A series of novel derivatives of indirubin were synthesized and evaluated for their anti-proliferative activity against human cancer cell lines of SGC7901,A549,HL-60,SK-BR-3 and HCT116.Most of the compounds displayed ...A series of novel derivatives of indirubin were synthesized and evaluated for their anti-proliferative activity against human cancer cell lines of SGC7901,A549,HL-60,SK-BR-3 and HCT116.Most of the compounds displayed more potent activity than Sunitinib.In addition,the derivatives showed improved water solubility,which may be favorable to their pharmacokinetic performances.展开更多
Objective Indirubin,isolated from Indigo Naturals,has been reported to have the inhibitory activity of MCF-7 human breast cancer cells in vitro.However,studies on its anti-breast cancer activity in vivo and the underl...Objective Indirubin,isolated from Indigo Naturals,has been reported to have the inhibitory activity of MCF-7 human breast cancer cells in vitro.However,studies on its anti-breast cancer activity in vivo and the underlying mechanism are insufficient.We explored whether indirubin could trigger ferroptosis of breast cancer cells to exert anti-tumor activity.Methods Bioinformatical analysis was performed to detect the expression of prostaglandin-endoperoxide synthase 2(Ptgs2)in breast cancer tissues and Ptgs2-related prognosis for patients with breast cancer.The inhibitory effects of indirubin on 4T1 cells were assessed using MTT assay and LDH activity detection.The levels of 4-HNE,GPX4,PTGS2 and GSK-3βproteins were detected by Western blotting,and the mRNA of Ptgs2 was tested by qPCR.The contents of GSH and MDA were determined by commercial kits.Molecular docking was employed to study the interaction between indirubin and GSK-3β.A 4T1 murine breast cancer was adopted to evaluate the in vivo antitumor activity of indirubin.Results Indirubin promoted ferroptosis of 4T1 breast cancer cells with depleting of GSH,increased MDA and 4-HNE levels,as well as decreased GPX4 expression.Indirubin suppressed 4T1 breast tumor in vivo.The mechanism study showed indirubin up-regulated Ptgs2 expression by promoting phosphorylation(Ser 9)of GSK-3β.Conclusion Indirubin suppresses 4T1 murine breast cancer in vitro and in vivo by induction of ferroptosis.展开更多
Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer＇s disease. Here, we found that indirubin-3′-monoxime improved th...Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer＇s disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SHSY5 Y cells exposed to amyloid-beta 25–35（Aβ25–35）, and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β（GSK-3β）. Our results suggest that indirubin-3′-monoxime reduced Aβ25–35-induced apoptosis by suppressing tau hyperphosphorylation via a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer＇s disease.展开更多
The binding between indirubin and calf thymus DNA in vitro has been verified by meansof the isotope labelling method, spectrophotometric method and thermal denaturation meas-urements. The λ_max 207 nm of indirubin sh...The binding between indirubin and calf thymus DNA in vitro has been verified by meansof the isotope labelling method, spectrophotometric method and thermal denaturation meas-urements. The λ_max 207 nm of indirubin shifted toward longer wave length with decrease ofabsorbance after the incubation of indirubin with DNA. The escalation of Tm value of DNAinduced by indirubin was about 2.4°C and it was reproducible. The binding force between themwas rather weak, as indirubin molecules were easily released during the precipitation withalcohol or the gel filtration. The binding was not affected by sodium chloride even at high con-centration but greatly decreased (to 20-30% of the control) in the presence of 8 M urea.These results showed that the binding between indirubin and DNA might be of hydrogen bondrather than ionic. The amount of bound ~3H-indirubin was directly proportional to the con-centration of indirubin. However, it increased abruptly when the concentration of indirubinreached 1.5×10^(-4) M. This suggested another binding force in the latter instance. By using spectrophotometric analysis and Scatchard plot it was found that calf thymusDNA bound 46 indirubin molecules/1000 nucleotides. The association constant (K) was5.7×10~6.展开更多
