Synergistic antitumor activity of artesunate and HDAC inhibitors through elevating heme synthesis via synergistic upregulation of ALAS1 expression
Synergistic antitumor activity of artesunate and HDAC inhibitors through elevating heme synthesis via synergistic upregulation of ALAS1 expression
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青蒿琥酯和 HDAC 抑制剂通过协同上调 ALAS1 表达来提高血红素合成，从而发挥协同抗肿瘤活性
DOI：
10.1016/j.apsb.2019.05.001
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发表时间：
2019-09-01
影响因子：
14.5
通讯作者：
Sun, Hongbin
中科院分区：
文献类型：
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作者：
Chen, Cai-Ping;Chen, Kun;Sun, Hongbin
青蒿素及其衍生物（ART）显示出血红素依赖性抗肿瘤活性。另一方面，已知组蛋白去乙酰化酶抑制剂（HDACi）能够促进红系细胞中血红素的合成。然而，HDACi对非红细胞中血红素稳态的影响仍然未知。我们设想HDACi和青蒿琥酯（ARS）的组合可能通过调节血红素合成而具有协同抗肿瘤活性。体外研究显示ARS和HDACi的组合通过诱导细胞死亡而发挥协同肿瘤抑制作用。此外，该组合在异种移植模型中表现出比ARS或HDACi单一疗法更有效的抗肿瘤活性，而没有明显的毒性。重要的是，机制研究显示HDACi与ARS协调以增加5-氨基乙酰丙酸合酶（ALAS 1）表达，以及随后的血红素产生，导致ARS的细胞毒性增强。值得注意的是，敲低ALAS 1显著减弱了ARS和HDACi对肿瘤抑制的协同作用，表明ALAS 1上调在介导ARS细胞毒性中的关键作用。总之，我们的研究揭示了ARS和HDACi协同抗肿瘤作用的机制。这一发现表明，通过基于ART和其他血红素合成调节剂的组合来调节血红素合成途径代表了一种有前途的实体瘤治疗方法。(C)2019中国药学会、中国医学科学院药物研究所。制作和主办：Elsevier B. V.
Artemisinin and its derivatives (ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors (HDACi) were known to be able to promote heme synthesis in erythroid cells. Nevertheless, the effect of HDACi on heme homeostasis in non-erythrocytes remains unknown. We envisioned that the combination of HDACi and artesunate (ARS) might have synergistic antitumor activity through modulating heme synthesis. In vitro studies revealed that combination of ARS and HDACi exerted synergistic tumor inhibition by inducing cell death. Moreover, this combination exhibited more effective antitumor activity than either ARS or HDACi monotherapy in xenograft models without apparent toxicity. Importantly, mechanistic studies revealed that HDACi coordinated with ARS to increase 5-aminolevulinate synthase (ALAS1) expression, and subsequent heme production, leading to enhanced cytotoxicity of ARS. Notably, knocking down ALAS1 significantly blunted the synergistic effect of ARS and HDACi on tumor inhibition, indicating a critical role of ALAS1 upregulation in mediating ARS cytotoxicity. Collectively, our study revealed the mechanism of synergistic antitumor action of ARS and HDACi. This finding indicates that modulation of heme synthesis pathway by the combination based on ARTs and other heme synthesis modulators represents a promising therapeutic approach to solid tumors. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.