Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients ha...Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients have imatinib resistance and treatment difficulties due to heterogeneity after progression,but little is known about the mechanism.A key transcription factor in hematopoiesis,MYB,has been reported to increase abnormally in several types of aggressive blood disorders including CML.Methods:This study used a zebrafish model to explore the relationship between BCR/ABL1 and c-myb in CML progression.A CML zebrafish model was crossed with a c-myb hyperactivity transgenic line.Results:It was found that both exogenous BCR/ABL1 and c-myb could up-regulate the expression of neutrophil-related genes.More seriously,neutrophil accumulation was observed when BCR/ABL1 was combined with c-myb overexpression.Further studies showed that c-myb may be one of the downstream targets of BCR/ABL1 and the effect of BCR/ABL1 on neutrophils was c-myb dependent.Taking advantage of this inheritable in vivo model,it was shown that a combination of imatinib and flavopiridol,a cyclin-dependent kinase inhibitor targeting MYB,could more effectively alleviate the aggressive phenotype of the double transgene line.Conclusion:In summary,this study suggests that c-myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression.The model used in the study could be helpful in high-throughput drug screening in CML transformation.展开更多
目的:检测flavopiridol联合泰素对人卵巢癌细胞系SKOV3、裸鼠人卵巢癌皮下及腹腔移植瘤模型的治疗作用。方法:应用CCK-8法、流式细胞术和原位细胞凋亡检测法(TUNEL)检测flavopiridol和泰素作用后卵巢癌细胞系SKOV3的细胞存活率和凋亡率...目的:检测flavopiridol联合泰素对人卵巢癌细胞系SKOV3、裸鼠人卵巢癌皮下及腹腔移植瘤模型的治疗作用。方法:应用CCK-8法、流式细胞术和原位细胞凋亡检测法(TUNEL)检测flavopiridol和泰素作用后卵巢癌细胞系SKOV3的细胞存活率和凋亡率;应用逆转录-多聚酶链反应(RT-PCR)检测作用前后细胞中cyclinD1的表达:应用ELISA法检测细胞中活性caspase-3的表达。建立裸鼠人卵巢癌皮下及腹腔移植瘤模型,观测flavopiridol和泰素治疗前后裸鼠肿瘤体积的变化并计算抑瘤率,用TUNEL和免疫组化法分别检测作用前后肿瘤组织中的凋亡情况和微血管密度(MVD)值。结果:flavopiri-dol(300nmol/L)或泰素(1μmol/L)单独应用24h均能显著降低细胞存活率,增强caspase-3活性,诱导细胞凋亡,并下调细胞中cyclinD1的表达。Taxol先作用24h再用flavopiridol作用24h的联合用药对二者的上述作用产生显著的协同效应:联合用药后细胞存活率为(5.2±0.8)%,凋亡率为(51.10±2.52)%,caspase-3活性相对值为0.602±0.008,cy-clinD1相对表达水平为0.264±0.076。Flavopiridol和泰素单独应用均能显著抑制皮下移植瘤生长(抑瘤率分别为84.5%和85.7%),并降低肿瘤组织MVD值(分别为12.4±4.7vs 35.2±10.3和15.2±2.9 vs 35.2±10.3)。二者联合应用抑瘤作用稍差(抑瘤率68.9%),抑制MVD作用(23.0±5.1 vs 35.2±10.3)也不及单药治疗。结论:Flavopiridol和泰素均能通过致凋亡作用显著抑制卵巢癌细胞及移植瘤生长,二者联合应用对体外培养的卵巢癌细胞具有协同杀伤作用,但体内治疗中无协同抑瘤作用。展开更多
As an important intermediate to study cyclin-dependent kinase （CDK） inhibitors, 2-ary1-8-（piperidin-4-y1）-5,7-dimethoxy-4H- chromen-4-one derivatives were prepared using 13-diketone route with low yield. In our st...As an important intermediate to study cyclin-dependent kinase （CDK） inhibitors, 2-ary1-8-（piperidin-4-y1）-5,7-dimethoxy-4H- chromen-4-one derivatives were prepared using 13-diketone route with low yield. In our study, chalcone route has been investigated and the result suggested that the benzaldehydes substituted with electron-donating group give much better yield than β-diketone route. This new method will be an efficient way to start further research on new anticancer flavonoids.展开更多