Background Multidrug resistance （MDR） is a main reason for paclitaxel （TAX） treatment failure. Indirubin-3＇-monoxime （IRO） and Matrine are traditional Chinese medicines, which may reverse the resistance of tumo...Background Multidrug resistance （MDR） is a main reason for paclitaxel （TAX） treatment failure. Indirubin-3＇-monoxime （IRO） and Matrine are traditional Chinese medicines, which may reverse the resistance of tumor cells to some chemotherapy drugs, but the relationship between paclitaxel resistance and Matrine is still unclear. The aim of this study was to explore the potential molecular mechanism of IRO and Matrine in reversal of TAX resistance. Methods In this study, MTT assay was used to measure the non-cytotoxic dosage of IRO and Matrine on NCI-H520/TAX25 cells and determine the reversal extent of TAX resistance under non-toxic doses. In addition, RT-PCR and Western blotting were used to evaluate the mRNA expression and the protein level of survivin, Oct-4, and Sox-2 in NCI-H520fTAX25 ceils using semi-quantitative methods. Results There was no obvious inhibition on sensitive cell strains and drug-resistant strains, when the final concentration was at lest 4 IJmol/L for IRO and 100 IJmol/L for Matrine. So 4 tJmol/L of IRO and 100 pmol/L of Matrine were considered as the reversal dosage. When 4 IJmol/L of IRO or 100 pmol/L of Matrine were used together with TAX, the sensitivity to TAX increased evidently in NCI-H520/TAX2 cells; the reversal rate of IRO and Matrine was about 1.92 （43.56/22.6 nmol/L） and 1.74 （43.56/25.0 nmol/L）, respectively. The mRNA expression and the protein ievel of survivin, Oct-4, and Sox-2 in NCI-H520/TAX25 decreased significantly （P 〈0.05） after addition of IRO or Matrine in TAX treatment, compared to that of TAX treatment alone. Conclusion The decrease in both mRNA expression and protein level of survivin, Oct-4, and Sox-2 might be the molecular mechanism, by which IRO and Matrine mediate the reversal of TAX resistance.展开更多
Indirubin,indigo and isoindigo are the core representatives of a rather small category of bisindole alkaloids referred to as indigoids.These compounds are the coloured constituents of the natural dyes Indigo and the f...Indirubin,indigo and isoindigo are the core representatives of a rather small category of bisindole alkaloids referred to as indigoids.These compounds are the coloured constituents of the natural dyes Indigo and the famous molluscan Tyrian purple,used throughout the centuries for textile dying.In contrast with Indigo dyes,the major constituents of molluscan purple dyes are展开更多
文摘A series of novel derivatives of indirubin were synthesized and evaluated for their anti-proliferative activity against human cancer cell lines of SGC7901,A549,HL-60,SK-BR-3 and HCT116.Most of the compounds displayed more potent activity than Sunitinib.In addition,the derivatives showed improved water solubility,which may be favorable to their pharmacokinetic performances.
基金This work was supported by the Yunnan Provincial Science and Technology Department-Applied Basic Research Joint Special Funds of Yunnan University of Chinese Medicine(2019FF002(-007),2017FF116(-015))National Natural Science Foundation of China(81560661,81960780).
文摘Objective Indirubin,isolated from Indigo Naturals,has been reported to have the inhibitory activity of MCF-7 human breast cancer cells in vitro.However,studies on its anti-breast cancer activity in vivo and the underlying mechanism are insufficient.We explored whether indirubin could trigger ferroptosis of breast cancer cells to exert anti-tumor activity.Methods Bioinformatical analysis was performed to detect the expression of prostaglandin-endoperoxide synthase 2(Ptgs2)in breast cancer tissues and Ptgs2-related prognosis for patients with breast cancer.The inhibitory effects of indirubin on 4T1 cells were assessed using MTT assay and LDH activity detection.The levels of 4-HNE,GPX4,PTGS2 and GSK-3βproteins were detected by Western blotting,and the mRNA of Ptgs2 was tested by qPCR.The contents of GSH and MDA were determined by commercial kits.Molecular docking was employed to study the interaction between indirubin and GSK-3β.A 4T1 murine breast cancer was adopted to evaluate the in vivo antitumor activity of indirubin.Results Indirubin promoted ferroptosis of 4T1 breast cancer cells with depleting of GSH,increased MDA and 4-HNE levels,as well as decreased GPX4 expression.Indirubin suppressed 4T1 breast tumor in vivo.The mechanism study showed indirubin up-regulated Ptgs2 expression by promoting phosphorylation(Ser 9)of GSK-3β.Conclusion Indirubin suppresses 4T1 murine breast cancer in vitro and in vivo by induction of ferroptosis.
