INRS-Institut Armand-Frappier, 531, boulevard des Prairies, Laval, QC H7V 1B7, Canada.
Bioorg Med Chem. 2013 Nov 15;21(22):7182-93. doi: 10.1016/j.bmc.2013.08.057. Epub 2013 Sep 6.
Caffeic acid and its naturally occurring derivative caffeic acid phenethyl ester (CAPE) have antiproliferative and cytotoxic properties in a variety of cancer cell lines without displaying significant toxicity toward healthy cells, and are considered to be potential anticancer agents. However, little is known about their effects on prostate cancer cells. We synthesized and evaluated the effects of caffeic acid, CAPE (2) and 18 synthetic derivatives on cell viability and androgen-dependent cell proliferation, subcellular localisation and expression of androgen receptor (AR) and secretion of prostate-specific antigen (PSA) in LNCaP human hormone-dependent prostate cancer cells. Several synthetic derivatives of CAPE were strong, concentration-dependent cytotoxic agents in LNCaP cells with IC50 values in the 6.8-26.6 μM range, potencies that were up to five-fold greater than that of CAPE (33.7±4.0 μM). A number of caffeic acid derivatives were inhibitors of androgen-stimulated LNCaP cell proliferation with concomitant inhibition of DHT-stimulated PSA secretion. Compound 24 was the most cytotoxic and antiproliferative caffeic acid derivative (IC50 values of 6.8±0.3 and 2.4±0.8 μM, respectively) inhibiting DHT-stimulated cell proliferation and PSA secretion statistically significantly at concentrations as low as 0.3 μM. Exposure to DHT increased cytoplasmic and nuclear AR levels and co-treatment with increasing concentrations of compound 24 or CAPE (2), notably, further increased these levels. In conclusion, a number of synthetic derivatives of caffeic acid are potent inhibitors of androgen-dependent prostate cancer cell proliferation and viability, acting, at least in part, via an antiandrogenic mechanism that involves increased nuclear accumulation of (presumably inactive) AR.
没食子酸及其天然衍生物咖啡酸苯乙酯（CAPE）在多种癌细胞系中具有抗增殖和细胞毒性作用，而对健康细胞没有明显毒性，被认为是潜在的抗癌药物。然而，人们对它们对前列腺癌细胞的影响知之甚少。我们合成并评估了没食子酸、CAPE（2）和 18 种合成衍生物对 LNCaP 人激素依赖性前列腺癌细胞活力和雄激素依赖性细胞增殖、雄激素受体（AR）的亚细胞定位和表达以及前列腺特异性抗原（PSA）分泌的影响。CAPE 的几种合成衍生物是 LNCaP 细胞中强的、浓度依赖性细胞毒性剂，IC50 值在 6.8-26.6 μM 范围内，其效力比 CAPE（33.7±4.0 μM）高五倍。许多没食子酸衍生物是雄激素刺激的 LNCaP 细胞增殖的抑制剂，同时抑制 DHT 刺激的 PSA 分泌。化合物 24 是最具细胞毒性和增殖抑制作用的没食子酸衍生物（IC50 值分别为 6.8±0.3 和 2.4±0.8 μM），在低至 0.3 μM 的浓度下即可显著抑制 DHT 刺激的细胞增殖和 PSA 分泌。暴露于 DHT 增加了细胞质和核内 AR 水平，并用越来越高浓度的化合物 24 或 CAPE（2）共同处理，明显进一步增加了这些水平。总之，一些没食子酸的合成衍生物是雄激素依赖性前列腺癌细胞增殖和活力的有效抑制剂，至少部分通过一种抗雄激素机制起作用，该机制涉及（推测无活性的）AR 的核内积累增加。
