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Kenneth K W To Daniel C Poon Yuming Wei Fang Wang Ge Lin Liwu Fu 《British journal of pharmacology》2015,172(16):4089-4106
Background and Purpose
Pelitinib is a potent irreversible EGFR TK inhibitor currently in clinical trials for the treatment of lung cancer. Hyperthermia has been applied concomitantly with chemotherapy and radiotherapy to enhance treatment outcome. In this study, we investigated the ability of the combination of pelitinib with other conventional anticancer drugs to specifically target cancer cells with up-regulated efflux transporters ABCB1/ABCG2 after hyperthermia as a novel way to eradicate the cancer stem-like cells responsible for cancer recurrence.Experimental Approach
Alterations in intracellular topotecan accumulation, the efflux of fluorescent probe substrates, expression and ATPase activity of ABCB1/ABCG2 and tumoursphere formation capacity of side population (SP) cells sorted after hyperthermia were examined to elucidate the mechanism of pelitinib-induced chemosensitization.Key Results
While pelitinib did not modulate ABCB1/ABCG2 expressions, the combination of pelitinib with transporter substrate anticancer drugs induced more marked apoptosis, specifically in cells exposed to hyperthermia. The flow cytometric assay showed that both ABCB1- and ABCG2-mediated drug effluxes were significantly inhibited by pelitinib in a concentration-dependent manner. The inhibition kinetics suggested that pelitinib is a competitive inhibitor of ABCB1/ABCG2, which is consistent with its ability to stimulate their ATPase activity. SP cells sorted after hyperthermia were found to be more resistant to anticancer drugs, presumably due to the up-regulation of ABCB1 and ABCG2. Importantly, pelitinib specifically enhanced the chemosensitivity but reduced the tumoursphere formation capacity of these SP cells.Conclusions and Implications
This study demonstrated a novel approach, exploiting drug resistance, to selectively kill cancer stem-like cells after hyperthermia. 相似文献3.
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Wei-Ling Chang Chih-Shiang Chang Po-Cheng Chiang Yunn-Fang Ho Ju-Fang Liu Kai-Wei Chang Jih-Hwa Guh 《British journal of pharmacology》2010,160(7):1677-1689
BACKGROUND AND PURPOSE
The c-Jun N-terminal kinase (JNK) and tubulin are, frequently, targets for developing anti-cancer drugs. A major obstacle to successful development is P-glycoprotein (P-gp)-mediated resistance. Here, we have assessed a compound that inhibited growth of cancer cells, for effects on JNK and tubulin and as a substrate for P-gp.EXPERIMENTAL APPROACH
Several pharmacological and biochemical assays were used to characterize signalling pathways of 2-phenyl-5-(pyrrolidin-1-yl)-1-(3,4,5-trimethoxybenzyl)-1H-benzimidazole (PPTMB), a benzimidazole analogue, in prostate cancer cells.KEY RESULTS
PPTMB inhibited proliferation of several human prostate cancer cell lines. It displayed similar activity against a P-gp-rich cell line, indicating that PPTMB was not a substrate for P-gp. PPTMB induced G2/M arrest of the cell cycle and subsequent apoptosis, using flow cytometry. Tubulin polymerization assays and Western blot analysis showed that PPTMB directly acted on tubulin and caused disruption of microtubule dynamics, inducing mitotic arrest and sustained high levels of cyclin B1 expression and Cdk1 activation. Subsequently, mitochondria-related apoptotic cascades were induced, including Bcl-2 and Bcl-xL phosphorylation, Mcl-1 down-regulation, truncated Bad formation and activation of caspase-9 and -3. PPTMB stimulated JNK phosphorylation at Thr183/Tyr185. SP600125, a specific JNK inhibitor, significantly inhibited apoptotic signalling, indicating that JNK plays a key role in PPTMB action. PPTMB showed a 10-fold higher potency against prostate cancer cells than normal prostate cells.CONCLUSIONS AND IMPLICATIONS
PPTMB is an effective anti-cancer agent. It disrupted microtubule dynamics, leading to mitotic arrest of the cell cycle and JNK activation, which in turn stimulated the mitochondria-related apoptotic cascades in prostate cancer cells. 相似文献5.
