龙华医院临床研究中心肖宁课题组揭示中西医结合抗白血病新机制

2022-07-29 上海中医药大学附属龙华医院 网络

揭示中药提取物喜树碱衍生物及临床抗肿瘤靶向药拓扑替康的抗急性淋巴白血病作用新机制。

近日,由上海中医药大学附属龙华医院临床研究中心肖宁副研究员领衔的联合研究团队在国际权威期刊《Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease》 (2022 JCR: Q1/IF6.633) 上以长文 (Regular paper) 形式在线发表了题为“Anti-leukemic effects of topoisomerase I inhibitors mediated by de-SUMOylase SENP1”的最新研究成果,揭示中药提取物喜树碱衍生物及临床抗肿瘤靶向药拓扑替康的抗急性淋巴白血病作用新机制。

急性淋巴细胞白血病 (ALL) 是一种与造血干细胞相关的恶性克隆性疾病,在儿童及青少年中最为常见。近年受益于支持性护理改善与风险分级的联合化疗策略,ALL患儿5年生存率已超80%,但仍有15%-20%的患儿预后不甚理想且存在因耐药复发所致恶性进展风险。本研究通过分析61例初-复发配对儿童ALL样本的全转录组RNA测序结果,发现SUMO特异性蛋白酶家族重要成员SENP1在复发样本中呈特异性高表达。该家族对细胞内SUMO小分子循环利用、靶蛋白SUMO化修饰动态平衡及功能起决定性作用。本研究首次证实去SUMO化酶 (de-SUMOlyase) SENP1在ALL细胞中的生物学功能,即SENP1表达沉默在不显著改变ALL细胞对临床常用化疗药物如6-巯基嘌呤 (6-MP)、6-硫代鸟嘌呤 (6-TG)、阿糖胞苷 (Ara-c)、长春新碱 (VCR)、雷替曲塞 (RTX)、柔红霉素 (DNR) 等的药物敏感性的情况下,会加速ALL细胞凋亡继而抑制其恶性增殖。

中医认为白血病的发生与“邪毒”密不可分,患者既有先天禀赋不足,又有后天失养,或药毒所伤,或盛邪入侵。认为“邪之所凑,其气必虚”是该病的发生基础;瘀毒不去,新血不生,气血两虚。治疗上则主要从“毒”、“正虚邪实”、“伏邪”、“卫气营血”等方面着手,方法则以中药为主,其它治疗手段为辅。本研究通过对抗癌中药单体化合物小分子库进行筛选,发现喜树碱 (CPT) 衍生物7-乙基喜树碱(7E-CPT)可特异性降低ALL细胞中的SENP1表达水平,且同属CPT衍生物的抗卵巢癌/肺癌靶向药拓扑替康(TPT)具有类似作用,二者不仅可显著诱导ALL细胞凋亡,且抗实体瘤靶向药TPT在小鼠体内呈现出对ALL很强的抗肿瘤效应。CPT是中药喜树果的有效成分之一,喜树果源于我国南方特有的山茱萸目珙桐科乔木喜树。喜树果味苦、涩,性寒,有毒,归脾、胃、肝经;主要功效为清热解毒,散结消癥,抗癌化瘀;临床主治食道癌,贲门癌,胃癌,肠癌,肝癌,白血病,牛皮癣,疮肿等。喜树果用于白血病的治疗过往见于一些传统中医名老专家,显示具有较好的临床疗效,但干预机制不明与实验证据缺乏阻碍了其后续推广应用。本研究综合运用分子细胞生物学等研究方法,从机制上阐释了去SUMO化酶SENP1可特异性介导DNA拓扑异构酶Ⅰ (TOP1) 的去SUMO化修饰以稳定TOP1蛋白,继而减弱7E-CPT对TOP1的靶向抑制作用以及对ALL细胞的促凋亡效应,从而介导TOP1抑制剂7E-CPT/TPT的抗白血病作用。

龙华医院临床研究中心肖宁副研究员为本文通讯作者,龙华医院肿瘤三科李和根主任医师与上海儿童医学中心李慧副研究员为本文共同通讯作者。龙华医院临床医学院2019级中西医结合基础专业硕士研究生牛群与龙华医院肿瘤三科主治医师侯宛昕、骨伤科主治医师严寅杰为本文共同第一作者。联合研究团队特别致谢上海儿童医学中心周斌兵教授与龙华医院郑培永教授对该研究工作的指导与支持。本研究得到了国家自然科学基金、上海市科委青年科技启明星计划及上海市临床重点专科项目等多个项目或基金的资助。

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