PHARMACOLOGICAL RESEARCH
·
2024
·
IF 9.1
Yilan Huang,Siwei Wang,Xiaojun Zhang,Chen Yang,Sikai Wang,Hongxia Cheng,Aiwu Ke,Chao Gao,Kun Guo
Lenvatinib is a frontline tyrosine kinase inhibitor for patients with advanced hepatocellular carcinoma (HCC). However, just 25% of patients benefit from the treatment, and acquired resistance always develops. To date, there are neither effective medications to combat lenvatinib resistance nor accurate markers that might predict how well a patient would respond to the lenvatinib treatment. Thus, novel strategies to recognize and deal with lenvatinib resistance are desperately needed. In the current study, a robust Lenvatinib Resistance index (LRi) model to predict lenvatinib response status in HCC was first established. Subsequently, five candidate drugs (Mercaptopurine, AACOCF3, NU1025, Fasudil, and Exisulind) that were capable of reversing lenvatinib resistance signature were initially selected by performing the connectivity map (CMap) analysis, and fasudil finally stood out by conducting a series of cellular functional assays in vitro and xenograft mouse model. Transcriptomics revealed that the co-administration of lenvatinib and fasudil overcame lenvatinib resistance by remodeling the hedgehog signaling pathway. Mechanistically, the feedback activation of EGFR by lenvatinib led to the activation of the GLI2-ABCC1 pathway, which supported the HCC cell's survival and proliferation. Notably, co-administration of lenvatinib and fasudil significantly inhibited IHH, the upstream switch of the hedgehog pathway, to counteract GLI2 activation and finally enhance the effectiveness of lenvatinib. These findings elucidated a novel EGFR-mediated mechanism of lenvatinib resistance and provided a practical approach to overcoming drug resistance in HCC through meaningful drug repurposing strategies.
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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癌症生物学
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Xu-Mei Gan,Wei-Jie Chen,Yu-Hang Xie,Cui-Xia Wang,Yan-Qiu Deng,Zhen-Wei Zhang
A series of new dihydropyrano[2,3- b ]indoles were designed, synthesized, and meticulously evaluated for their antiproliferative activities against multiple human tumor cell lines, including A549, MCF-7, DU145, HeLa, and HepG2 cells. Among these derivatives, compound 4k exhibited the most potent antitumor activity against non-small cell lung cancer (NSCLC) A549 cells. Further mechanistic investigations showed that 4k arrested the A549 cell cycle at the S phase but triggered only weak apoptosis. Instead, 4k eliminated cells through non-apoptotic mechanisms involving the simultaneous inhibition of autophagy and induction of ferroptosis in NSCLC by elevating reactive oxygen species (ROS) levels, reducing mitochondrial membrane potential (MMP), and downregulating glutathione peroxidase 4 (GPX4) expression. Moreover, 4k also showed potent in vivo antitumor activity in a fluorescent zebrafish xenograft model. Additionally, the potential target proteins were predicted and preliminarily validated using network pharmacology and molecular docking. Collectively, our findings identified 4k as a dual modulator that blocks autophagy and sequentially triggers ferroptosis, offering a promising therapeutic strategy to overcome apoptosis resistance.
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PubMed
高影响因子
TALANTA
·
2020
·
IF 5.339
Yue-Yue Chang,Hai-Long Wu,Huan Fang,Tong Wang,Yang-Zi Ouyang,Xiao-Dong Sun,Gao-Yan Tong,Yu-Jie Ding,Ru-Qin Yu
Three intelligent chemometric multi-way calibration methods including alternating trilinear decomposition (ATLD), alternating trilinear decomposition assisted multivariate curve resolution (ATLD-MCR) and multivariate curve resolution-alternating least squares (MCR-ALS) combined with high performance liquid chromatography-diode array detection (HPLC-DAD) were used to quantify ten molecular targeted anti-tumor drugs in three complex biological matrices (plasma, urine and cell culture media matrices). All analytes can be successfully eluted in 6.5 min. In this experiment, various degrees of time shifts occurred in different samples. While slight time shifts exist in the chromatographic analysis , satisfactory results can be obtained by the three proposed methods. When the time shift was large (5.6 s), the average spiked recoveries obtained by ATLD analysis were in the range of 58.9%–116.5%, which was less than satisfactory. However, the average recoveries obtained by MCR-ALS and ATLD-MCR analysis were 89.8%–114.8% and 84.5%–106.1% respectively, and more satisfactory results were obtained. For further research, ATLD-MCR and MCR-ALS methods were compared, and the results were evaluated by statistical tests. Accuracies of concentrations obtained by them were considered to be no significant difference. In addition, compared with other methods currently published, the proposed chemometric methods combined with the HPLC-DAD can rapidly, simultaneously and accurately determine varieties of molecular targeted anti-tumor drugs in different complex biological matrices even in the presence of severe peak overlaps, severe time shifts, slight baseline drifts and different unknown background interferences.
