Antiandrogenic effects of novel androgen synthesis inhibitors on hormone-dependent prostate cancer.
Antiandrogenic effects of novel androgen synthesis inhibitors on hormone-dependent prostate cancer.
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发表时间：
2000-12
期刊：
影响因子：
11.2
通讯作者：
B. Long;D. Grigoryev;I. Nnane;Yang Liu;Y. Ling;Angela Brodie
中科院分区：
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作者：
B. Long;D. Grigoryev;I. Nnane;Yang Liu;Y. Ling;Angela Brodie
我们发现，除了是17α-羟基酶/C17，20-裂解酶和/或5α-还原酶的有效抑制剂外，我们的一些新型雄激素合成抑制剂还与LNCaP前列腺癌细胞中表达的突变的雄激素受体(AR)和激素依赖性前列腺癌中表达的野生型AR相互作用。测定了这些化合物在体外和体内对激素依赖型人前列腺癌细胞增殖的影响。L-2和L-10为β-4-3-酮-孕烷衍生物。L-35和L-37是β-3-β-雄烷类化合物，L-36和L-39是β-3-酮-雄烷类化合物。L-2、L-10和L-36(低浓度的L-36)刺激LNCaP细胞的生长，表明它们与LNCaP细胞表达的突变AR相互作用。L-35、L-37和L-39作为LNCaP-AR拮抗剂。为了确定我们的新化合物是否对突变的LNCaP AR具有特异性的生长调控作用，我们进行了LNCaP细胞和稳定转染野生型AR(命名为PC-3AR)的PC-3细胞的竞争结合研究。无论AR受体的类型如何，我们所有的新化合物都能有效地阻止合成雄激素甲基三烯醇酮[17α-甲基-(~3H)-R1881]与LNCaP AR和野生型AR的结合。L-36、L-37和L-39(5.0微米)可抑制90%的结合，而L-35可抑制30%的结合。为了确定化合物是作为激动剂还是拮抗剂，将pMAMneLUC报告基因导入LNCaP细胞和PC-3AR细胞。当荧光素酶活性被双氢睾酮诱导时，所有化合物都被发现是转录活性的有效抑制剂，并且两种受体类型的抑制模式相似。L-2、L-10和L-36为AR激动剂，L-35、L-37和L-39为野生型AR拮抗剂。在体内试验中，L-39是唯一被证明有效地抑制LNCaP前列腺癌生长的AR拮抗剂。L-39可使雄性SCID小鼠LNCaP肿瘤生长速度减慢至与摘除睾丸相同的水平，显著减轻肿瘤重量(P<；0.05)，显著降低血清前列腺特异性抗原水平(P<；0.02)，显著降低血清睾酮水平(P<；0.05)。L-39在对表达野生型AR的PC-82前列腺癌异种移植瘤的测试中也被证明是有效的。这些结果表明，我们的一些化合物最初被开发为雄激素合成的抑制剂，也与人的AR相互作用，并调节激素依赖的前列腺癌细胞的增殖。因此，具有多功能活性的化合物，如L-39，有望用于雄激素依赖型前列腺癌的治疗。
We have found that in addition to being potent inhibitors of 17alpha-hydroxylase/C17,20-lyase and/or 5alpha-reductase, some of our novel androgen synthesis inhibitors also interact with the mutated androgen receptor (AR) expressed in LNCaP prostate cancer cells and the wild-type AR expressed in hormone-dependent prostatic carcinomas. The effects of these compounds on the proliferation of hormone-dependent human prostatic cancer cells were determined in vitro and in vivo. L-2 and L-10 are delta4-3-one-pregnane derivatives. L-35 and L-37 are delta5-3beta-ol-androstane derivatives, and L-36 and L-39 are delta4-3-one-androstane-derived compounds. L-2, L-10, and L-36 (L-36 at low concentrations) stimulated the growth of LNCaP cells, indicating that they were interacting agonistically with the mutated AR expressed in LNCaP cells. L-35, L-37, and L-39 acted as LNCaP AR antagonists. To determine whether the growth modulatory effects of our novel compounds were specific for the mutated LNCaP AR, competitive binding studies were performed with LNCaP cells and PC-3 cells stably transfected with the wild-type AR (designated PC-3AR). Regardless of AR receptor type, all of our novel compounds were effective at preventing binding of the synthetic androgen methyl-trienolone[17alpha-methyl-(3H)-R1881 to both the LNCaP AR and the wildtype AR. L-36, L-37, and L-39 (5.0 microM) prevented binding by >90%, whereas L-35 inhibited binding by 30%. To determine whether the compounds were acting as agonists or antagonists, LNCaP cells and PC-3AR cells were transfected with the pMAMneoLUC reporter gene. When luciferase activity was induced by dihydrotestosterone, all of the compounds were found to be potent inhibitors of transcriptional activity, and the pattern of inhibition was similar for both receptor types. However, L-2, L-10, and L-36 were determined to be AR agonists, and L-35, L-37, and L-39 were wild-type AR antagonists. When tested in vivo, L-39 was the only AR antagonist that proved to be effective at inhibiting the growth of LNCaP prostate tumor growth. L-39 slowed tumor growth rate in LNCaP tumors grown in male SCID mice to the same level as orchidectomy, significantly reduced tumor weights (P < 0.05), significantly lowered serum levels of prostate-specific antigen (P < 0.02), and significanty lowered serum levels of testosterone (P < 0.05). L-39 also proved to be effective when tested against the PC-82 prostate cancer xenograft that expresses wild-type AR. These results show that some of our compounds initially developed to be inhibitors of androgen synthesis also interact with the human AR and modulate the proliferation of hormone-dependent prostatic cancer cells. Therefore, compounds such as L-39, which have multifunctional activities, hold promise for the treatment of androgen-dependent prostate tumors.