BACKGROUND AND PURPOSE
Recently, the DNA damage response (DDR) has emerged as a promising target for anticancer drug development. In our previous study, we identified several DDR-inhibiting compounds via high-content screening of a small molecule library using γH2AX foci as a biomarker. Here, we studied the effects of the DNA damage response inhibitor DDRI-18 (3,3′-(1H,3′H-5,5′-bibenzo[d]imidazole-2,2′-diyl)dianiline) on DDR.EXPERIMENTAL APPROACH
Osteosarcoma U2OS cells were treated with etoposide to induce DDR. The nuclear foci of γH2AX and other signalling molecules in DDR were visualized by immunofluorescence and quantified using an IN Cell Analyzer. The DNA repair capacity of cells was analysed using the comet assay and in vivo DNA end-joining assay. Cell survival after drug treatment was quantified using the MTT assay, and apoptotic cell death was analysed by Annexin V staining and flow cytometry.KEY RESULTS
DDRI-18 inhibited the non-homologous end-joining (NHEJ) DNA repair process and delayed the resolution of DNA damage-related proteins (γH2AX, ATM and BRCA1) from DNA lesions at a later phase of DDR. Furthermore, DDRI-18 enhanced the cytotoxic effects of anticancer DNA-damaging drugs, including etoposide, camptothecin, doxorubicin and bleomycin. This synergistic effect on cell death was shown to be due to caspase-dependent apoptosis.CONCLUSIONS AND IMPLICATIONS
We identified a chemical compound, DDRI-18, that has chemosensitization activity. Although the target molecule and mechanism of action of DDRI-18 remain unknown, DDRI-18 is an effective chemosensitizing agent and may improve the therapy with classical anticancer drugs. 相似文献6.
ML Pinzón-Daza R Garzón PO Couraud IA Romero B Weksler D Ghigo A Bosia C Riganti 《British journal of pharmacology》2012,167(7):1431-1447
BACKGROUND AND PURPOSE
The passage of drugs across the blood–brain barrier (BBB) limits the efficacy of chemotherapy in brain tumours. For instance, the anticancer drug doxorubicin, which is effective against glioblastoma in vitro, has poor efficacy in vivo, because it is extruded by P-glycoprotein (Pgp/ABCB1), multidrug resistance-related proteins and breast cancer resistance protein (BCRP/ABCG2) in BBB cells. The aim of this study was to convert poorly permeant drugs like doxorubicin into drugs able to cross the BBB.EXPERIMENTAL APPROACH
Experiments were performed on primary human cerebral microvascular endothelial hCMEC/D3 cells, alone and co-cultured with human brain and epithelial tumour cells.KEY RESULTS
Statins reduced the efflux activity of Pgp/ABCB1 and BCRP/ABCG2 in hCMEC/D3 cells by increasing the synthesis of NO, which elicits the nitration of critical tyrosine residues on these transporters. Statins also increased the number of low-density lipoprotein (LDL) receptors exposed on the surface of BBB cells, as well as on tumour cells like human glioblastoma. We showed that the association of statins plus drug-loaded nanoparticles engineered as LDLs was effective as a vehicle for non-permeant drugs like doxorubicin to cross the BBB, allowing its delivery into primary and metastatic brain tumour cells and to achieve significant anti-tumour cytotoxicity.CONCLUSIONS AND IMPLICATIONS
We suggest that our ‘Trojan horse’ approach, based on the administration of statins plus a LDL receptor-targeted liposomal drug, might have potential applications in the pharmacological therapy of different brain diseases for which the BBB represents an obstacle. 相似文献7.