研究领域:
分析化学
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药物分析
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化学计量学
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DOI
PubMed
高影响因子
JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2019
·Vol. 38
·期 1
·1-13
·
IF 5.646
Yang Lehe,Lin Shichong,Kang Yanting,Xiang Youqun,Xu Lingyuan,Li Jifa,Dai Xuanxuan,Liang Guang,Huang Xiaoying,Zhao Chengguang
Background Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that rhein has significant antitumor effects, supporting its potential use as an antitumor agent. The IL6/STAT3 signaling pathway has been suggested as an attractive target for the discovery of novel cancer therapeutics.Methods The human pancreatic cancer cell lines AsPC-1, Patu8988T, BxPC-3 and PANC-1, and immunodeficient mice were chosen as models to study the effects of rhein. The potent antiproliferative and proapoptotic effects of rhein were examined by cell viability, cellular morphology, apoptosis and colony formation assays. The STAT3 luciferase report assay, immunostaining analysis and Western blot analysis revealed the inhibition of the IL6/STAT3 signaling axis.Results Apoptosis was induced by adjunctive use of rhein with epidermal growth factor receptor (EGFR) inhibitors in pancreatic cancer cells as verified by cell apoptosis analysis and changes in the expression level of apoptotic/anti-apoptotic proteins BCL-2, BAX, Caspase 3 and Cl-PARP. Suppression of the phosphorylation of STAT3 and EGFR were also observed as a result of the treatment with a combination of rhein and EGFR inhibitors. Most interestingly, it was found that rhein considerably sensitized cells to erlotinib, thus suppressing tumor growth in PANC-1 and BxPC-3 xenograft models. The in vivo anti-tumor effect was associated with increased apoptosis and combined inhibition of the STAT3 and EGFR pathways in tumor remnants.Conclusion sRhein sensitizes human pancreatic cancer cells to EGFR inhibitors through inhibition of STAT3. Taken together, the results indicate that rhein offers a novel blueprint for pancreatic cancer therapy, particularly when combined with EGFR inhibitors.
研究领域:
肿瘤学
·
药理学
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分子生物学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2019
·
IF 3.743
Tianhua Liu,Ling Zuo,Dongqing Guo,Xinlou Chai,Jie Xu,Zhaorui Cui,Zhiyi Wang,Chunying Hou
Lung cancer is the leading cause of cancer-related deaths. Ginsenoside Rg3 is the main ingredient of Ginseng which is used to treat non-small cell lung cancer (NSCLC). It has been found to enhance the efficiency of chemotherapy thereby reducing its side effects. Previous studies found that ginsenoside Rg3 can reduce the occurrence of NSCLC by inducing DNA damage. Yet, its anti-DNA damaging effects and mechanisms in tumor cells are still not fully understood. This study explored the effect of ginsenoside Rg3 on DNA repair and VRK1/P53BP1 signaling pathway. Ginsenoside Rg3 treatment significantly decreased the incidence and invasionin a mouse model of lung cancer induced by urethane. The results of cell survival assay and single cell gel electrophoresis showed that ginsenoside Rg3 protected lung adenocarcinoma cells from DNA damage as well as inhibited the proliferation of tumor cells. Ginsenoside Rg3 increased the mRNA and protein expression of VRK1 in NSCLC cells as measured by RT-qPCR and western blot, respectively. These findings suggests that ginsenoside Rg3 regulates VRK1 signaling. Immunofluorescence assays showed that P53BP1 and VRK1 protein level increased, and the VRK1 protein translocated between the nuclei and cytoplasm. Finally, this conclusion was confirmed by the reverse validation in VRK1-knockdown cells. Taken together, these results show that ginsenoside Rg3 upregulate VRK1 expression and P53BP1 foci formation in response to DNA damage thereby inhibiting the tumorigenesis and viability of cancer cells. These findings reveal the role of Rg3 in lung cancer and provides therapeutic targets for developing new drugs in the prevention and treatment of lung 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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癌症治疗
