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Abstract：
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.
摘要：
据报道，青蒿素及其衍生物（ARTs）具有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对非红细胞血红素稳态的影响尚不清楚.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。体外研究表明，ARS和HDACi的组合通过诱导细胞死亡发挥协同肿瘤抑制作用。此外，在无明显毒性的异种移植模型中,这种联合疗法比ARS或HDACi单药疗法显示出更有效的抗肿瘤活性.重要的是,机制研究表明，HDACi与ARS协调以增加5-氨基乙酰丙酸合酶（ALAS1）的表达，以及随后的血红素生产，导致ARS的细胞毒性增强。值得注意的是,敲除ALAS1显著减弱ARS和HDACi对肿瘤抑制的协同作用，表明ALAS1上调在介导ARS细胞毒性中的关键作用。总的来说，我们的研究揭示了ARS和HDACi的协同抗肿瘤作用机制。该发现表明,通过基于ART和其他血红素合成调节剂的组合调节血红素合成途径代表了一种有希望的实体瘤治疗方法。
