents. However, the therapeutic potential and mechanisms of the total saponins from P. polyphylla var. yunnanensis (PPT) against bladder cancer, particularly their ability to overcome chemoresistance, remain unexplored. Aim of the study This study aimed to investigate PPT's anti-bladder cancer effects and mechanisms, with a focus on its potential to overcome cisplatin resistance. Materials and methods We established a UPLC-DAD method for saponin profiling and developed an eco-friendly extraction protocol using hydroxypropyl- β -cyclodextrin-assisted extraction combined with macroporous resin purification to prepare PPT. Anti-cancer efficacy was assessed in bladder cancer cell lines, mouse/zebrafish xenograft models, and cisplatin-resistant models. Mechanistic investigations integrated network pharmacology, metabolomics, molecular docking, and experimental validations (siRNA silencing, western blotting, flow cytometry, molecular dynamics simulations, cellular thermal shift assay, and surface plasmon resonance). Results The hydroxypropyl- β -cyclodextrin-based extraction system enhanced PPT purity by 15-fold, with the purified fraction showing dose-dependent anti-bladder cancer activity in vitro and in vivo . Mechanistically, PPT exerted anti-proliferative, pro-apoptotic, anti-lipogenic, and chemosensitizing effects by inhibiting the growth factor receptor binding protein 2 (GRB2)-mediated Akt-SREBP1 signaling axis. Notably, polyphyllin VII, a key constituent of PPT, was identified as a novel GRB2 inhibitor, potently suppressing bladder cancer progression and overcoming cisplatin resistance. Conclusion This study demonstrates that targeting the GRB2-Akt-SREBP1 signaling axis is a promising strategy for bladder cancer therapy, further establishing PPT as a multicomponent phytomedicine and PPVII as a novel GRB2 inhibitor with high translational potential.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
·
IF 4.8
Jianfa Wu,Lingli Jiang,Sihong Wang,Lei Peng,Rong Zhang,Zhou Liu
The involvement of Interferon-stimulated exonuclease gene 20 (ISG20) has been reported in renal clear cell carcinoma, hepatocellular carcinoma, and cervical cancer. However, its role in ovarian cancer chemotherapy remains unclear. In this study, we conducted a comparative analysis of TGF-β1 and ISG20 in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells and tissues using qRT-PCR and a tissue immunofluorescence analysis. We also investigated the impact of ISG20-targeted drugs (IFN-γ) and TGF-β1 inhibitors on cisplatin response both in vivo and in vitro. Additionally, we assessed the effects of TGF-β1 or ISG20 on the polarization of tumor-associated macrophages through flow cytometry and ELISA analysis. Our findings revealed that ISG20 expression was lower in cisplatin-resistant tissues compared to cisplatin-sensitive tissues; however, overexpression of ISG20 sensitized ovarian cancer to cisplatin treatment. Furthermore, activation of ISG20 expression with IFN-γ or TGF-β1 inhibitors enhanced the sensitivity of ovarian cancer cells to cisplatin therapy. Notably, our results demonstrated that TGF-β1 promoted M2-type macrophage polarization as well as PI3K/mTOR pathway activation by suppressing ISG20 expression both in vivo and in vitro. In conclusion, our study highlights the critical role played by ISG20 within the network underlying cisplatin resistance in ovarian cancer. Targeting ISG20 using IFN-γ or TGF-β1 inhibitors may represent a promising therapeutic strategy for treating ovarian cancer.
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BIOORGANIC CHEMISTRY
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2023
·
IF 5.1
Rui Li,Weiheng Zhao,Chen Jin,Huihua Xiong
Platinum(II)–based drugs play an important role in many chemotherapeutic protocols, but their further clinical applications are hindered by the development of drug resistance and serious side effects. Therefore, to reverse cisplatin (CDDP) resistance in tandem with reduced side effects, nine novel platinum(IV) complexes modified with key pharmacophore of Olaparib were synthesized and evaluated for biological activities. Among them, the optimal complex 8–2 showed good inhibitory activity against PARP–1 and superior anticancer effects over CDDP on parental (MDA–MB–231, IC 50 = 1.13 μM) and CDDP –resistant triple–negative breast cancer (TNBC) cell line (MDA–MB–231/CDDP, IC 50 = 1.72 μM). Detailed mechanisms revealed that compared with Olaparib and CDDP, the enhanced intracellular accumulation of 8–2 could efficiently reverse CDDP resistance in MDA–MB–231/CDDP cells via inhibiting DNA repair–associated mechanisms, enhancing DNA damage, and activating mitochondrion–dependent apoptosis pathway. Furthermore, 8–2 obtained higher tumor growth inhibition rate (64.1 %) than CDDP (26.5 %) in MDA–MB–231/CDDP xenografts, but it did not induce significant toxicity in vivo and in intro , making it a potential drug candidate for the treatment of TNBC.
