Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry , Wuhan University , Wuhan 430072 , P.R. China.
Department of Orthopedics , Renmin Hospital of Wuhan University , Wuhan 430060 , P.R. China.
Nano Lett. 2019 Nov 13;19(11):8049-8058. doi: 10.1021/acs.nanolett.9b03245. Epub 2019 Oct 2.
Pyroptosis is a lytic and inflammatory form of programmed cell death and could be induced by chemotherapy drugs via caspase-3 mediation. However, the key protein gasdermin E (GSDME, translated by the gene) during the caspase-3-mediated pyroptosis process is absent in most tumor cells because of the hypermethylation of (deafness autosomal dominant 5) gene. Here, we develop a strategy of combining decitabine (DAC) with chemotherapy nanodrugs to trigger pyroptosis of tumor cells by epigenetics, further enhancing the immunological effect of chemotherapy. DAC is pre-performed with specific tumor-bearing mice for demethylation of the gene in tumor cells. Subsequently, a commonly used tumor-targeting nanoliposome loaded with cisplatin (LipoDDP) is used to administrate drugs for activating the caspase-3 pathway in tumor cells and trigger pyroptosis. Experiments demonstrate that the reversal of GSDME silencing in tumor cells is achieved and facilitates the occurrence of pyroptosis. According to the anti-tumor activities, anti-metastasis results, and inhibition of recurrence, this pyroptosis-based chemotherapy strategy enhances immunological effects of chemotherapy and also provides an important insight into tumor immunotherapy.
细胞焦亡是一种裂解性和炎症性的程序性细胞死亡方式，可以通过半胱天冬酶-3 介导的方式被化疗药物诱导。然而，由于 （耳聋常染色体显性 5 号）基因的超甲基化，在半胱天冬酶-3 介导的细胞焦亡过程中的关键蛋白 Gasdermin E（GSDME，由 基因翻译）在大多数肿瘤细胞中缺失。在这里，我们开发了一种联合地西他滨（DAC）与化疗纳米药物的策略，通过表观遗传触发肿瘤细胞的细胞焦亡，进一步增强化疗的免疫效应。DAC 预先在特定的荷瘤小鼠中进行，以在肿瘤细胞中去甲基化 基因。随后，使用一种常用的载顺铂的肿瘤靶向脂质体（LipoDDP）给药，以激活肿瘤细胞中的半胱天冬酶-3 途径并引发细胞焦亡。实验表明，肿瘤细胞中 GSDME 沉默的逆转促进了细胞焦亡的发生。根据抗肿瘤活性、抗转移结果和复发抑制情况，这种基于细胞焦亡的化疗策略增强了化疗的免疫效应，也为肿瘤免疫治疗提供了重要的见解。
