目的探讨五味子甲素(schizandrin A or deoxyschizan-drin,schA)对白血病细胞K562/ADR、HL60/ADR、乳腺癌细胞MCF-7/ADR多药耐药的逆转作用,并初步探讨其逆转机制。方法 MTT法检测schA对耐药细胞的逆转作用;流式细胞仪检测schA对细胞内...目的探讨五味子甲素(schizandrin A or deoxyschizan-drin,schA)对白血病细胞K562/ADR、HL60/ADR、乳腺癌细胞MCF-7/ADR多药耐药的逆转作用,并初步探讨其逆转机制。方法 MTT法检测schA对耐药细胞的逆转作用;流式细胞仪检测schA对细胞内柔红霉素、罗丹明-123含量和细胞表面P-gp表达水平的变化;用Real-time PCR方法检测schA对细胞内mdr1 mRNA和mrp1 mRNA表达;生化检测法检测schA对细胞内GSH含量的变化。结果耐药逆转实验显示:不同浓度的schA对作用机制不同的化疗药物耐药产生不同的逆转效果;蓄积实验表明schA可增加柔红霉素、罗丹明123在耐药细胞内的蓄积,并且有良好的剂量依赖关系;schA处理K562/ADR、HL60/ADR细胞24 h后,能降低P-gp蛋白和mdr1、mrp1基因的表达;schA处理K562/ADR、HL60/ADR细胞4 h后,可降低细胞内谷胱甘肽含量。结论 schA对耐药机制不同的细胞株K562/ADR、HL60/ADR均有耐药逆转作用,推测可能是与抑制细胞表面的P-gp蛋白功能和表达,降低mdr1、mrp1耐药基因的表达和降低细胞内谷胱甘肽含量有关,schA通过影响上述机制,进而增加细胞内的药物浓度,达到有效杀灭肿瘤细胞的作用。展开更多
Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel ...Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds.展开更多
Objective:To investigate the molecular effects ofNerium oleanderleaf distillate on paclitaxel and vincristine resistant(MCF-7/Pac and MCF-7/Vinc)cells and sensitive(MCF-7/S)cell lines.Methods:Nerium oleander(N.oleande...Objective:To investigate the molecular effects ofNerium oleanderleaf distillate on paclitaxel and vincristine resistant(MCF-7/Pac and MCF-7/Vinc)cells and sensitive(MCF-7/S)cell lines.Methods:Nerium oleander(N.oleander)leaf extract was obtained by hydrodistillation method.The toxicological effects ofN.oleanderdistillate,previously suggested as medicinal food supplement,on drug resistant cells were evaluated by XTT tests.MDR modulation potential of the plant material was evaluated by flow cytometry and fluorescent microscopy.Paclitaxel and vincristine were applied to the sublines in combination with N.oleanderdistillate.Results:Fractional inhibitory indices show thatN.oleanderdistillate did not increase the antiproliferative effects of anticancer drugs.N.oleandertreatment in to MCF-7/Pac and MCF-7/Vinc did not inhibit P-gp activity and MDR1 gene expression level.Conclusions:As a result it may be suggested that althoughN.oleanderdistillate has some medicinal effects as food supplement it may not be suitable as an MDR modulator for drug resistant breast cancer cells.展开更多
TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concen...TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.展开更多
OBJECTIVE The aim of the study was to examine the reversal effects of ultrasound （US） on the MDR in HepG2/ADM, a HepG2 cell line resistant to Adriamycin （ADM）, and to study the mechanism of US action.METHODS Using...OBJECTIVE The aim of the study was to examine the reversal effects of ultrasound （US） on the MDR in HepG2/ADM, a HepG2 cell line resistant to Adriamycin （ADM）, and to study the mechanism of US action.METHODS Using the MTT assay, the effects of US on MDR in HepG2/ADR cells were studied. Before and after the treatment with 0.5 W/cm^2 low intensity ultrasound （LIUS）, the expression of the MDR-related genes, mdrl, mrp and lrp was assayed with the reverse transcriptase polymerase chain reaction （RT-PCR） and the levels of their respective protein expression determined by flow cytometry. By using confocal laser scanning microscopy （CLSM）, we examined the intracellular daunorubicin （DNR） distribution, and the effects on the cells of treatment with US or DNR.RESULTS LIUS significantly reversed MDR in HepG2/ADR cells. After treatment with LIUS at 0.5 W/cm^2, chemosensitivity to ADM and DNR increased 3.35-fold and 2.81-fold, respectively. The reversal activity by LIUS plus verapamil （VER） was stronger than with either US or VER alone. After treatment with 0.5 W/cm^2, the expression of both the MDR1 and the MRP mRNA genes began to decline （P 〈 0.01 and P 〈 0.05, respectively）; the expression of LRP showed no significant changes. Changes in the expression of the P-glycoprotein （P-gp） and MRP were similar to those of their mRNA expressions. Results of the CLSM showed that administration of US （0. 5 W/cm^2） or VER （15.7 uM） with DNR to HepGa/ADM cells showed a significant change in the distribution of DNR in the cells.CONCLUSION Our results show that LIUS can reverse MDR. The reversal effects are stronger than those of either US or VER alone, when combined with VER administration. As LIUS is noninvasive causing no toxicity, it might have potential for clinical application. The reversal mechanism needs further study.展开更多
基金supported by the National Natural Science Foundation of P.R.China(Nos.81170492,81370673)National High Technology Research and Development Program 863 of P.R.China(No.2012AA022703)+2 种基金National Key Basic Research Program 973 of P.R.China(No.2010CB732404)Key Medical Projects of Jiangsu Province(No.BL2014078)Key Discipline of Jiangsu Province(2011-2015)
文摘Multidrug resistance remains a serious clinical problem in the successful therapy of malignant diseases. It occurs in cultured tumor cell lines, as well as in human cancers. Therefore, it is critical to develop novel anticancer drugs with multidrug-resistance modulating potential to increase the survival rate of leukemia patients. Plant-derived natural products have been used for the treatment of various diseases for thousands of years. This review summarizes the anticancer and multidrug-resistance reversing properties of the extracts and bioactive compounds from traditional medicinal plants in different leukemia cell lines. Further mechanistic studies will pave the road to establish the anticancer potential of plant-derived natural compounds.