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JOURNAL OF ETHNOPHARMACOLOGY
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2025
·
IF 5.4
Yingling Luan,Kunshuang Shen,Le Yang,Jingzhe Gao,Ning Zhang,Qin Feng,Shengnan Zhu,Hui Sun,Yan Zhang,Ye Sun,Zhengcan Zhou,Ying Han,Xijun Wang
Ethnopharmacological relevance As a traditional medicine, Asini Corii Colla (E’jiao) demonstrates significant efficacy and a favorable safety profile in the treatment of Chemotherapy-induced anemia (CIA). However, its definitive hematopoietic constituents and pharmacodynamic mechanisms remain uncharacterized. Aim of the study To investigate peptides derived from E’jiao with hematopoietic activity in the cisplatin-induced anemia rat model and explore their underlying mechanisms. Methods and methods This study established a chemically induced anemia model by injecting cisplatin. The anti-anemic efficacy of E’jiao was validated through hematological analysis. Nano-liquid chromatography-mass spectrometry (Nano LC-MS) was employed to analyze peptides absorbed into blood in rats. Combined with network pharmacology and molecular weight screening, we preliminarily identified peptides exhibiting potential hematopoietic activity. Molecular docking technology was further utilized to evaluate the binding patterns and affinity of the candidate peptides with erythropoietin (EPO). Results The results demonstrated that E’jiao significantly enhanced erythropoiesis in CIA rats. Nano LC-MS identified 35 peptides absorbed into blood from E’jiao; these bioactive peptides primarily originated from collagen type I alpha 1 chain (COL1A1) and collagen type I alpha 2 chain (COL1A2). Molecular docking analysis revealed that three peptides: GEAGPAGPAGPIGPVGAR (P-GE), GPAGPTGPVGK (P-GP), and SGQPGTVGPAGVRG (P-SG) formed stable binding configurations with the α-helical domain of EPO. The study suggests that three bioactive peptides within E’jiao may exert hematopoietic functions by stabilizing the active conformation of EPO, prolonging its plasma half-life, and enhancing its biological activity. Conclusion This integrative approach combining chemotherapeutic anemia modeling, peptidomics, and molecular docking provides novel insights into the peptide-mediated hematopoietic mechanisms of E’jiao, providing evidence for elucidating the biological mechanisms by which E’jiao peptides regulate hematopoiesis and offering novel perspectives for researching active components in animal-derived medicines.
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Journal of Biomedical Nanotechnology
·
2016
·Vol. 12
·期 1
·69-78
·
IF 3.929
Yu Haiyang,Tang Zhaohui,Li Mingqiang,Song Wantong,Zhang Dawei,Zhang Ying,Yang Yan,Sun Hai,Deng Mingxiao,Chen Xuesi
A series of novel polypeptide-based graft copolymer poly(L-glutamic acid)-graft-methoxy poly(ethylene glycol) (PLG-g-mPEG) was synthesized through a Steglich esterification reaction of PLG with mPEG. The structure of the copolymers was confirmed by nuclear magnetic resonance
spectra (NMR) and gel permeation chromatography (GPC). MTT assay demonstrated that the PLG-g-mPEGs had good cell compatibility. The unreacted carboxyl groups of the PLG-g-mPEGs were used to complex cisplatin to form polymer-metal complex nanoparticles (CDDP/PLG-g-mPEG)
for cancer therapy. The average hydrodynamic radius of the CDDP/PLG-g-mPEG nanoparticles was in the range of 14–25 nm, which was beneficial for solid tumor targeting delivery. A sustained release without initial burst was achieved for the CDDP/PLG-g-mPEG nanoparticles,
indicating that the CDDP-loaded nanoparticles had great potential to suppress the drug release in blood circulation before the nanoparticles had arrived at targeting tumors. The CDDP/PLG-g-mPEG nanoparticles showed a much longer blood retention profile as compared with the free CDDP.