Gui'e Xie Xun Zhu Qing Li Minghui Gu Zhenjian He Jueheng Wu Jun Li Yongcheng Lin Mengfeng Li Zhigang She Jie Yuan 《British journal of pharmacology》2010,159(3):689-697
Background and purpose:
The aims of this study were to investigate the anti-cancer activity of SZ-685C, an anthracycline analogue isolated from marine-derived mangrove endophytic fungi, and to explore the molecular mechanisms underlying such activity.Experimental approach:
The effect of SZ-685C on the viability of cancer cell lines was investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. SZ-685C-induced apoptosis was assessed by Annexin V-fluorescein isothiocyanate/propidium iodide staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assay and analysis of caspase activation. The effect of SZ-685C on the Akt/FOXO pathway was studied using Western blotting analysis, and the in vivo anti-tumour efficacy was examined in an MDA-MB-435 breast cancer xenograft model.Key results:
SZ-685C suppressed the proliferation of six cancer cell lines derived from human breast cancer, prostate cancer, glioma and hepatoma (IC50 values ranged from 3.0 to 9.6 µM) and the growth of breast cancer xenografts in mice. SZ-685C had a direct apoptosis-inducing effect through both the extrinsic and intrinsic apoptotic pathways, as shown by activation of caspase-8 and 9 as well as effector caspase-3 and poly (ADP-ribose) polymerase. Phosphorylation of Akt and its downstream effectors, forkhead box protein O1 and forkhead box protein O3a, was down-regulated in SZ-685C-treated cancer cells. Furthermore, the pro-apoptotic protein Bim was up-regulated by SZ-685C treatment consistent with FOXO dephosphorylation.Conclusions and implications:
SZ-685C could induce apoptosis through the Akt/FOXO pathway, which consequently leads to the observed anti-tumour effect both in vitro and in vivo. Our data suggest that SZ-685C may be a potentially promising Akt inhibitor and anti-cancer drug candidate. 相似文献8.
Background and purpose:
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptotic death in a variety of cancer cells without marked toxicity to most normal cells. We previously reported that wogonin, a potent anticancer agent from a Chinese herb, up-regulates p53 in prostate cancer cells. In this study, the effects of combinations of TRAIL and wogonin on a human prostate cancer cell line LNCaP, resistant to TRAIL, was evaluated for evidence of synergy in triggering apoptosis.Experimental approach:
Western blot assay and the ‘comet’ assay were used to study the underlying mechanisms of cell death and search for any mechanisms of enhancement of TRAIL-induced apoptosis in the presence of wogonin.Key results:
During combined treatment with wogonin and TRAIL, cytotoxicity, poly(ADP-ribose) polymerase cleavage and caspase activation were associated with up-regulation of p53 through DNA damage and reactive oxygen species (ROS) generation. N-acetylcysteine (NAC), an antioxidant, inhibited ROS generation and synergistic interaction between TRAIL and wogonin. Experimental results in human colon cancer HCT116 cells demonstrated that p53-dependent Puma up-regulation played an important role; deficiency in either p53 or Puma prevented wogonin-enhanced TRAIL-induced apoptosis.Conclusions and implications:
The present studies suggest that wogonin enhances TRAIL-induced cytotoxicity through up-regulation of p53 and Puma, mediated by ROS. 相似文献9.
Ai-hui XU Zhi-min HU Jian-bo QU Shang-ming LIU Ali Kazim Abbas SYED Hui-qing YUAN Hong-xiang LOU 《Acta pharmacologica Sinica》2010,31(5):609-615
Aim:
To investigate the cytotoxic effects of four cyclic bisbibenzyls, Riccardin C (Ric), Pakyonol (Pak), Marchantin M (Mar), and Plagiochin E (Pla) against chemoresistant prostate cancer PC3 cells.Methods:
Cell growth was assayed by MTT method, and apoptotic related protein Bcl-2 and Bax, poly(ADP-ribose) polymerase (PARP) were examined by Western blotting. Cell cycle and apoptosis of PC3 cells were evaluated with flow cytometry and morphologic examinations.Results:
The four compounds inhibited proliferation and elicited cell death in a dose- and time-dependent manner with IC50 values of 3.22 μmol/L for Ric, 7.98 μmol/L for Pak, 5.45 μmol/L for Mar, and 5.99 μmol/L for Pla, respectively. Furthermore, exposed to these chemicals caused a decrease in the antiapoptotic protein Bcl-2 and an increase in proapoptotic Bax expression. PARP cleavage and caspase-3 activity were also observed.Conclusion:
The results suggest that cyclic bisbibenzyls could be used for the development of novel therapeutic chemicals against prostate cancer. 相似文献10.
