Sanchez Marisa, Xia Zebin, Rico-Bautista Elizabeth, Cao Xihua, Cuddy Michael, Castro David J, Correa Ricardo G, Chen Liqun, Yu Jinghua, Bobkov Andrey, Ruvolo Vivian, Andreeff Michael, Oshima Robert G, Matsuzawa Shu-Ichi, Reed John C, Zhang Xiao-Kun, Hansel Donna, Wolf Dieter A, Dawson Marcia I
Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, USA.
Oregon Health and Science University School of Medicine, Portland, OR, USA.
Oncotarget. 2018 May 18;9(38):25057-25074. doi: 10.18632/oncotarget.25285.
Di(1-indol-3-yl)(4-trifluoromethylphenyl)methane (DIM-Ph-4-CF) is an analog of orphan nuclear receptor 4A1 (NR4A1) ligand cytosporone B. We have synthesized several oxidation products of DIM-Ph-4-CF, focusing on analogs with electron-withdrawing or donating groups at their phenyl ring 4-positions, and examined their anti-cancer activity and mechanism-of-action. Mesylates (DIM-Ph-4-X OMss) having CF, COMe and Cl groups were more effective inhibitors of cancer cell viability than their precursors. F NMR spectroscopy and differential scanning calorimetry strongly indicated interactions of DIM-Ph-4-CF OMs with the NR4A1 ligand binding domain, and compound-induced apoptosis of prostate cancer cells was dependent on NR4A1. DIM-Ph-4-CF3 OMs showed robust inhibition of LNCaP prostate cancer xenografts with no apparent toxicity. and , DIM-Ph-4-CF3 OMs activated proapoptotic unfolded protein response (UPR) signaling in prostate cancer cells. Independently of DIM-Ph-4-CF OMs, the bulk of NR4A1 localized to the cytoplasm in various cancer cell lines, suggesting a cytoplasmic mechanism-of-action of DIM-Ph-4-CF OMs in UPR induction and cell death. In summary, the data suggest that oxidized analogs of DIM-Ph-4-CF3 possess potent and safe anti-cancer activity which is mediated through UPR signaling downstream of NR4A1 binding.
二（1-吲哚-3-基）（4-三氟甲基苯基）甲烷（DIM-Ph-4-CF）是孤儿核受体4A1（NR4A1）配体环孢菌素B的类似物。我们合成了几种DIM-Ph-4-CF的氧化产物，重点关注在其苯环4位带有吸电子或供电子基团的类似物，并研究了它们的抗癌活性和作用机制。具有CF、COMe和Cl基团的甲磺酸盐（DIM-Ph-4-X OMss）比其前体更有效地抑制癌细胞活力。19F核磁共振光谱和差示扫描量热法强烈表明DIM-Ph-4-CF OMs与NR4A1配体结合域相互作用，且化合物诱导的前列腺癌细胞凋亡依赖于NR4A1。DIM-Ph-4-CF3 OMs对LNCaP前列腺癌异种移植瘤表现出强大的抑制作用且无明显毒性。此外，DIM-Ph-4-CF3 OMs激活前列腺癌细胞中的促凋亡未折叠蛋白反应（UPR）信号。与DIM-Ph-4-CF OMs无关，在各种癌细胞系中，大部分NR4A1定位于细胞质，这表明DIM-Ph-4-CF OMs在UPR诱导和细胞死亡中存在细胞质作用机制。总之，数据表明DIM-Ph-4-CF3的氧化类似物具有强大且安全的抗癌活性，其通过NR4A1结合下游的UPR信号介导。
