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Discovery of a novel rhein-SAHA hybrid as a multi-targeted anti-glioblastoma drug

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Summary

Glioblastoma multiforme (GBM) is the most common malignant tumor of the central nervous system (CNS). Effective treatments remain limited. Therefore, novel chemotherapy drugs with high efficiency and few adverse effects are urgently needed. Histone deacetylase (HDAC) and serum and glucocorticoid-regulated protein kinase 1 (SGK1) are targets for the prevention and treatment of GBM. Rhein has antitumor and SGK1 suppression effects, although its biological activity is limited by poor bioavailability. To improve the drug-like properties of rhein, we constructed a novel rhein-hydroxyethyl hydroxamic acid derivative (SYSUP007), which combined rhein with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA). In the present study, the human GBM cell lines, T98G, U87 and U251, were used to investigate the anticancer effects of SYSUP007 in vitro. We found that SYSUP007 was more effective in inhibiting glioma cell proliferation, invasion and migration in vitro compared with the effects of rhein and SAHA. We also confirmed that SYSUP007 increased the expression of Ac-K100 and NDRG1 (targets of HDAC and SGK1). The present study indicates the potential that SYSUP007, as a novel rhein and SAHA derivative, for development as an anti-cancer therapy.

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Funding

This study was supported by grants to R. Pi from Guangdong Provincial International Cooperation Project of Science & Technology (No. 2013B051000038), The National Natural Science Foundation of China (No. 31371070 and 81671264) and the Fundamental Research Funds for the Central Universities (No. 15ykjc08b) and a grant to J. Chen from The National Natural Science Foundation of China (No. 81703539).

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Author notes

  1. Jingkao Chen and Bingling Luo contributed equally to this work.

Authors and Affiliations

  1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China

    Jingkao Chen & Rongbiao Pi

  2. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, 510515, China

    Jingkao Chen

  3. Zhongshan Cancer Center, Sun Yat-Sen University, Guangzhou, 510080, China

    Bingling Luo & Shijun Wen

  4. International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-dementia Drugs of Guangdong, Guangzhou, 510006, China

    Rongbiao Pi

  5. Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Rongbiao Pi

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  1. Jingkao Chen
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Chen, J., Luo, B., Wen, S. et al. Discovery of a novel rhein-SAHA hybrid as a multi-targeted anti-glioblastoma drug. Invest New Drugs 38, 755–764 (2020). https://doi.org/10.1007/s10637-019-00821-4

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