基金supported by the Nanjing Medical Science and Technique Development Foundation of China,No.QRX11199a grant from the Nanjing Science and Technology Commission Project of China,No.201303010a grant from the Health Research Project in Nanjing City of China,No.YKK14101
文摘Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer＇s disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SHSY5 Y cells exposed to amyloid-beta 25–35（Aβ25–35）, and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β（GSK-3β）. Our results suggest that indirubin-3′-monoxime reduced Aβ25–35-induced apoptosis by suppressing tau hyperphosphorylation via a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer＇s disease.
文摘The binding between indirubin and calf thymus DNA in vitro has been verified by meansof the isotope labelling method, spectrophotometric method and thermal denaturation meas-urements. The λ_max 207 nm of indirubin shifted toward longer wave length with decrease ofabsorbance after the incubation of indirubin with DNA. The escalation of Tm value of DNAinduced by indirubin was about 2.4°C and it was reproducible. The binding force between themwas rather weak, as indirubin molecules were easily released during the precipitation withalcohol or the gel filtration. The binding was not affected by sodium chloride even at high con-centration but greatly decreased (to 20-30% of the control) in the presence of 8 M urea.These results showed that the binding between indirubin and DNA might be of hydrogen bondrather than ionic. The amount of bound ~3H-indirubin was directly proportional to the con-centration of indirubin. However, it increased abruptly when the concentration of indirubinreached 1.5×10^(-4) M. This suggested another binding force in the latter instance. By using spectrophotometric analysis and Scatchard plot it was found that calf thymusDNA bound 46 indirubin molecules/1000 nucleotides. The association constant (K) was5.7×10~6.
文摘Background Multidrug resistance （MDR） is a main reason for paclitaxel （TAX） treatment failure. Indirubin-3＇-monoxime （IRO） and Matrine are traditional Chinese medicines, which may reverse the resistance of tumor cells to some chemotherapy drugs, but the relationship between paclitaxel resistance and Matrine is still unclear. The aim of this study was to explore the potential molecular mechanism of IRO and Matrine in reversal of TAX resistance. Methods In this study, MTT assay was used to measure the non-cytotoxic dosage of IRO and Matrine on NCI-H520/TAX25 cells and determine the reversal extent of TAX resistance under non-toxic doses. In addition, RT-PCR and Western blotting were used to evaluate the mRNA expression and the protein level of survivin, Oct-4, and Sox-2 in NCI-H520fTAX25 ceils using semi-quantitative methods. Results There was no obvious inhibition on sensitive cell strains and drug-resistant strains, when the final concentration was at lest 4 IJmol/L for IRO and 100 IJmol/L for Matrine. So 4 tJmol/L of IRO and 100 pmol/L of Matrine were considered as the reversal dosage. When 4 IJmol/L of IRO or 100 pmol/L of Matrine were used together with TAX, the sensitivity to TAX increased evidently in NCI-H520/TAX2 cells; the reversal rate of IRO and Matrine was about 1.92 （43.56/22.6 nmol/L） and 1.74 （43.56/25.0 nmol/L）, respectively. The mRNA expression and the protein ievel of survivin, Oct-4, and Sox-2 in NCI-H520/TAX25 decreased significantly （P 〈0.05） after addition of IRO or Matrine in TAX treatment, compared to that of TAX treatment alone. Conclusion The decrease in both mRNA expression and protein level of survivin, Oct-4, and Sox-2 might be the molecular mechanism, by which IRO and Matrine mediate the reversal of TAX resistance.
文摘Indirubin,indigo and isoindigo are the core representatives of a rather small category of bisindole alkaloids referred to as indigoids.These compounds are the coloured constituents of the natural dyes Indigo and the famous molluscan Tyrian purple,used throughout the centuries for textile dying.In contrast with Indigo dyes,the major constituents of molluscan purple dyes are
