Design and synthesis of isothiocyanate-containing hybrid androgen receptor (AR) antagonist to downregulate AR and induce ferroptosis in GSH-Deficient prostate cancer cells.
Design and synthesis of isothiocyanate-containing hybrid androgen receptor (AR) antagonist to downregulate AR and induce ferroptosis in GSH-Deficient prostate cancer cells.
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DOI：
10.1111/cbdd.13826
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发表时间：
2021-05
影响因子：
3
通讯作者：
Prins GS
中科院分区：
文献类型：
--
作者：
Qin Z;Ou S;Xu L;Sorensen K;Zhang Y;Hu DP;Yang Z;Hu WY;Chen F;Prins GS
持续的雄激素受体（AR）信号传导和逃避凋亡是去势抵抗性前列腺癌（CRPC）治疗的主要障碍。我们设计并合成了含异硫氰酸酯（ITC）的杂合AR拮抗剂（ITC - ARi），并合理地将ITC - ARi与谷胱甘肽（GSH）合成抑制剂丁硫氨酸亚砜亚胺（BSO）联合使用，以有效下调CRPC细胞中的AR/AR剪接变体并诱导铁死亡。具有代表性的ITC - ARi 13是一种AR配体，它包含一个N - 乙酰半胱氨酸掩蔽的ITC部分，并在水溶液中逐渐释放出母体未结合的ITC 12b。当与BSO联合使用时，13的体外抗前列腺癌活性，如生长抑制和AR下调，显著增强。这种药物组合导致显著的脂质过氧化，并且铁螯合剂、抗氧化剂或血红素加氧酶 - 1抑制剂可有效挽救细胞活力，这支持了铁死亡的诱导。13和BSO协同下调AR并诱导铁死亡，可能是通过增加13/12b对细胞靶点的可及性、提高细胞内游离亚铁离子水平以及削弱以GSH为中心的细胞防御和适应能力来实现的。对ITC - ARi和GSH合成抑制剂联合使用的进一步研究可能会产生一种针对CRPC的新方法。
Sustained androgen receptor (AR) signaling and apoptosis evasion are among the main hurdles of castration-resistant prostate cancer (CRPC) treatment. We designed and synthesized isothiocyanate (ITC)-containing hybrid AR antagonist (ITC-ARi) and rationally combined ITC-ARi with GSH synthesis inhibitor buthionine sulfoximine (BSO) to efficiently downregulate AR/AR splice variant and induce ferroptosis in CRPC cells. The representative ITC-ARi 13 is an AR ligand that contains an N-acetyl cysteine-masked ITC moiety and gradually releases parental unconjugated ITC 12b in aqueous solution. The in vitro anti-PCa activities of 13, such as growth inhibition and AR downregulation, are significantly enhanced when combined with BSO. The drug combination caused notable lipid peroxidation and the cell viability was effectively rescued by iron chelator, antioxidants or the inhibitor of heme oxygenase-1, supporting the induction of ferroptosis. 13 and BSO cooperatively downregulate AR and induce ferroptosis likely through increasing the accessibility of 13/12b to cellular targets, escalating free intracellular ferrous iron and attenuating GSH-centered cellular defense and adaptation. Further studies on the combination of ITC-ARi and GSH synthesis inhibitor could result in a new modality against CRPC.
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影响因子：
7.3
作者：
Guo, Chuangxing;Linton, Angelica;Fanjul, Andrea N.
通讯作者：
Fanjul, Andrea N.
影响因子：
28.2
作者：
Korpal, Manav;Korn, Joshua M.;Zhu, Ping
通讯作者：
Zhu, Ping
影响因子：
4.1
作者：
Conaway, CC;Krzeminski, J;Chung, FL
通讯作者：
Chung, FL
影响因子：
4.7
作者：
Bhattacharya, Arup;Li, Yun;Zhang, Yuesheng
通讯作者：
Zhang, Yuesheng
DOI：
10.1038/ncpuro1296
发表时间：
2009-02
期刊：
NATURE CLINICAL PRACTICE UROLOGY
影响因子：
--
作者：
Harris, William P.;Mostaghel, Elahe A.;Nelson, Peter S.;Montgomery, Bruce
通讯作者：
Montgomery, Bruce