Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress
Inhibition of transcription by dactinomycin reveals a new characteristic of immunogenic cell stress
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DOI：
10.15252/emmm.201911622
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发表时间：
2020-04-23
影响因子：
11.1
通讯作者：
Kroemer, Guido
中科院分区：
文献类型：
--
作者：
Humeau, Juliette;Sauvat, Allan;Kroemer, Guido
化疗仍然是治疗大多数肿瘤性疾病的标准治疗方法。来自肿瘤医疗设备的某些化疗药物能够触发导致免疫原性细胞死亡（ICD）的死前应激信号，从而诱导抗肿瘤免疫应答并介导长期肿瘤生长减少。在这里，我们使用了一个建立在人工智能基础上的模型，在50，000种化合物的库中识别出抗癌药物，这些药物根据其分子描述符被预测会诱导ICD。该算法使我们鉴定出放线菌素D（DACT，最著名的是放线菌素D），一种高效的细胞毒性剂和ICD诱导剂，可介导体内免疫依赖性抗癌作用。由于DACT通常用作DNA至RNA转录的抑制剂，因此我们研究了其他实验建立或算法选择的临床使用的ICD诱导剂是否也具有这一特征。作为一个共同的主题，一组药理学ICD刺激物抑制转录，其次是翻译。这些结果确立了RNA合成的抑制作为ICD诱导的初始事件。
Chemotherapy still constitutes the standard of care for the treatment of most neoplastic diseases. Certain chemotherapeutics from the oncological armamentarium are able to trigger pre-mortem stress signals that lead to immunogenic cell death (ICD), thus inducing an antitumor immune response and mediating long-term tumor growth reduction. Here, we used an established model, built on artificial intelligence to identify, among a library of 50,000 compounds, anticancer agents that, based on their molecular descriptors, were predicted to induce ICD. This algorithm led us to the identification of dactinomycin (DACT, best known as actinomycin D), a highly potent cytotoxicant and ICD inducer that mediates immune-dependent anticancer effects in vivo. Since DACT is commonly used as an inhibitor of DNA to RNA transcription, we investigated whether other experimentally established or algorithm-selected, clinically employed ICD inducers would share this characteristic. As a common leitmotif, a panel of pharmacological ICD stimulators inhibited transcription and secondarily translation. These results establish the inhibition of RNA synthesis as an initial event for ICD induction.