Objective
To describe the development and assessment of monographs as an assignment to incorporate evidence-based medicine (EBM) and pharmacoeconomic principles into a third-year pharmacoeconomic course.Design
Eight newly FDA-approved drugs were assigned to 16 teams of students, where each drug was assigned to 2 teams. Teams had to research their drug, write a professional monograph, deliver an oral presentation, and answer questions posed by faculty judges. One team was asked to present evidence for inclusion of the drug into a formulary, while another team presented evidence against inclusion.Assessment
The teams'' average score on the written report was 99.1%; on the oral presentation, 92.5%, and on the online quiz given at the end of the presentations, 77%.Conclusions
Monographs are a successful method of incorporating and integrating learning across different concepts, as well as increasing relevance of pharmacoeconomics in the PharmD curriculum. 相似文献11.
Ying-tao LIU Yi LI Zi-fu HUANG Zhi-jian XU Zhuo YANG Zhu-xi CHEN Kai-xian CHEN Ji-ye SHI Wei-lia ng ZHU 《Acta pharmacologica Sinica》2014,35(3):419-431
Aim: To develop a reliable computational approach for predicting potential drug targets based merely on protein sequence. Methods: With drug target and non-target datasets prepared and 3 classification algorithms (Support Vector Machine, Neural Network and Decision Tree), a multi-algorithm and multi-model based strategy was employed for constructing models to predict potential drug targets. Results: Twenty one prediction models for each of the 3 algorithms were successfully developed. Our evaluation results showed that --30% of human proteins were potential drug targets, and--40% of putative targets for the drugs undergoing phase II clinical trials were probably non-targets. A public web server named D3TPredictor (http://www.d3pharma.com/d3tpredictor) was constructed to provide easy access. Conclusion: Reliable and robust drug target prediction based on protein sequences is achieved using the multi-algorithm and multi- model strategy. 相似文献
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Guo-hai SHI Ding-wei YE Xu-dong YAO Shi-ling ZHANG Bo DAI Hai-liang ZHANG Yi-jun SHEN Yao ZHU Yi-ping ZHU Wen-jun XIAO Chun-guang MA 《Acta pharmacologica Sinica》2010,31(7):867-873
Aim:
To investigate whether microRNA-21 was involved in mediating the chemoresistance of prostate cancer cells to docetaxel.Methods:
A microarray technique was used to determine the miRNA profile in docetaxel-resistant PC3 cells. Real-time PCR was used to confirm the array results. miR-21 mimics and inhibitors were synthesized and introduced to cells using Lipofectamine 2000. Cell proliferation was examined with the CCK-8 assay. Luciferase reporter containing PDCD 3′UTR was constructed and the activity was detected by a dual luciferase assay. PDCD4 protein expression was evaluated using Western blot.Results:
A docetaxel-resistant prostate cancer PC3 cell line (PC3R) was established . Using microarrays, miR-21 was found to be up-regulated in PC3R cells. Ectopic expression of miR-21 increased the resistance to docetaxel in PC3 wild type cells. In contrast, silencing of miR-21 in PC3R cells sensitized the cells to docetaxel. The IC50 values for miR-21-silencing cells and control cells were 28.31 and 35.89 nmol/L, respectively. PDCD4, a direct target gene of miR-21, could mediate chemoresistance to docetaxel in PC3 cells.Conclusion:
Our findings suggest that miR-21 contributed to the resistance of PC3 cells to docetaxel, and that targeting miR-21 may offer a promising therapeutic approach in sensitizing prostate cancer to docetaxel treatment. 相似文献13.