基金National Key R&D Program of ChinaGrant/Award Number:2018YFA0801000+5 种基金National Natural Science Foundation of ChinaGrant/Award Number:32170830Natural Science Foundation of Guangdong ProvinceChinaGrant/Award Number:2021A1515010422South China University of Technology。
文摘Background:Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia(CML)therapy,CML still faces the challenges of drug resistance and progression to blast crisis.Twenty-five percent of patients have imatinib resistance and treatment difficulties due to heterogeneity after progression,but little is known about the mechanism.A key transcription factor in hematopoiesis,MYB,has been reported to increase abnormally in several types of aggressive blood disorders including CML.Methods:This study used a zebrafish model to explore the relationship between BCR/ABL1 and c-myb in CML progression.A CML zebrafish model was crossed with a c-myb hyperactivity transgenic line.Results:It was found that both exogenous BCR/ABL1 and c-myb could up-regulate the expression of neutrophil-related genes.More seriously,neutrophil accumulation was observed when BCR/ABL1 was combined with c-myb overexpression.Further studies showed that c-myb may be one of the downstream targets of BCR/ABL1 and the effect of BCR/ABL1 on neutrophils was c-myb dependent.Taking advantage of this inheritable in vivo model,it was shown that a combination of imatinib and flavopiridol,a cyclin-dependent kinase inhibitor targeting MYB,could more effectively alleviate the aggressive phenotype of the double transgene line.Conclusion:In summary,this study suggests that c-myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression.The model used in the study could be helpful in high-throughput drug screening in CML transformation.
文摘目的:检测flavopiridol联合泰素对人卵巢癌细胞系SKOV3、裸鼠人卵巢癌皮下及腹腔移植瘤模型的治疗作用。方法:应用CCK-8法、流式细胞术和原位细胞凋亡检测法(TUNEL)检测flavopiridol和泰素作用后卵巢癌细胞系SKOV3的细胞存活率和凋亡率;应用逆转录-多聚酶链反应(RT-PCR)检测作用前后细胞中cyclinD1的表达:应用ELISA法检测细胞中活性caspase-3的表达。建立裸鼠人卵巢癌皮下及腹腔移植瘤模型,观测flavopiridol和泰素治疗前后裸鼠肿瘤体积的变化并计算抑瘤率,用TUNEL和免疫组化法分别检测作用前后肿瘤组织中的凋亡情况和微血管密度(MVD)值。结果:flavopiri-dol(300nmol/L)或泰素(1μmol/L)单独应用24h均能显著降低细胞存活率,增强caspase-3活性,诱导细胞凋亡,并下调细胞中cyclinD1的表达。Taxol先作用24h再用flavopiridol作用24h的联合用药对二者的上述作用产生显著的协同效应:联合用药后细胞存活率为(5.2±0.8)%,凋亡率为(51.10±2.52)%,caspase-3活性相对值为0.602±0.008,cy-clinD1相对表达水平为0.264±0.076。Flavopiridol和泰素单独应用均能显著抑制皮下移植瘤生长(抑瘤率分别为84.5%和85.7%),并降低肿瘤组织MVD值(分别为12.4±4.7vs 35.2±10.3和15.2±2.9 vs 35.2±10.3)。二者联合应用抑瘤作用稍差(抑瘤率68.9%),抑制MVD作用(23.0±5.1 vs 35.2±10.3)也不及单药治疗。结论:Flavopiridol和泰素均能通过致凋亡作用显著抑制卵巢癌细胞及移植瘤生长,二者联合应用对体外培养的卵巢癌细胞具有协同杀伤作用,但体内治疗中无协同抑瘤作用。
基金We are grateful to the National Natural Science Foundation of China （No. 20272033） for financial support for this work.
文摘As an important intermediate to study cyclin-dependent kinase （CDK） inhibitors, 2-ary1-8-（piperidin-4-y1）-5,7-dimethoxy-4H- chromen-4-one derivatives were prepared using 13-diketone route with low yield. In our study, chalcone route has been investigated and the result suggested that the benzaldehydes substituted with electron-donating group give much better yield than β-diketone route. This new method will be an efficient way to start further research on new anticancer flavonoids.
