OBJECTIVE To investigate the cardioprotective effect of novel danshensu derivatives against doxorubicin(Dox)cardiotoxicity and their synergistic anti-tumor effect with Dox on breast cancer cells.METHODS Two new Danshe...OBJECTIVE To investigate the cardioprotective effect of novel danshensu derivatives against doxorubicin(Dox)cardiotoxicity and their synergistic anti-tumor effect with Dox on breast cancer cells.METHODS Two new Danshensu derivatives were synthesized by conjugation with tetramethylpyrizine and/or4-(3-thioxo-3 H-1,2-dithiol-4-yl)-benzoic acid and tested for protective effects against Dox induced cardiotoxicity in cell and zebrafish.H9c2 cardiomyoblasts were co-treated with Dox and Danshensu derivatives for 24 h and then were measured for cell viability and cytotoxicity by MTT and LDH assays.The expression levels of mitochondrial biogenesis related proteins PGC-1α,NRF-1and Nrf2 were detected by Western blotting and qPCR.Moreover,in a Dox-induced cardiotoxicity model of zebrafish,zebrafish embryos were treated with Dox for 36 h,followed by measurement of numerous ventricular function parameters including heart rate,stroke volume,cardiac output and fractional shortening.In addition,the synergistic anti-tumor effects of the Danshensu derivatives and Dox had been studied in MCF-7 breast cancer cells.The effects of the Danshensu derivatives on the cell death and metabolism of MCF-7 cells were measured using apoptosis assay and Seahorse Metabolic Analyzers respectively.RESULTS Our results showed that the Danshensu derivatives were more potent than the parental compounds in ameliorating Dox-induced cytotoxicity in H9c2 cells and significantly preserving stroke volume of heart function in Dox-treated zebrafish.Further mechanistic studies identified that the danshensu derivatives increased mitochondrial copy numbers and protein expressions of PGC-1α,NRF-1 and Nrf2 in H9c2 cells.In addition,the Danshensu derivatives enhanced Dox-induced apoptosis,and decreased glycolysis and mitochondrial function in MCF-7 tumor cells.CONCLUSION Our results revealed that two new Danshensu derivatives displayed promising cardioprotective effects against Dox induced cardiotoxicity both in vivo and in vitro,at least partially through activating mitochondrial biogenesis.Also,the new Danshensu derivatives potentiated the anticancer effects of Dox in breast tumor cells involving induction of glycolytic inhibition and mitochondrial dysfunction.展开更多
According to LN?,theoretical&true elongation of tensile,and by adopting the increasing function of formulas with the derivation and analogy methods,the elongation formula of 0<(1+ε)^1/ε<e&0<ε^1/ε&...According to LN?,theoretical&true elongation of tensile,and by adopting the increasing function of formulas with the derivation and analogy methods,the elongation formula of 0<(1+ε)^1/ε<e&0<ε^1/ε<1&four convergences are deduced too whenε>1 and 0<ε<1.The inequalities of LNε<εand LN(1+ε)<εand LN(1+ε)>LNεare deduced ifε>1 and 0<ε<1 in material dynamics.Finally the conclusions of LNε<εand LNε<LN(1+ε)<εare deduced together ifε>1 and 0<ε<1.展开更多
Background: Gemcitabine is a deoxycytidine analog, which is used as first-line agent for pancreatic cancer therapy, and its efficacy relied on its intracellular conversion to active triphosphate form. However, adminis...Background: Gemcitabine is a deoxycytidine analog, which is used as first-line agent for pancreatic cancer therapy, and its efficacy relied on its intracellular conversion to active triphosphate form. However, administration with gemcitabine still has limited effect on the overall survival of patients with pancreatic cancer. Objective: We aimed to study the combination effect of gemcitabine and doxorubicin to pancreatic cancer cells BxPC3 and PANC1, and unveil the mechanism. Methods: The study was performed in pancreatic cancer cells PANC1 and BxPC3, the contribution of UMP/CMP kinase 1 (CMPK1) to gemcitabine in PANC1 and BxPC3 cells was measured by transfection of CMPK1 plasmid or CMPK1 siRNA treatment to adjust the expression of CMPK1 in the cells;then analyzed the cell vitality and migration after treated with 1% IC50 of doxorubicin and gemcitabine or only with gemcitabine;the activity of CMPK1 and the effect of doxorubicin to the reaction was measured by HPLC assay in vitro;at last, docking analysis by computer was used to calculate the possible interaction sites of CMPK1 to DOX. Results: The sensitivity of PANC1 and BxPC3 cells to gemcitabine was improved when increasing the expression of CMPK1, and decreased when knockout CMPK1 by CMPK1 siRNA in BxPC3 cells;when combined with doxorubicin, the sensitivity of PANC1 and BxPC3 cells to gemcitabine also increased, and the cells migration reduced;we further found out that by adding 10 μM doxorubicin, the catalyzing activity of CMPK1 elevated about 2 times in vitro;the docking result showed that the association of CMPK1 to DOX was mainly by hydrogen bond and ionic interaction. Conclusion: CMPK1 can catalyze gemcitabine to its active form within the cells so that the sensitivity of the cells to gemcitabine elevated, and doxorubicin may enhance the cytotoxic effect to pancreatic cancer by up-regulate the activity of CMPK1, the combination of these deoxycytidine analogs with DOX might exert better efficacy.展开更多