Aim:
To examine whether two naturally occurring sesquiterpenoids (ST1 and ST2) with anti-proliferative activity in prostate cancer cells inhibit androgen receptor (AR) signaling.Methods:
Human prostate cancer cell lines LNCaP and PC3 were used. The expression of AR, AR translocation into the nucleus, and expression levels of AR coactivators ARA70 and steroid receptor coactivator-1 (SRC-1) in LNCaP cells were examined using real-time PCR and Western blot. Changes in prostate-specific antigen (PSA) protein levels, PSA promoter activity, and androgen response element (ARE)-mediated reporter gene activity were examined using enzyme-linked immunoabsorbent assay (ELISA) and transient transfection assays. Co-immunoprecipitation was performed to analyze the interaction between AR and the AR coactivators in ST1- and ST2-treated cells.Results:
In LNCaP cells, ST1 and ST2 (40 μmol/L) led to a significant decrease in the expression of AR as well as a reduction of AR translocation into the nucleus, but had no effect on AR protein translation. ST1 and ST2 treatment also resulted in a significant decrease in the level of PSA protein secreted into the medium and was able to suppress PSA promoter-dependent and ARE-dependent luciferase activity. Furthermore, decreased expression of ARA70 and SRC-1 was observed when LNCaP cells were exposed to ST1 and ST2, which interfered with their ability to interact with AR.Conclusion:
The observations suggest that suppression of AR transactivation by ST1 and ST2 may be mediated, in part, by inhibiting AR nuclear translocation and/or interfering with the interaction between AR and its coactivators ARA70 and SRC-1. Therefore, sesquiterpenoids could be developed as novel therapeutic agents for treating prostate cancer. 相似文献14.
Background:
Incorporation of drug restriction policy into electronic drug order entries (DOEs) can promote responsible medication use and resource utilization when implemented systematically.Objective:
To identify drugs that require further incorporation of formulary restriction policy into their DOEs after migration to an electronic health record with computerized prescriber order entry (CPOE).Methods:
After transition to CPOE, test orders for formulary restricted drugs were entered in the CPOE environment. Data were collected about rationale for drug restriction, type of formulary restriction, presence of incorporation of restriction policy into the DOE, and whether incorporation was consistent with a recommended method. Restricted drugs requiring revision of policy incorporation into their DOEs were analyzed to create a prioritized task list based on rationale for the restriction.Results:
Of all restricted drugs, 63.6% (287/451) did not have restriction policy incorporated into their DOEs consistent with the recommended method and therefore required revision. Eighteen percent (81/451) of restricted drugs had no incorporation of restriction policy in their DOEs. Safety was the rationale for restriction in 21% (17/81) of these, which received highest priority for revision. When drugs were orderable but restricted, 61.9% (78/126) lacked optimal incorporation of policy in DOEs to promote adherence. When drugs were not orderable, 64% (206/322) did not provide guidance to formulary alternatives in DOEs when they should have.Conclusion:
After transition to CPOE, almost two-thirds of all analyzed restricted drugs lacked optimal incorporation of formulary restriction policies in their DOEs. DOEs with restrictions related to safety reasons were among those most frequently requiring revision. Some DOEs can better promote adherence and provide guidance to prescribers through revision. Predefined, systematic implementation strategies should be used during changes in computerized drug use processes. 相似文献15.
Dancik Y Anissimov YG Jepps OG Roberts MS 《British journal of clinical pharmacology》2012,73(4):564-578
AIMS
To relate the varying dermal, subcutaneous and muscle microdialysate concentrations found in man after topical application to the nature of the drug applied and to the underlying physiology.METHODS
We developed a physiologically based pharmacokinetic model in which transport to deeper tissues was determined by tissue diffusion, blood, lymphatic and intersitial flow transport and drug properties. The model was applied to interpret published human microdialysis data, estimated in vitro dermal diffusion and protein binding affinity of drugs that have been previously applied topically in vivo and measured in deep cutaneous tissues over time.RESULTS
Deeper tissue microdialysis concentrations for various drugs in vivo vary widely. Here, we show that carriage by the blood to the deeper tissues below topical application sites facilitates the transport of highly plasma protein bound drugs that penetrate the skin, leading to rapid and significant concentrations in those tissues. Hence, the fractional concentration for the highly plasma protein bound diclofenac in deeper tissues is 0.79 times that in a probe 4.5 mm below a superficial probe whereas the corresponding fractional concentration for the poorly protein bound nicotine is 0.02. Their corresponding estimated in vivo lag times for appearance of the drugs in the deeper probes were 1.1 min for diclofenac and 30 min for nicotine.CONCLUSIONS
Poorly plasma protein bound drugs are mainly transported to deeper tissues after topical application by tissue diffusion whereas the transport of highly plasma protein bound drugs is additionally facilitated by convective blood, lymphatic and interstitial transport to deep tissues. 相似文献16.