This indicated that the CDDP-loaded nanoparticles had much more opportunity to accumulate in tumor tissue by exerting the EPR effect. In vitro tests demonstrated that the CDDP/PLG-g-mPEG nanoparticles could inhibit the proliferation of HeLa, MCF-7 and A549 cancer cells. At equal
dose (4 mg kg–1), the CDDP/PLG-g-mPEG nanoparticles showed comparable in vivo antitumor efficacy and significantly lower systemic toxicity as compared with free cis-Diaminedichloroplatinum (cisplatin, CDDP) in MCF-7 tumor bearing mice. These suggested that the
CDDP/PLG-g-mPEG nanoparticle drug delivery system had a great potential to be used for cancer therapy.
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CHEMICAL ENGINEERING JOURNAL
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2025
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IF 13.2
Min Wu,Zhouxue Wu,Weizhou Wang,Yunxue Zheng,Hongxia Li,Yuan Huang,Liping Deng,Yingqi Gu,Jingfeng Rong,Xiaoyin Zhang,Wen Yang,Yue Chen,Shaozhi Fu,Jingbo Wu
The hypoxic tumor microenvironment (TME) is a key factor contributing to the poor efficacy of traditional radiotherapy (RT) and chemotherapy in the treatment of solid tumors. Here, we have developed a chitosan nanosystem consisting of cisplatin (CDDP) nanoparticles (NPs) modified with mono-antibodies (mAbs) against Bifidobacterium (Bi) (mAb@CDDP-NPs). Bi is designated as a “target” to be implanted in the hypoxic TME. Before administering nanosystem therapy, Bi was pre-implanted in the hypoxic region of the tumor. The mAb@CDDP-NPs then achieved targeted enrichment in the weakly acidic hypoxic region where Bi had localized. Subsequently, the chitosan-encapsulated structure of mAb@CDDP-NPs swelled and ruptured, ultimately releasing CDDP. The new therapeutic method of mAb@CDDP-NPs + RT has been proven to have an excellent targeted anti-tumor effect in the CT26 and 4 T1 tumor-bearing mouse models. This method not only possesses the anti-tumor effects of RT and chemotherapy, but also effectively regulates immunosuppressive TME. It presents as an increase in infiltration of mature DCs, CD8 + T, and NK cells, and a decrease in infiltration of MDSC cells. Moreover, the mAb@CDDP-NPs nanosystem significantly reduces the adverse reactions of CDDP. The successful construction of the mAb@CDDP-NPs nanosystem and the development of a novel treatment model that combines mAb@CDDP-NPs with RT for anti-tumor therapy is expected to provide new insights for the treatment of solid tumors.
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Cancer Management and Research
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2023
·
IF 3.3
Ping Huang,Shi-Xia Du
Objective The effect of PUE on enhancing the anti-cancerous efficacy of DDP on drug-resistant A549/DDP cancer and the underlying mechanisms were thoroughly investigated.Materials and Methods The cytotoxicity of PUE, DDP, and PUE + DDP to A549 cells and A549/DDP cells, respectively, is determined by cell apoptosis experiments. Anti-proliferation effect of PUE, DDP, and PUE + DDP on A549 cells and A549/DDP cells is evaluated by the cell cloning assay. Qualitative and quantitative analysis of the levels of PUE, DDP, and PUE + DDP of cell proliferation-related genes and proteins expressions in A549/DDP cells are determined by Western blot assay. The levels of VEGF in A549/DDP cells after different treatment strategies are determined by ELISA assay. Qualitative and quantitative determination of VEGF expression in tumor tissues are done by immunohistochemical staining.Results In vitro cellular experiments revealed that co-incubation of A549/DDP cells with PUE and DDP led to a dramatically decreased cell viability and cell survival rate compared with the cells only treated by DDP. Such a stimulating effect of PUE on DDP was further confirmed in vivo with results shown that the A549/DDP cancer-bearing mice treaded by combination therapy achieved the lowest tumor growth rate and longest survival time.Conclusion Taking these results together, we can draw the conclusion that the PUE enhances the anti-tumor effect of DDP on the drug-resistant A549 cancer in vivo and in vitro through activation of the Wnt signaling pathway.
