青蒿素衍生物SM1044诱导survivin降解治疗弥漫大B细胞淋巴瘤的作用及相关分子机制的研究

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin’s lymphoma with a long-term survival of 60%.How to further improve the therapeutic efficacy and prognosis of patients is crucial to current treatments of DLBCL. Survivin is an inhibitor of apoptosis over-expressed in a variety of human cancers.Over-expression of survivin has been proved to be an independent predictor for poor prognosis of DLBCL,thus becoming a potential target for drug development and clinical management. More degradation of survivin will undoubtedly improve treatment efficacies in DLBCL patients. The stability of survivin increases when combined with Hsp90, while SM1044, a new drug artemisinin derivatives developed in our lab, also has the binding sites for Hsp90.Based on our pilot study, it is speculated that SM1044 could probably reduce the combination of Hsp90 and survivin through competitive binding to Hsp90,increase autophagic degradation of survivin, then effectively reduce the level of survivin, and ultimately enhance the apoptosis of DLBCL. This study is to confirm the therapeutic effect of SM1044 on DLBCL and to investigate the related molecular mechanisms in vivo and in vitro by experiments of molecular biology and pathology, which is expected to provide experimental and theoretical basis for developments of new drugs in the treatment of DLBCL.

弥漫大B细胞淋巴瘤（DLBCL）是最常见的侵袭性非霍奇金淋巴瘤，患者的长期生存率只有60%，如何进一步提高患者疗效并改善预后是当前诊治DLBCL的关键。凋亡抑制蛋白survivin在恶性肿瘤组织中高表达，已被证实为DLBCL预后不良的独立预测因子，是治疗DLBCL的潜在靶点，增加其降解无疑将提高DLBCL的疗效。Hsp90可与survivin结合增加其稳定性，我们前期研制的新药青蒿素衍生物SM1044具有Hsp90的结合位点，基于前期预实验，我们推测SM1044可能通过与Hsp90的竞争性结合使Hsp90与survivin的结合减少，增加survivin的自噬性降解，有效降低survivin的水平，最终提高DLBCL的凋亡。本课题将通过体内、体外实验，运用分子生物学、组织病理学等手段证明SM1044对DLBCL的治疗作用及相关的分子机制，有望为DLBCL治疗新药的开发提供实验及理论依据。

弥漫大B细胞淋巴瘤（DLBCL）是最常见的侵袭性非霍奇金淋巴瘤，患者的长期生存率只有60%，如何进一步提高患者疗效并改善预后是当前诊治DLBCL的关键。凋亡抑制蛋白survivin在恶性肿瘤组织中高表达，已被证实为DLBCL预后不良的独立预测因子，是治疗DLBCL的潜在靶点，增加其降解无疑将提高DLBCL的疗效。. 我们前期研制的新药SM1044是一种新型水溶性抗疟药青蒿素衍生物。本课题通过体内、体外实验，运用分子生物学、组织病理学等手段证明SM1044对DLBCL的治疗作用及相关的分子机制，有望为DLBCL治疗新药的开发提供实验及理论依据。. 在本项研究中，我们的研究结果发现SM1044可以诱导DLBCL细胞系SU-DHL-4发生自噬依赖性凋亡，其机制为增强抗凋亡蛋白Survivin的乙酰化，促使其与自噬特异性蛋白LC3结合并被自噬所降解，最终导致凋亡的发生。我们进一步在其他DLBCL细胞系中验证了SM1044诱导自噬依赖性凋亡的机制，并深入研究了SM1044诱导自噬的分子机制。我们发现SM1044还刺激神经酰胺的从头合成，进而激活CaMKK2-AMPK-ULK1轴，从而导致自噬的开始。最后在动物模型中证实了SM1044的疗效。. 本课题通过体内、体外实验，证实了SM1044对DLBCL的治疗作用，并阐明了其具体作用机制，为DLBCL的新型药物靶向治疗提供了新的思路和策略，并为其进一步的临床转化奠定基础。