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Darwich AS Henderson K Burgin A Ward N Whittam J Ammori BJ Ashcroft DM Rostami-Hodjegan A 《British journal of clinical pharmacology》2012,74(5):774-787
AIMS
To identify the most commonly prescribed drugs in a bariatric surgery population and to assess existing evidence regarding trends in oral drug bioavailability post bariatric surgery.METHODS
A retrospective audit was undertaken to document commonly prescribed drugs amongst patients undergoing bariatric surgery in an NHS hospital in the UK and to assess practice for drug administration following bariatric surgery. The available literature was examined for trends relating to drug permeability and solubility with regards to the Biopharmaceutics Classification System (BCS) and main route of elimination.RESULTS
No significant difference in the ‘post/pre surgery oral drug exposure ratio’ (ppR) was apparent between BCS class I to IV drugs, with regards to dose number (Do) or main route of elimination. Drugs classified as ‘solubility limited’ displayed an overall reduction as compared with ‘freely soluble’ compounds, as well as an unaltered and increased ppR.CONCLUSION
Clinical studies establishing guidelines for commonly prescribed drugs, and the monitoring of drugs exhibiting a narrow therapeutic window or without a readily assessed clinical endpoint, are warranted. Using mechanistically based pharmacokinetic modelling for simulating the multivariate nature of changes in drug exposure may serve as a useful tool in the further understanding of postoperative trends in oral drug exposure and in developing practical clinical guidance. 相似文献18.
AIM
Drug dosage adjustments in renal impairment are usually based on estimated individual pharmacokinetics. The extent of pharmacokinetic changes in patients with renal impairment must be known for this estimation. If measured data are not available, an estimate based on drug elimination in urine of healthy subjects or patients with normal renal function is commonly made. This is not reliable, however, if renal drug metabolism is involved, as is presumably the case for many peptide and protein drugs. In the present study a new method to predict pharmacokinetic changes for such drugs based on molecular weight was derived.METHODS
Articles reporting measured pharmacokinetics of peptide and protein drugs in patients with severe renal impairment or end-stage renal disease were identified from the scientific literature, the pharmacokinetic parameter values were extracted and a statistical data synthesis was performed. A sigmoid Emax model was applied and fitted to the data and the prediction error was analyzed.RESULTS
Overall, 98 peptide and protein drugs were identified. Relevant pharmacokinetic data in patients with renal impairment were found for 21 of these drugs. The average drug clearance was 30% and the average prolongation in half-life was 3.1-fold for low molecular weight peptides or proteins. The median root squared percentage of the prediction error was 18% (drug clearance) and 12% (half-life).CONCLUSION
An apparently continuous non-linear relationship between molecular weight and pharmacokinetic alterations in patients with severe renal impairment was found. The derived equations could be used as a rough guide for decisions on drug dosage adjustments in such patients. 相似文献19.
Moulis G Sommet A Durrieu G Bagheri H Lapeyre-Mestre M Montastruc JL;French Association of PharmacoVigilance Centres 《British journal of clinical pharmacology》2012,74(1):201-204
AIM
To investigate trends in spontaneous reporting to the French Pharmacovigilance system of ‘serious’ (SADRs) and ‘non-serious’ (NSADRs) adverse drug reactions over time.METHODS
Annual SADR : NSADR ratios were calculated for each drug and their evolution tested with linear trend tests.RESULTS
Among the 39 new active substances commercialized in France in 2000, 16 had sufficient data to perform linear trend tests. An increasing linear relation was found for five widely prescribed drugs, a non-significant increasing trend for eight others, i.e. drugs mostly used in hospitals.CONCLUSION
ADR reports mainly concern NSADRs during first years of marketing. Reports of SADRs are proportionally more frequent later. 相似文献20.
Radziwon-Balicka A Medina C O'Driscoll L Treumann A Bazou D Inkielewicz-Stepniak I Radomski A Jow H Radomski M 《British journal of pharmacology》2012,167(4):787-804