Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC).
Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC).
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SBI-46是一种抗雄激素的组蛋白去乙酰化酶抑制剂，是针对去势抵抗性前列腺癌（CRPC）开发的主要化合物。我们确定了SBI-46对CRPC的体外和体内模型的抗癌作用。在我们的研究结果中，SBI-46下调CRPC细胞中AR和AR剪接变体（SV）的表达及其下游靶基因。此外，SBI-46在DHT存在下抑制AR表达和核定位。我们进一步证明SBI-46通过激活促凋亡基因Bax、裂解的PARP和裂解的caspase-9以及下调抗凋亡基因Bcl 2和BCl-xL的表达来诱导凋亡。此外，口服施用SBI-46消除了表达AR或AR和AR-SV两者的C4-2B和22 Rv 1 CRPC异种移植肿瘤的生长。最后，我们的结果表明，SBI-46通过抑制CRPC临床前模型中的AR和AR-SV发挥抗癌作用。背景资料：表观遗传修饰影响雄激素受体（AR）激活，通常导致前列腺癌（PCa）的发展和进展。沉默组蛋白修饰酶（组蛋白去乙酰化酶-HDAC）在遗传上或抑制PCa的临床前模型中的PCa增殖;然而，临床研究的结果并不令人鼓舞。同样，PCa患者最终对雄激素消融治疗（ADT）产生耐药性。我们的目标是开发包含抗雄激素和HDAC抑制部分的双作用小分子，其可以克服ADT的耐药性并有效抑制去势抵抗性前列腺癌（CRPC）的生长。研究方法：合成了几种合理设计的抗雄激素HDAC抑制剂（HDACi），并在体外和体内研究了它们对CRPC生长的功效。结果如下：在筛选我们新开发的小分子时，我们观察到SBI-46显著抑制AR+ CRPC细胞的增殖，但不抑制AR-CRPC和正常永生化前列腺上皮细胞（RWPE 1）或正常肾细胞（HEK-293和VERO）的增殖。分子分析证实，SBI-46下调CRPC细胞中AR+和AR-剪接变体（AR-SV）的表达。进一步的研究揭示了CRPC细胞中AR下游（PSA）事件的下调。SBI-46的口服给药消除了异种移植裸鼠模型中表达AR或AR和AR-SV两者的C4-2B和22 Rv 1 CRPC异种移植肿瘤的生长。此外，免疫组织化学分析证实SBI-46抑制异种移植肿瘤组织中的AR信号传导。结论：这些结果表明，SBI-46是通过下调AR和AR-SV两者的表达来抑制CRPC的临床前模型的有效药剂。此外，这些结果表明SBI-46可能是治疗CRPC的有效化合物。
SBI-46, an antiandrogen-equipped histone deacetylase inhibitor, is the lead compound developed for targeting castration-resistant prostate cancer (CRPC). We determined the anticancer effect of SBI-46 on in vitro and in vivo models of CRPC. In our results, SBI-46 downregulates AR and AR-splice variant (SV) expression and its downstream target genes in CRPC cells. Additionally, SBI-46 inhibits AR expression and nuclear localization in the presence of DHT. We further demonstrated that SBI-46 induces apoptosis by activating the pro-apoptotic genes Bax, cleaved PARP, and cleaved caspase-9, as well as downregulating the expression of the antiapoptotic genes Bcl2 and BCl-xL. Additionally, the oral administration of SBI-46 abrogates the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV. Finally, our results demonstrate that SBI-46 exerts an anticancer effect by inhibiting AR and AR-SV in preclinical models of CRPC. Background: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). Methods: Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. Results: While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR+ CRPC cells but not AR- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR+ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. Conclusion: These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.
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影响因子：
4
作者：
Gryder BE;Akbashev MJ;Rood MK;Raftery ED;Meyers WM;Dillard P;Khan S;Oyelere AK
通讯作者：
Oyelere AK
影响因子：
5.7
作者：
Delcuve GP;Khan DH;Davie JR
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Davie JR
影响因子：
5.6
作者：
Mohler ML;Sikdar A;Ponnusamy S;Hwang DJ;He Y;Miller DD;Narayanan R
通讯作者：
Narayanan R
影响因子：
46.9
作者：
Bantscheff, Marcus;Hopf, Carsten;Drewes, Gerard
通讯作者：
Drewes, Gerard
影响因子：
3.6
作者：
Devlin, Nancy;Herdman, Michael;Holmstrom, Stefan
通讯作者：
Holmstrom, Stefan