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产品关联
DOI
PubMed
高影响因子
CYTOTECHNOLOGY
·
2019
·Vol. 71
·期 4
·785-795
·
IF 1.672
Zhou Leilei,Weng Qi,Zheng Yixin,Zhou Yuqin,Li Qingyong,Li Fengzhi
Drug uptake and efflux are two of the critical factors required in order to be able to define drug efficacy. This study aims to investigate cytotoxicity and uptake mechanisms of two FL118 analogues (7-Q20 and val-FL118) in parallel with FL118 in three-dimensional multi-cellular spheroids model. The influence of compound concentration, time, temperature, cell lines, and the inhibitors of P-gp, BCRP and LAT1 on drug uptake and efflux were investigated. In vitro cytotoxicity studies revealed that FL118, 7-Q20 and val-FL118 exhibited sensitive cytotoxicity to the HCT-116 cell line and the water-soluble compound 7-Q20 showed the lowest IC 50 . Cellular uptake and efflux of FL118 was independent of efflux pump proteins. Uptake and efflux of 7-Q20 were affected by P-gp, which was one of reasons that caused a lower uptake at 37 °C than at 4 °C. The carrier protein LAT1 played a role in the cellular intakes of val-FL118. These findings provided basic information for FL118 and the two novel FL118 derivatives for further development.
研究领域:
药理学
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肿瘤学
·
细胞生物学
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DOI
PubMed
高影响因子
CANCER CHEMOTHERAPY AND PHARMACOLOGY
·
2019
·Vol. 84
·期 3
·527-537
·
IF 3.008
Weng Qi,Zhou Leilei,Xia Lihua,Zheng Yixin,Zhang Xiangli,Li Fengzhi,Li Qingyong
Purpose Recent researches are attempting to verify that the 3D cell models can provide a gap bridge between in vitro and in vivo for anticancer drug evaluations. The aim of this study was to continue the development of novel in vitro 3D cell models and the investigation of the cellular uptake mechanism of camptothecin (CPT) and its derivatives [FL118 (10,11-methylenedioxy-20( S )-camptothecin), 9-Q20 (9- p -trifluoromethylphenyl-10,11-methylenedioxy-20( S )-camptothecin)] in 2D and 3D cell models. Methods The 3D cell models were established using ultralow attachment 96-well plates. The cytotoxicity of CPT, FL118, and 9-Q20 was evaluated by MTT method. The effects of compound concentration, incubation time, temperature, and transporter inhibitors on the cellular uptake of CPT, FL118, and 9-Q20 were examined in 2D and 3D cell models. Results The cytotoxicity of CPT, FL118, and 9-Q20 was lower in 3D cell models than 2D cell models. In 2D Caco-2 cell model, the uptake rate of CPT, FL118, and 9-Q20 was faster during the early time of incubation. In 3D Caco-2 cell model, the uptake capacity of CPT, FL118, and 9-Q20 was significantly improved over time. In 3D Caco-2 cell model, Verapamil (P-gp inhibitor) and Gefitinib (BCRP inhibitor) more significantly increased the uptake of CPT and 9-Q20. In contrast, P-gp and BCRP did not affect the accumulation of FL118 in 2D and 3D Caco-2 cell models. The accumulation of CPT, FL118, and 9-Q20 was greater in HepG2 cells than HCT116 cells. Conclusion The 3D cell models provided more potency information on the process of cellular uptake of CPT, FL118, and 9-Q20, which more objectively reflected the drug sensitivity and drug resistance in vivo compared with the 2D cell models.