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Bioengineered
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2022
·
IF 6.832
Mingming Ma,Qiao Luo,Lijing Fan,Weilong Li,Qiang Li,Yu Meng,Chen Yun,Hongwei Wu,Yongping Lu,Shuang Cui,Fanna Liu,Bo Hu,Baozhang Guan,Huanhuan Liu,Shengling Huang,Wenxue Liang,Stanislao Morgera,Bernhard Krämer,Shaodong Luan,Lianghong Yin,Berthold Hocher
Acute kidney injury (AKI) is a susceptible factor for chronic kidney disease (CKD). There is still a lack of effective prevention methods in clinical practice. This study investigated the protective effect of the urinary exosomes from premature infants on cisplatin-induced acute kidney injury. Here we isolated exosomes from the fresh urine of premature infants. A C57BL/6 mice model of cisplatin-induced acute kidney injury was given 100 ug urinary exosomes 24 hours after model establishment. The kidneys were collected for pathological examination and the evaluation of renal tubular damage and apoptosis. In the in vitro experiment, human renal cortex/proximal tubular cells (HK-2) were induced by cisplatin to assess the effect of the urine exosomes from premature infants. Exosome microRNA (miRNA) sequencing technology was applied to investigate the miRNAs enriched in exosomes and the dual-luciferase gene reporter system to examine the targeting relationship of the miRNA with target genes. The results indicated that the urinary exosomes could decrease the serum creatinine level and the apoptosis of renal tubular cells, and reduce mice mortality. In addition, miR-30a-5p was the most abundant miRNA in the exosomes. It protected HK-2 cells from cisplatin-induced apoptosis by targeting and down-regulating the mitogen-activated protein kinase 8 (MAPK8). Together, our findings identified that the urinary exosomes derived from premature infants alleviated cisplatin-induced acute kidney injury and inhibited the apoptosis of HK-2 via miR-30a-5p, which could target MAPK8. These findings implied that urinary exosomes from premature infants riched in miR-30a-5p might become a potential treatment for AKI.
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JOURNAL OF PHARMACY AND PHARMACOLOGY
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2024
·
IF 2.8
Gong Enhui,Pan Jiongwei,Ye Zaiting,Cai Xiaoping,Zheng Hao,Yin Zhangyong,Jiang Yiwei,Wang Xin,Cao Zhuo
ObjectivesReportedly, ganoderic acid A (GA-A) increases the sensitivity of hepatocellular carcinoma cells to cisplatin (DDP) chemotherapy. Therefore, this study aims to fathom the influence of GA-A on lung cancer cells.MethodsAfter the construction of A549/DDP cells through exposure to DDP, the effects of GA-A on A549 and A549/DDP cells were revealed by cellular functional assays, western blot and quantitative reverse transcription PCR (qRT-PCR). The DDP-resistant lung cancer tumor was established in vivo, followed by further validation of the mechanism of GA-A.ResultsGA-A suppressed the viability, migration, and invasion while downregulating Beclin and autophagy marker LC3II/LC3I levels and upregulating P62 levels in A549 and A549/DDP cells. These effects were reversed by circFLNA overexpression. Also, GA-A reinforced the sensitivity of A549/DDP cells to DDP, elevated the apoptosis and regulated the circFLNA/miR-486-3p/cytochrome P450 family 1 subfamily A member 1 (CYP1A1)/X-ray repair cross-complementing 1 (XRCC1) axis. The reversal effects of circFLNA overexpression on GA-A-induced viability and apoptosis of A549/DDP cells could all be counteracted in the presence of 3MA. GA-A inhibited lung cancer tumor growth and blocked autophagy.ConclusionGA-A suppresses autophagy by regulating the circFLNA/miR-486-3p/CYP1A1/XRCC1 axis to strengthen the sensitivity of lung cancer cells to DDP.
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RSC Advances
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2024
·Vol. 14
·期 11
·7517-7527
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IF 3.9
Yihong Yang,Genlan Ye,Xiaozhong Qiu
Intraoperative bleeding is a pivotal factor in the initiation of early recurrence and tumor metastasis following breast cancer excision. Distinct advantages are conferred upon postoperative breast cancer treatment through the utilization of locally administered implant therapies. This study devised a novel 3D sponge implant containing cisplatin-loaded chitosan–calcium alginate MPs capable of exerting combined chemotherapy and hemostasis effects. This innovative local drug-delivery implant absorbed blood and residual tumor cells post-tumor resection. Furthermore, the cisplatin-loaded chitosan–calcium alginate MPs sustainably targeted and eliminated cancer cells, thereby diminishing the risk of local recurrence and distant metastasis. This hydrogel material can also contribute to breast reconstruction, indicating the potential application of the 3D sponge in drug delivery for breast cancer treatment.
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