Systemic MEK inhibition enhances the efficacy of 5-aminolevulinic acid-photodynamic therapy
Systemic MEK inhibition enhances the efficacy of 5-aminolevulinic acid-photodynamic therapy
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DOI：
10.1038/s41416-019-0586-3
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发表时间：
2019-10-29
影响因子：
8.8
通讯作者：
Hirasawa, Kensuke
中科院分区：
文献类型：
--
作者：
Chelakkot, Vipin Shankar;Som, Jayoti;Hirasawa, Kensuke
背景：原卟啉IX （PpIX）在5-氨基乙酰丙酸（5-ALA）处理的癌细胞中优先积累。光动力疗法（PDT）利用积累的PpIX通过光诱导活性氧（ROS）的产生来触发细胞死亡。我们之前证明了致癌的Ras/MEK可以减少PpIX在癌细胞中的积累。在这里，我们研究了MEK抑制剂联合治疗是否会提高5-ALA-PDT的疗效。方法：采用5-ALA-PDT、MEK抑制剂或MEK抑制剂与5-ALAPDT同时作用于肿瘤细胞和肿瘤小鼠模型，评价其治疗效果。结果：Ras/MEK负调控细胞对5-ALA-PDT的敏感性，因为用MEK抑制剂预处理的癌细胞被5-ALA-PDT更有效地杀死。MEK抑制促进5- ala - pdt诱导的ROS生成和程序性细胞死亡。此外，在小鼠癌症模型中，与单药治疗相比，5-ALA-PDT和一种系统性MEK抑制剂联合使用可显著抑制肿瘤生长。值得注意的是，44%患有人类结肠肿瘤的小鼠在联合治疗后表现出完全的反应。结论：我们展示了一种通过调节5-ALA-PDT敏感性的细胞信号通路来促进5-ALA-PDT疗效的新策略。该临床前研究为利用已被批准用于治疗癌症的MEK抑制剂在临床中提高5-ALA-PDT的疗效提供了强有力的基础。
BACKGROUND: Protoporphyrin IX (PpIX) gets accumulated preferentially in 5-aminolevulinic acid (5-ALA)-treated cancer cells. Photodynamic therapy (PDT) utilises the accumulated PpIX to trigger cell death by light-induced generation of reactive oxygen species (ROS). We previously demonstrated that oncogenic Ras/MEK decreases PpIX accumulation in cancer cells. Here, we investigated whether combined therapy with a MEK inhibitor would improve 5-ALA-PDT efficacy.METHODS: Cancer cells and mice models of cancer were treated with 5-ALA-PDT, MEK inhibitor or both MEK inhibitor and 5-ALAPDT, and treatment efficacies were evaluated.RESULTS: Ras/MEK negatively regulates the cellular sensitivity to 5-ALA-PDT as cancer cells pre-treated with a MEK inhibitor were killed more efficiently by 5-ALA-PDT. MEK inhibition promoted 5-ALA-PDT-induced ROS generation and programmed cell death. Furthermore, the combination of 5-ALA-PDT and a systemic MEK inhibitor significantly suppressed tumour growth compared with either monotherapy in mouse models of cancer. Remarkably, 44% of mice bearing human colon tumours showed a complete response with the combined treatment.CONCLUSION: We demonstrate a novel strategy to promote 5-ALA-PDT efficacy by targeting a cell signalling pathway regulating its sensitivity. This preclinical study provides a strong basis for utilising MEK inhibitors, which are approved for treating cancers, to enhance 5-ALA-PDT efficacy in the clinic.