研究领域:
药理学
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肿瘤学
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细胞生物学
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药物开发
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产品关联
DOI
PubMed
高影响因子
Cancer Management and Research
·
2018
·
IF 3.702
Xuanxuan Dai,Junru Zhang,Guilong Guo,Yuepiao Cai,Ri Cui,Changtian Yin,Weidong Liu,Rajamanickam Vinothkumar,Tingting Zhang,Guang Liang,Xiaohua Zhang
Introduction Targeted therapies using epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutations, leading to the approval of gefitinib and erlotinib as standard first-line clinical treatment. Inevitably, a considerable proportion of patients develop resistance to EGFR-TKIs due to the acquisition of secondary mutations within EGFR. Therefore, alternative strategies to target NSCLC are desperately needed. Materials and methods In this study, we have evaluated the effect of a reactive oxygen species (ROS)-inducing agent WZ35, a mono-carbonyl analog of curcumin, to target an inherent biological property of cancer cells, increased oxidative stress. To study whether WZ35 can inhibit NSCLC tumorigenesis, we used gefitinib- and erlotinib-resistant cell line H1975. Results In this study, we show that WZ35 treatment dramatically decreases cell viability and induces apoptosis in H1975 cells through the generation of ROS. We also found that the antitumor activity of WZ35 involved ROS-mediated activation of the endoplasmic reticulum stress pathway and mitochondrial dysfunction. Furthermore, WZ35 significantly inhibited H1975 xenograft tumor growth through the inhibition of cell proliferation and induction of apoptosis. Discussion These findings show that WZ35 may be a promising candidate for the treatment of EGFR-TKI-resistant NSCLC.
研究领域:
肿瘤学
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药理学
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细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
CHEMICAL & PHARMACEUTICAL BULLETIN
·
2021
·Vol. 69
·期 11
·1054-1060
·
IF 1.645
Yuqin Zhou,Weitong Hu,Xiangli Zhang,Yi Wang,Wenya Zhuang,Fengzhi Li,Qingyong Li
In the evaluation of the druggability of candidate compounds, it was vital to predict the oral bioavailability of compounds from apparent permeability (Papp) across Caco-2 cell-culture model of intestinal epithelium cultured on commercial transwell plate inserts. The study was to investigate the transport characteristics and permeability of FL118 (10, 11-Methylenedioxy-20(S)-camptothecin) derivatives 7-Q6 (7-(4-Ethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin) and 7-Q20 (7-(4-Trifluoromethylphenyl)-10, 11-methylenedioxy-20(S)-camptothecin). Transport characteristics and permeability of the tested compounds to the small intestine were assessed at different concentrations (0.5, 1 µM) via Caco-2 cell monolayers model in vitro. Uptake studies based on Caco-2 cells, including temperatures, concentrations, and the influence of efflux transporters, were combined to confirm the transport characteristics of the tested compounds. Furthermore, cytotoxicity results showed that the concentrations used in the experiments were non-toxic and harmless to cells. In addition, The Papp of 7-Q6 was (3.69 ± 1.07) × 10−6 cm/s with efflux ratio (ER) 0.98, while the Papp of 7-Q20 was (7.78 ± 0.89) × 10−6 cm/s with ER 1.05 for apical-to-basolateral (AP→BL) at 0.5 µM, suggesting that 7-Q20 might possess higher oral bioavailability in vivo. Furthermore, P-glycoprotein (P-gp) was proved to slightly affect the accumulations of 7-Q20, while the absorption of 7-Q6 was irrelevant with P-gp and breast cancer resistant protein (BCRP) based on the cellular uptake assays. Accordingly, 7-Q6 was completely absorbed by passive diffusion, and 7-Q20 was mainly dependent on passive diffusion with being effluxed by P-gp slightly. Meanwhile, both 7-Q6 and 7-Q20 were potential antitumor drugs that might exhibit high oral bioavailability in the body.
