There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and th...There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression.The targeted peptide D(RWYD)(abbreviated RD),with nanomolar affinity to integrinα6 was identified by peptide scanning techniques such as alanine scanning,truncation,and D-substitution.Herein,we developed a therapeutic nanoparticle based on the integrinα6-targeted peptide for treating CNS-ALL.The self-assembled proapoptotic nanopeptide_(D)(RWYD)-_(D)(KLAKLAK)_(2)-G_(D)(FFY)(abbreviated RD-KLA-Gffy)contains the integrinα6-targeted peptide RD,the well-known proapoptotic peptide_(D)(KLAKLAK)_(2)(abbreviated KLA),and the self-assembling tetrapeptide GD(FFY)(abbreviated Gffy).The functional mechanism of RD-KLA-Gffy is clarified using different experiments.Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis,thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity.Moreover,the combined use of RD-KLA-Gffy and methotrexate(MTX)shows a potent antitumor effect in treating CNS-ALL,indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX,which shows promise for application in CNS-ALL therapy.展开更多
目的预测丝裂原活化蛋白激酶(mitogenactivated protein kinase10,MAPK10)及整合素α6(Integrinα6)在声门上型喉癌中对紫杉醇+顺铂+5氟尿嘧啶(TPF)诱导化疗方案敏感性的价值。方法将2014年9月~2016年9月在我科治疗的57例声门上型喉鳞...目的预测丝裂原活化蛋白激酶(mitogenactivated protein kinase10,MAPK10)及整合素α6(Integrinα6)在声门上型喉癌中对紫杉醇+顺铂+5氟尿嘧啶(TPF)诱导化疗方案敏感性的价值。方法将2014年9月~2016年9月在我科治疗的57例声门上型喉鳞状细胞癌患者纳入研究。所有患者接受2个周期的TPF方案诱导化疗,并将患者按照疗效分为化疗敏感组和化疗耐受组。采用免疫组化对所有患者病理标本中MAPK10及Itga6表达进行检测,并分析mRNA与蛋白表达一致性,以及蛋白表达与患者临床病理资料之间的关系。结果 MAPK10在敏感组中表达率较高为90.48%,Itga6在耐受组中表达率较高为83.33%,两组之间差异有统计学意义。MAPK10在耐受组中表达水平低于敏感组,Itga6 mRNA高于敏感组,差异有统计学意义。一致性检验表明MAPK10及Itga6在耐受组之中mRNA表达及与蛋白表达一致性较高。MAPK10及Itga6的表达与年龄、性别、肿瘤直径无关;MAPK10的表达与临床分期、病理分级相关,阳性率越低患者病情越重。Spearman等级相关分析结果表明MAPK10与Itga6表达水平之间存在负相关关系,在敏感组喉癌组织中MAPK10与Itga6表达水平之间同样存在负相关关系。结论 MAPK10在对化疗耐受的喉癌组织中表达下调,而Itga6表达上调,且表达水平之间存在负相关关系,因此有可能成为喉癌诱导化疗疗效预测的分子标志物。展开更多
基金supported by grants from the National Natural Science Foundation of China (81972531, 82373175, 82102775, and 82002466)the Major Scientific and Technological Projects of Guangdong Province (2019B020202002)the Young Talents Program of Sun Yat-sen University Cancer Center (YTP-SYSUCC-0067)
文摘There is currently no effective targeted therapeutic strategy for the treatment of central nervous system acute lymphoblastic leukemia(CNS-ALL).Integrinα6 is considered a potential target for CNS-ALL diagnosis and therapy because of its role in promoting CNS-ALL disease progression.The targeted peptide D(RWYD)(abbreviated RD),with nanomolar affinity to integrinα6 was identified by peptide scanning techniques such as alanine scanning,truncation,and D-substitution.Herein,we developed a therapeutic nanoparticle based on the integrinα6-targeted peptide for treating CNS-ALL.The self-assembled proapoptotic nanopeptide_(D)(RWYD)-_(D)(KLAKLAK)_(2)-G_(D)(FFY)(abbreviated RD-KLA-Gffy)contains the integrinα6-targeted peptide RD,the well-known proapoptotic peptide_(D)(KLAKLAK)_(2)(abbreviated KLA),and the self-assembling tetrapeptide GD(FFY)(abbreviated Gffy).The functional mechanism of RD-KLA-Gffy is clarified using different experiments.Our results demonstrate that RD-KLA-Gffy is highly enriched in CNS-ALL lesions and induces tumor cell apoptosis,thus reducing CNS-ALL disease burden and prolonging the survival of CNS-ALL mice without obvious toxicity.Moreover,the combined use of RD-KLA-Gffy and methotrexate(MTX)shows a potent antitumor effect in treating CNS-ALL,indicating that RD-KLA-Gffy plays an important role in suppressing CNS-ALL progression either as a single agent or in combination with MTX,which shows promise for application in CNS-ALL therapy.