基金The project supported by grants from the Science and Technology Development Fund of Macao,China(014/2011/A1and 078/2011/A3)Research Committee,University of Macao〔MYRG138(Y1-Y4)-ICMS12-LMY〕
文摘OBJECTIVE To investigate the cardioprotective effect of novel danshensu derivatives against doxorubicin(Dox)cardiotoxicity and their synergistic anti-tumor effect with Dox on breast cancer cells.METHODS Two new Danshensu derivatives were synthesized by conjugation with tetramethylpyrizine and/or4-(3-thioxo-3 H-1,2-dithiol-4-yl)-benzoic acid and tested for protective effects against Dox induced cardiotoxicity in cell and zebrafish.H9c2 cardiomyoblasts were co-treated with Dox and Danshensu derivatives for 24 h and then were measured for cell viability and cytotoxicity by MTT and LDH assays.The expression levels of mitochondrial biogenesis related proteins PGC-1α,NRF-1and Nrf2 were detected by Western blotting and qPCR.Moreover,in a Dox-induced cardiotoxicity model of zebrafish,zebrafish embryos were treated with Dox for 36 h,followed by measurement of numerous ventricular function parameters including heart rate,stroke volume,cardiac output and fractional shortening.In addition,the synergistic anti-tumor effects of the Danshensu derivatives and Dox had been studied in MCF-7 breast cancer cells.The effects of the Danshensu derivatives on the cell death and metabolism of MCF-7 cells were measured using apoptosis assay and Seahorse Metabolic Analyzers respectively.RESULTS Our results showed that the Danshensu derivatives were more potent than the parental compounds in ameliorating Dox-induced cytotoxicity in H9c2 cells and significantly preserving stroke volume of heart function in Dox-treated zebrafish.Further mechanistic studies identified that the danshensu derivatives increased mitochondrial copy numbers and protein expressions of PGC-1α,NRF-1 and Nrf2 in H9c2 cells.In addition,the Danshensu derivatives enhanced Dox-induced apoptosis,and decreased glycolysis and mitochondrial function in MCF-7 tumor cells.CONCLUSION Our results revealed that two new Danshensu derivatives displayed promising cardioprotective effects against Dox induced cardiotoxicity both in vivo and in vitro,at least partially through activating mitochondrial biogenesis.Also,the new Danshensu derivatives potentiated the anticancer effects of Dox in breast tumor cells involving induction of glycolytic inhibition and mitochondrial dysfunction.
基金KNRF(the Korea of National Research Foundation)under the Specified base program 96-0300-11-01-3.
文摘According to LN?,theoretical&true elongation of tensile,and by adopting the increasing function of formulas with the derivation and analogy methods,the elongation formula of 0<(1+ε)^1/ε<e&0<ε^1/ε<1&four convergences are deduced too whenε>1 and 0<ε<1.The inequalities of LNε<εand LN(1+ε)<εand LN(1+ε)>LNεare deduced ifε>1 and 0<ε<1 in material dynamics.Finally the conclusions of LNε<εand LNε<LN(1+ε)<εare deduced together ifε>1 and 0<ε<1.
文摘Background: Gemcitabine is a deoxycytidine analog, which is used as first-line agent for pancreatic cancer therapy, and its efficacy relied on its intracellular conversion to active triphosphate form. However, administration with gemcitabine still has limited effect on the overall survival of patients with pancreatic cancer. Objective: We aimed to study the combination effect of gemcitabine and doxorubicin to pancreatic cancer cells BxPC3 and PANC1, and unveil the mechanism. Methods: The study was performed in pancreatic cancer cells PANC1 and BxPC3, the contribution of UMP/CMP kinase 1 (CMPK1) to gemcitabine in PANC1 and BxPC3 cells was measured by transfection of CMPK1 plasmid or CMPK1 siRNA treatment to adjust the expression of CMPK1 in the cells;then analyzed the cell vitality and migration after treated with 1% IC50 of doxorubicin and gemcitabine or only with gemcitabine;the activity of CMPK1 and the effect of doxorubicin to the reaction was measured by HPLC assay in vitro;at last, docking analysis by computer was used to calculate the possible interaction sites of CMPK1 to DOX. Results: The sensitivity of PANC1 and BxPC3 cells to gemcitabine was improved when increasing the expression of CMPK1, and decreased when knockout CMPK1 by CMPK1 siRNA in BxPC3 cells;when combined with doxorubicin, the sensitivity of PANC1 and BxPC3 cells to gemcitabine also increased, and the cells migration reduced;we further found out that by adding 10 μM doxorubicin, the catalyzing activity of CMPK1 elevated about 2 times in vitro;the docking result showed that the association of CMPK1 to DOX was mainly by hydrogen bond and ionic interaction. Conclusion: CMPK1 can catalyze gemcitabine to its active form within the cells so that the sensitivity of the cells to gemcitabine elevated, and doxorubicin may enhance the cytotoxic effect to pancreatic cancer by up-regulate the activity of CMPK1, the combination of these deoxycytidine analogs with DOX might exert better efficacy.
