Gastroenterology Report
·
2020
·Vol. 8
·期 6
·465-475
·
IF 2.96
Hou Yong-Qiang,Wang Ying-Ying,Wang Xing-Can,Liu Yao,Zhang Chun-Ze,Chen Zhe-Sheng,Zhang Zhe,Wang Wei,Kong De-Xin
BackgroundColorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Novel drugs for CRC therapy are urgently needed. Digoxin has been in clinical use for treatment of heart failure and atrial arrhythmias for many years. Fragmentary reports suggested that digoxin might have antitumor efficacy on CRC. Here, we aimed to investigate the antitumor effect of digoxin on human CRC cells and the underlying mechanism.MethodsCell viability was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay and plate colony formation assay. The effects of digoxin on cell-cycle distribution and apoptosis were analysed by flow cytometry. The anti-metastatic effect on tumor cells was determined by wound-healing assay and transwell assay. Anti-angiogenic effect was examined by determining the inhibition against proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs). Mechanism study was performed by Western blot, enzyme-linked immunosorbent assay (ELISA), and gelatin-zymography assay.ResultsDigoxin potently inhibited cell proliferation, induced G1-phase and G2/M-phase arrest in colorectal-cancer HCT8 and SW620 cells, respectively. No obvious apoptosis was observed in the treated cells. Anti-metastatic activities were shown on HCT8 cells by inhibiting the migration and invasion. Meanwhile, the expression of MMP2, MMP9, and phosphorylated Integrinβ1 were decreased. Digoxin inhibited the proliferation, migration, and tube formation of HUVECs and reduced HIF1α expression and vascular endothelial growth factor A (VEGF-A) secretion in HCT8 cells, suggesting anti-angiogenic activity. Furthermore, digoxin significantly reversed ABCB1-mediated multidrug resistance on SW620/Ad300 cells.ConclusionOur findings suggest that digoxin has the potential to be applied as an antitumor drug via inhibiting proliferation and metastasis as well as reversing the ABCB1-mediated multidrug resistance of colorectal cancer.
研究领域:
肿瘤学
·
药理学
·
细胞生物学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2019
·
IF 7.901
Qida Hu,Wangteng Wu,Meng Wang,Shiyi Shao,Piaopiao Jin,Qi Chen,Hongzhen Bai,Xinyu Zhao,Junming Huang,Jianwei Wang,Guping Tang,Tingbo Liang
Malignancies treated by insoluble targeted agents show low dose exposure and therapeutic responses, therefore easily develop drug resistance. Nanoparticle-modified drugs might disrupt chemoresistance by increasing dose exposure and altering resistance pathways, as administrated via the intravenous route to maximize efficacy. Herein, we proposed a self-assembled nanocapsulation strategy to construct a nanocomplex with multiarm polymer and novel dendrimer series (MAP-mG3) for encapsulating insoluble inhibitors by nucleotide lock. MAP-mG3 delivering the mammalian target of rapamycin (mTOR) inhibitor OSI-027 (MAP-mG3/OSI-027) showed higher loading capacity, enhanced solubility, controlled release, and increased intracellular tumoral accumulation. MAP-mG3/OSI-027, more efficiently than the free targeted agents, attenuated mTOR phosphorylation and inhibited growth of pancreatic cancer cells. In addition, MAP-mG3/OSI-027 reverted chemoresistance to OSI-027 in drug resistance pancreatic cancer by increasing intracellular dose exposure, as well as regulating ABCB1 expression and compensatory pathways. The optimized nanocapsulation design provides an effective strategy to engineer and reactivate insoluble targeted agents for chemoresistant applications.