研究领域:
药理学
·
药物递送
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细胞生物学
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癌症研究
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 23
·期 4
·2018
·
IF 6.208
Yan Zhang,Pei Ma,Zhiguang Duan,Yannan Liu,Yu Mi,Daidi Fan
Lung adenocarcinoma (LAC) is a common lung cancer with a high malignancy that urgently needs to be treated with effective drugs. Ginsenoside Rh4 exhibits outstanding antitumor activities. However, few studies reported its effects on growth, metastasis and molecular mechanisms in LAC. Here, Rh4 is certified to show a strong anti-LAC efficiency in vitro and in vivo. Results of flow cytometry and Western blot are obtained to exhibited that Rh4 markedly restrained cellular proliferation and colony formation by arresting the cell cycle in the G1 phase. Results from a wound healing assay and transwell assays demonstrated that Rh4 is active in the antimigration and anti-invasion of LAC. The analysis of Western blot, immunofluorescence and RT-qPCR confirmed that Rh4 reverses the epithelial–mesenchymal transition (EMT) through upregulating the gene expression of E-cadherin and downregulating that of snail, N-cadherin and vimentin. In vivo results from immunohistochemistry show consistent trends with cellular studies. Furthermore, Rh4 suppresses the Janus kinases2/signal transducer and activator of the transcription3 (JAK2/STAT3) signaling pathway stimulated by TGF-β1. Silencing the STAT3 signal or co-treating with AG490 both enhanced the EMT attenuation caused by Rh4, which revealed that Rh4 suppressed EMT via inhibiting the JAK2/STAT3 signaling pathway. These findings explore the capacity and mechanism of Rh4 on the antimetastasis of LAC, providing evidence for Rh4 to LAC therapy.Keywords:ginsenoside Rh4;lung adenocarcinoma;metastasis;cell cycle;JAK/STAT signaling
研究领域:
肿瘤学
·
分子生物学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF APPLIED POLYMER SCIENCE
·
2022
·Vol. 139
·期 27
·e52444
·
IF 3.057
Yulin Jiang,Jing Wang,Juehan Wang,Yi Zhuang,Lin Qi,Ganjun Feng,Li Zhang
In this research, we successfully prepared a new kind of core-shell microspheres (PNIPAM@GO) composed of hydrophilic poly (N-isopropyl acrylamide) (PNIPAM) nanoparticles as the core and amphiphilic graphene oxide (GO) nanosheets as the shell through hydrogen bonding and self-assembly in organic solvent. The temperature-sensitive behavior of the PNIPAM core made its average size decrease from 888.3 nm to 630.3 nm with temperature increasing from 25°C to 50°C. And the GO shell could give PNIPAM@GO microspheres remarkable photothermal effects in water under NIR laser irradiation (808 nm) for 20 min. Further, doxorubicin (DOX) and 5-fluorouracil (5-FU) were loaded into the core and the shell with loading efficiency of 81% and 11%, respectively. By turning on/off NIR irradiation, the PNIPAM@GO microspheres could respond to the heat generated from GO shell by volume shrinkage, thus on-demand controlling the drug release. The in vitro biological assessment verified that the samples prepared here were biocompatible. The developed platform shows a potential application in chemo-photothermal therapy of cancers in the future.
研究领域:
材料科学
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纳米技术
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生物医学工程
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药学
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癌症治疗
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产品关联
DOI
高影响因子
Molecular Cancer
·
2022
·Vol. 21
·期 1
·1-17
·
IF 41.444
Pan Zhenzhen,Wang Kai,Wang Xiniao,Jia Zhirong,Yang Yuqi,Duan Yalei,Huang Lianzhan,Wu Zhuo-Xun,Zhang Jian-ye,Ding Xuansheng
Background The use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) brings remarkable benefits for the survival of patients with advanced NSCLC harboring EGFR mutations. Unfortunately, acquired resistance seems to be inevitable and limits the application of EGFR-TKIs in clinical practice. This study reported a common molecular mechanism sustaining resistance and potential treatment options to overcome EGFR-TKIs resistance.Methods EGFR-TKIs resistant NSCLC cells were established and confirmed by MTT assay. Cholesterol content was detected and the promotional function of cholesterol on NSCLC growth was determined in vivo. Then, we identified ERRα expression as the downstream factor of cholesterol-mediated drug resistance. To dissect the regulatory mechanism, we conducted experiments, including immunofluorescence, co-immunoprecipitation, luciferase reporter assay and chromatin immunoprecipitation assay.Results Long-term exposure to EGFR-TKIs generate drug resistance with the characteristic of cholesterol accumulation in lipid rafts, which promotes EGFR and Src to interact and lead EGFR/Src/Erk signaling reactivation-mediated SP1 nuclear translocation and ERRα re-expression. Further investigation identifies ERRα as a target gene of SP1. Functionally, re-expression of ERRα sustains cell proliferation by regulating ROS detoxification process. Lovastatin, a drug used to decrease cholesterol level, and XCT790, an inverse agonist of ERRα, overcome gefitinib and osimertinib resistance both in vitro and in vivo.Conclusion sOur study indicates that cholesterol/EGFR/Src/Erk/SP1 axis-induced ERRα re-expression promotes survival of gefitinib and osimertinib-resistant cancer cells. Besides, we demonstrate the potential of lowing cholesterol and downregulation of ERRα as effective adjuvant treatment of NSCLC.
研究领域:
肿瘤学
·
分子生物学
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药理学
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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）