Original articles
Cai-Ping Chen, Kun Chen, Zhiqi Feng, Xiaoan Wen, Hongbin Sun. Synergistic antitumor activity of artesunate and HDAC inhibitors through elevating heme synthesis via synergistic upregulation of ALAS1 expression[J]. Acta Pharmaceutica Sinica B, 2019, 9(5): 937-951

Synergistic antitumor activity of artesunate and HDAC inhibitors through elevating heme synthesis via synergistic upregulation of ALAS1 expression
Cai-Ping Chen, Kun Chen, Zhiqi Feng, Xiaoan Wen, Hongbin Sun
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
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 nonerythrocytes 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.
Key words:    Artesunate    HDAC inhibitor    Heme    ALAS1    Antitumor   
Received: 2019-01-24     Revised: 2019-05-08
DOI: 10.1016/j.apsb.2019.05.001
Funds: This work was supported by grants from the National Natural Science Foundation of China (grants 31501182, 81573299 and 81730094); the "111 Project" from the Ministry of Education of China to Hongbin Sun; the State Administration of Foreign Experts Affairs of China, China (No. 111-2-07); Fundamental Research Funds for the Central Universities, China (2632017ZD05).
Corresponding author: Hongbin Sun     Email:hongbinsun@cpu.edu.cn
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Cai-Ping Chen
Kun Chen
Zhiqi Feng
Xiaoan Wen
Hongbin Sun

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