研究领域:
药理学
·
纳米技术
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2021
·Vol. 13
·期 3
·303
·
IF 6.321
Jia Wen,Xiuge Gao,Qian Zhang,Benazir Sahito,Hongbin Si,Gonghe Li,Qi Ding,Wenda Wu,Eugenie Nepovimova,Shanxiang Jiang,Liping Wang,Kamil Kuca,Dawei Guo
Tilmicosin (TMS) is widely used to treat bacterial infections in veterinary medicine, but the clinical effect is limited by its poor solubility, bitterness, gastric instability, and intestinal efflux transport. Nanostructured lipid carriers (NLCs) are nowadays considered to be a promising vector of therapeutic drugs for oral administration. In this study, an orthogonal experimental design was applied for optimizing TMS-loaded NLCs (TMS-NLCs). The ratios of emulsifier to mixed lipids, stearic acid to oleic acid, drugs to mixed lipids, and cold water to hot emulsion were selected as the independent variables, while the hydrodynamic diameter (HD), drug loading (DL), and entrapment efficiency (EE) were the chosen responses. The optimized TMS-NLCs had a small HD, high DL, and EE of 276.85 ± 2.62 nm, 9.14 ± 0.04%, and 92.92 ± 0.42%, respectively. In addition, a low polydispersity index (0.231 ± 0.001) and high negative zeta potential (−31.10 ± 0.00 mV) indicated the excellent stability, which was further demonstrated by uniformly dispersed spherical nanoparticles under transmission electron microscopy. TMS-NLCs exhibited a slow and sustained release behavior in both simulated gastric juice and intestinal fluid. Furthermore, MDCK-chAbcg2/Abcb1 cell monolayers were successfully established to evaluate their absorption efficiency and potential mechanism. The results of biodirectional transport showed that TMS-NLCs could enhance the cellular uptake and inhibit the efflux function of drug transporters against TMS in MDCK-chAbcg2/Abcb1 cells. Moreover, the data revealed that TMS-NLCs could enter the cells mainly via the caveolae/lipid raft-mediated endocytosis and partially via macropinocytosis. Furthermore, TMS-NLCs showed the same antibacterial activity as free TMS. Taken together, the optimized NLCs were the promising oral delivery carrier for overcoming oral administration obstacle of TMS.Keywords:tilmicosin;nanostructured lipid carriers;orthogonal design;intestinal absorption;MDCK-chAbcg2/Abcb1 cell monolayer
研究领域:
药学
·
兽医学
·
纳米技术
·
药物递送系统
·
药代动力学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioengineered
·
2022
·
IF 6.832
Fan-Cheng Kong,Li-Qin Lang,Jie Hu,Xia-Ling Zhang,Ming-Kang Zhong,Chun-Lai Ma
Drug-resistant epilepsy (DRE) is a chronic condition derived from spontaneous changes and regulatory effects in the epileptic brain. As demethylation factors, ten-eleven translocation (TET) family members have become a focus in recent studies of neurological disorders. Here, we quantified and localized TET1, TET2 and 5-hydroxymethylcytosine (5-hmC) in the temporal lobe cortex of DRE patients (n = 27) and traumatic brain hemorrhage controls (n = 10) by immunochemical staining. TET2 and ATP binding cassette subfamily B member 1 (ABCB1) expression patterns were determined in the isolated brain capillaries of DRE patients. TET2 expression was significantly increased in the temporal cortical tissue of DRE patients with or without hippocampal sclerosis (HS) compared to control patients, while TET1 and 5-hmC showed no differences in expression. We also found that a particularly strong expression of TET2 in the vascular tissue of DRE patients. ABCB1 and TET2 have evidently higher expression in the vascular endothelium from the neocortex of DRE patients. In blood–brain barrier (BBB) model, TET2 depletion can cause attenuated expression and function of ABCB1. Data from a cohort study and experiments in a BBB model suggest that TET2 has a specific regulatory effect on ABCB1, which may serve as a potential mechanism and target in DRE.
研究领域:
神经病学
·
表观遗传学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2021
·
IF 15.881
Jia-Wei Wang,Qi-Wen Chen,Guo-Feng Luo,Zi-Yi Han,Wen-Fang Song,Juan Yang,Wei-Hai Chen,Xian-Zheng Zhang
The excessive lactate in the tumor microenvironment always leads to poor therapeutic outcomes of chemotherapy. In this study, a self-driven bioreactor (defined as SO@MDH, where SO is Shewanella oneidensis MR-1 and MDH is MIL-101 metal–organic framework nanoparticles/doxorubicin/hyaluronic acid) is rationally constructed via the integration of doxorubicin (DOX)-loaded metal–organic framework (MOF) MIL-101 nanoparticles with SO to sensitize chemotherapy. Owing to the intrinsic tumor tropism and electron-driven respiration of SO, the biohybrid SO@MDH could actively target and colonize hypoxic and eutrophic tumor regions and anaerobically metabolize lactate accompanied by the transfer of electrons to Fe3+, which is the key component of the MIL-101 nanoparticles. As a result, the intratumoral lactate would undergo continuous catabolism coupled with the reduction of Fe3+ to Fe2+ and the subsequent degradation of MIL-101 frameworks, leading to an expeditious drug release for effective chemotherapy. Meanwhile, the generated Fe2+ will be promptly oxidized by the abundant hydrogen peroxide in the tumor microenvironment to reproduce Fe3+, which is, in turn, beneficial to circularly catabolize lactate and boost chemotherapy. More importantly, the consumption of intratumoral lactic acid could significantly inhibit the expression of multidrug resistance-related ABCB1 protein (also named P-glycoprotein (P-gp)) for conquering drug-resistant tumors. SO@MDH demonstrated here holds high tumor specificity and promising chemotherapeutic efficacy for suppressing tumor growth and overcoming multidrug resistance, confirming its potential prospects in cancer therapy.
研究领域:
生物技术
·
癌症治疗
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纳米技术
·
生物化学
·
药学
✓ 已验证
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）