Kumar Rajeev, Verma Vikas, Sharma Vikas, Jain Ashish, Singh Vishal, Sarswat Amit, Maikhuri Jagdamba P, Sharma Vishnu L, Gupta Gopal
Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
Division of Medicinal & Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226 031, India.
Toxicol Appl Pharmacol. 2015 Mar 15;283(3):187-97. doi: 10.1016/j.taap.2015.01.017. Epub 2015 Feb 2.
Dietary consumption of phytoestrogens like genistein has been linked with lower incidence of prostate cancer. The estradiol-like benzopyran core of genistein confers estrogen receptor-β (ER-β) selectivity that imparts weak anti-proliferative activity against prostate cancer cells. DL-2-[4-(2-piperidinoethoxy)phenyl]-3-phenyl-2H-1-benzopyran (BP), a SERM designed with benzopyran core, targeted androgen independent prostate cancer (PC-3) cells 14-times more potently than genistein, ~25% more efficiently than tamoxifen and 6.5-times more actively than ICI-182780, without forfeiting significant specificity in comparison to genistein. BP increased apoptosis (annexin-V and TUNEL labeling), arrested cell cycle, and significantly increased caspase-3 activity along with mRNA expressions of estrogen receptor (ER)-β and FasL (qPCR) in PC-3 cells. In classical ERE-luc reporter assay BP behaved as a potent ER-α antagonist and ER-β agonist. Accordingly, it decreased expression of ER-α target PS2 (P<0.01) and increased expression of ER-β target TNF-α (P<0.05) genes in PC-3. ER-β deficient PC-3 (siRNA-transfected) was resistant to apoptotic and anti-proliferative actions of SERMs, including stimulation of FasL expression by BP. BP significantly inhibited phosphorylation of Akt and ERK-1/2, JNK and p38 in PC-3 (immunoblotting), and thus adopted a multi-pathway mechanism to exert a more potent anti-proliferative activity against prostate cancer cells than natural and synthetic SERMs. Its precise ER-subtype specific activity presents a unique lead structure for further optimization.
饮食中摄入染料木黄酮等植物雌激素与前列腺癌发病率较低有关。染料木黄酮的雌二醇样苯并吡喃核心赋予雌激素受体-β（ER-β）选择性，对前列腺癌细胞具有微弱的抗增殖活性。DL-2-[4-(2-哌啶基乙氧基)苯基]-3-苯基-2H-1-苯并吡喃（BP）是一种以苯并吡喃核心设计的选择性雌激素受体调节剂，靶向雄激素非依赖性前列腺癌（PC-3）细胞的效力比染料木黄酮高14倍，比他莫昔芬高约25%，比ICI-182780高6.5倍，与染料木黄酮相比，在特异性方面没有明显损失。BP增加了凋亡（膜联蛋白-V和TUNEL标记），使细胞周期停滞，并显著增加了PC-3细胞中半胱天冬酶-3的活性以及雌激素受体（ER）-β和FasL的mRNA表达（定量PCR）。在经典的雌激素反应元件荧光素酶报告基因检测中，BP表现为强效的ER-α拮抗剂和ER-β激动剂。因此，它降低了PC-3中ER-α靶标PS2的表达（P<0.01），并增加了ER-β靶标TNF-α的表达（P<0.05）基因。ER-β缺陷的PC-3（经小干扰RNA转染）对选择性雌激素受体调节剂的凋亡和抗增殖作用具有抗性，包括BP对FasL表达的刺激。BP显著抑制PC-3中Akt和ERK-1/2、JNK和p38的磷酸化（免疫印迹），因此采用多途径机制对前列腺癌细胞发挥比天然和合成选择性雌激素受体调节剂更强的抗增殖活性。其精确的ER亚型特异性活性为进一步优化提供了独特的先导结构。
