精确取代的苯并吡喃通过选择性调节雌激素受体靶向雄激素难治性前列腺癌细胞_瑞杰

针对病种：前列腺癌

发表时间：2015年3月

发表国家：美国

登载刊物：毒理学和应用药理学

研究单位：印度CSIR中央药物研究所内分泌科以及药物与过程化学科

研究人员：瑞杰库玛，维卡斯沃玛，维卡斯沙玛，等

主要结论：PC-3中ER-α靶标PS2的表达降低（P <0.01），ER-β靶标TNF-α（P <0.05）表达增加。 ER-β缺陷型PC-3（siRNA转染）对SERM的凋亡和抗增殖作用具有抗性，包括通过BP刺激FasL表达。 BP显著抑制PC-3（免疫印迹）中Akt和ERK-1/2，JNK和p38的磷酸化，从而采用多途径机制，对天然和合成的SERMs具有更强的针对前列腺癌细胞的抗增殖活性。其精确的ER-亚型特异性活性具有独特的引导结构，可进一步优化.

Toxicology & Applied Pharmacology, 2015, 283(3):187-97.

A precisely substituted benzopyran targets androgen refractory prostate cancer cells through selective modulation of estrogen receptors

Rajeev Kumar, Vikas Verma, Vikas Sharma, et al

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

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.

美国《毒理学和应用药理学》，2015年3月

精确取代的苯并吡喃通过选择性调节雌激素受体靶向雄激素难治性前列腺癌细胞

瑞杰库玛，维卡斯沃玛，维卡斯沙玛，等

印度CSIR中央药物研究所内分泌科以及药物与过程化学科

植物雌激素如金雀异黄素的饮食消耗与降低前列腺癌发病率有关。金雀异黄素的雌二醇样苯并吡喃核心赋予了雌激素受体-β（ER-β）选择性，赋予前列腺癌细胞弱的抗增殖活性。 DL-2- [4-（2-哌啶子基乙氧基）苯基] -3-苯基-2H-1-苯并吡喃（BP），用苯并吡喃核心设计的SERM，靶向雄激素非依赖性前列腺癌（PC-3）细胞比金雀异黄素更有效14倍，比他莫昔芬高出约25％，比ICI-182780活性高出6.5倍，与金雀异黄素相比，没有明显的特异性。 BP增加细胞凋亡（膜联蛋白-V和TUNEL标记），阻止细胞周期，并且PC-3细胞中雌激素受体（ER）-β和FasL（qPCR）的mRNA表达明显提高了胱天蛋白酶-3的活性。在典型ERE-luc报告分析中，BP是有效的ER-α拮抗剂和ER-β激动剂。因此，PC-3中ER-α靶标PS2的表达降低（P <0.01），ER-β靶标TNF-α（P <0.05）表达增加。 ER-β缺陷型PC-3（siRNA转染）对SERM的凋亡和抗增殖作用具有抗性，包括通过BP刺激FasL表达。 BP显著抑制PC-3（免疫印迹）中Akt和ERK-1/2，JNK和p38的磷酸化，从而采用多途径机制，对天然和合成的SERMs具有更强的针对前列腺癌细胞的抗增殖活性。其精确的ER-亚型特异性活性具有独特的引导结构，可进一步优化。