基金Supported by TUBITAK with the project number 111S039by the Selcuk University Research Fund with the project number 11401014
文摘Objective:To investigate the molecular effects ofNerium oleanderleaf distillate on paclitaxel and vincristine resistant(MCF-7/Pac and MCF-7/Vinc)cells and sensitive(MCF-7/S)cell lines.Methods:Nerium oleander(N.oleander)leaf extract was obtained by hydrodistillation method.The toxicological effects ofN.oleanderdistillate,previously suggested as medicinal food supplement,on drug resistant cells were evaluated by XTT tests.MDR modulation potential of the plant material was evaluated by flow cytometry and fluorescent microscopy.Paclitaxel and vincristine were applied to the sublines in combination with N.oleanderdistillate.Results:Fractional inhibitory indices show thatN.oleanderdistillate did not increase the antiproliferative effects of anticancer drugs.N.oleandertreatment in to MCF-7/Pac and MCF-7/Vinc did not inhibit P-gp activity and MDR1 gene expression level.Conclusions:As a result it may be suggested that althoughN.oleanderdistillate has some medicinal effects as food supplement it may not be suitable as an MDR modulator for drug resistant breast cancer cells.
基金This work is financially supported by the National Natural Science Foundation of China(No.51803001)the Research Foundation of Education Department of Anhui Province of China(No.KJ2018ZD003 and KJ2018A0006)the Academic and Technology Introduction Project of Anhui University(AU02303203).
文摘TPGS approved by FDA can be used as a P-gp inhibitor to effectively reverse multi-drug resistance(MDR)and as an anticancer agent for synergistic antitumor effects.However,the comparatively high critical micelle concentration(CMC),low drug loading(DL)and poor tumor target limit its further clinical application.To overcome these drawbacks,the pH-sensitive star-shaped TPGS copolymers were successfully constructed via using pentaerythritol as the initial materials,ortho esters as the pH-triggered linkages and TPGS active-ester as the terminated MDR material.The amphiphilic star-shaped TPGS copolymers could self-assemble into free and doxorubicin(DOX)-loaded micelles at neutral aqueous solutions.The micelles exhibited the lower CMC(8.2×10^(−5) mg/ml),higher DL(10.8%)and long-term storage and circulation stability,and showed enhanced cellular uptake,apoptosis,cytotoxicity,and growth inhibition for in vitro MCF-7/ADR and/or MCF-7/ADR multicellular spheroids and in vivo MCF-7/ADR tumors via efficiently targeted drug release at tumoral intracellular pH(5.0),MDR reversal of TPGS,and synergistic effect of DOX and TPGS.Therefore,the pH-sensitive micelles self-assembled from star-shaped TPGS copolymers with ortho ester linkages are potentially useful to clinically transform for enhanced MDR cancer treatment.
基金a grant from National Natural Science Foundation of China (No.30200060)
文摘OBJECTIVE The aim of the study was to examine the reversal effects of ultrasound （US） on the MDR in HepG2/ADM, a HepG2 cell line resistant to Adriamycin （ADM）, and to study the mechanism of US action.METHODS Using the MTT assay, the effects of US on MDR in HepG2/ADR cells were studied. Before and after the treatment with 0.5 W/cm^2 low intensity ultrasound （LIUS）, the expression of the MDR-related genes, mdrl, mrp and lrp was assayed with the reverse transcriptase polymerase chain reaction （RT-PCR） and the levels of their respective protein expression determined by flow cytometry. By using confocal laser scanning microscopy （CLSM）, we examined the intracellular daunorubicin （DNR） distribution, and the effects on the cells of treatment with US or DNR.RESULTS LIUS significantly reversed MDR in HepG2/ADR cells. After treatment with LIUS at 0.5 W/cm^2, chemosensitivity to ADM and DNR increased 3.35-fold and 2.81-fold, respectively. The reversal activity by LIUS plus verapamil （VER） was stronger than with either US or VER alone. After treatment with 0.5 W/cm^2, the expression of both the MDR1 and the MRP mRNA genes began to decline （P 〈 0.01 and P 〈 0.05, respectively）; the expression of LRP showed no significant changes. Changes in the expression of the P-glycoprotein （P-gp） and MRP were similar to those of their mRNA expressions. Results of the CLSM showed that administration of US （0. 5 W/cm^2） or VER （15.7 uM） with DNR to HepGa/ADM cells showed a significant change in the distribution of DNR in the cells.CONCLUSION Our results show that LIUS can reverse MDR. The reversal effects are stronger than those of either US or VER alone, when combined with VER administration. As LIUS is noninvasive causing no toxicity, it might have potential for clinical application. The reversal mechanism needs further study.
