Lupeol, a novel androgen receptor inhibitor: implications in prostate cancer therapy.
Lupeol, a novel androgen receptor inhibitor: implications in prostate cancer therapy.
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DOI：
10.1158/1078-0432.ccr-11-0916
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发表时间：
2011-08-15
期刊：
影响因子：
--
通讯作者：
Saleem M
中科院分区：
文献类型：
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作者：
Siddique HR;Mishra SK;Karnes RJ;Saleem M
用于治疗雄激素依赖性表型（ADPC）和去势抗性表型（CRPC）的前列腺癌（CaP）的常规疗法在结果上存在缺陷，因此有必要确定针对这两种疾病类型的AR的药物。我们提供了基于机制的证据，表明Lupeol （Lup-20(29)-en-3b-ol）在体外和体内都是一种有效的AR抑制剂。采用正常前列腺上皮细胞（RWPE-1）、LAPC4（野生功能AR/ADPC）、LNCaP（突变功能/AR/ADPC）和C4-2b（突变功能/AR/CRPC）细胞检测lupel抗AR活性。在富雄激素环境下生长的细胞经Lupeol处理后，检测其增殖、AR转录活性、AR竞争配体结合、AR- dna结合和AR- are /靶基因结合。进一步，进行了Lupeol-AR结合的硅分子模拟。将携带C4-2b和LNCaP细胞源性肿瘤的胸腺小鼠腹腔注射Lupeol （40 mg/kg， 3次/周），评估肿瘤生长和替代生物标志物。为了评估生物利用度，测定血清中lupeol水平。Lupeol显著抑制R1881（雄激素类似物）诱导的(1)AR转录活性和(2)PSA表达。Lupeol(1)与雄激素拮抗AR，(2)阻断AR与AR应答基因（包括PSA、TIPARP、SGK和IL-6）的结合，(3)抑制RNA Pol II向靶基因的募集。芦皮醇使CRPC细胞对抗激素治疗增敏。高效液相色谱分析表明，芦皮醇对小鼠具有生物利用度。Lupeol对动物ADPC和CRPC细胞的致瘤性均有抑制作用。血清和肿瘤组织显示PSA水平降低。Lupeol是一种有效的AR抑制剂，可作为治疗人CaP的潜在药物。
Conventional therapies to treat prostate cancer (CaP) of androgen-dependent phenotype (ADPC) and castration resistant phenotype (CRPC) are deficient in outcome which has necessitated a need to identify agents those could target AR for both disease types. We provide mechanism-based evidence that Lupeol (Lup-20(29)-en-3b-ol) is a potent inhibitor of AR in vitro and in vivo. Normal prostate epithelial cell (RWPE-1), LAPC4 (wild-functional AR/ADPC), LNCaP (mutant-functional/AR/ADPC) and C4-2b (mutant-functional/AR/CRPC) cells were used to test the anti-AR activity of Lupeol. Cells grown under androgen-rich environment and treated with Lupeol were tested for proliferation, AR-transcriptional activity, AR competitive ligand-binding, AR-DNA-binding and AR-ARE/target gene binding. Further, in silico molecular modeling for Lupeol-AR binding was performed. Athymic mice bearing C4-2b and LNCaP cell-originated tumors were treated intra-peritoneally with Lupeol (40 mg/kg; 3-times/week) and tumor growth and surrogate biomarkers were evaluated. To assess bioavailability, Lupeol-serum levels were measured. Lupeol significantly inhibited R1881 (androgen-analogue)-induced (1) transcriptional activity of AR and (2) expression of PSA. Lupeol (1) competed antagonistically with androgen for AR, (2) blocked the binding of AR to AR-responsive genes including PSA, TIPARP, SGK and IL-6, and (3) inhibited the recruitment of RNA Pol II to target genes. Lupeol sensitized CRPC cells to anti-hormone therapy. HPLC analysis showed that Lupeol is bioavailable to mice. Lupeol inhibited the tumorigenicity of both ADPC and CRPC cells in animals. Serum and tumor tissues exhibited reduced PSA levels. Lupeol, an effective AR inhibitor, could be developed as a potential agent to treat human CaP.