Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Center, Riyadh, 11211, KSA.
Breast Cancer Res Treat. 2011 Jul;128(1):97-107. doi: 10.1007/s10549-010-1089-3. Epub 2010 Aug 1.
We have investigated here the anti-breast cancer properties of two novel curcumin analogues, EAC and PAC. Apoptosis was assessed by the annexin V/propidium iodide (PI) assay on different breast cancer and normal cells. Immunoblotting analysis determined the effects of these agents on different apoptotic and oncogenic proteins. Furthermore, flow cytometry and Elispot were utilised to investigate the effects on the cell cycle and the production of cytokines, respectively. Breast cancer tumour xenografts were developed in nude mice. Finally, (18)F-radiolabeled PAC and curcumin were produced to study their bioavailability and tissue biodistribution in mice. PAC is five times more efficient than curcumin and EAC in inducing apoptosis, mainly via the internal mitochondrial route. This effect was 10-fold higher against ER-negative as compared to ER-positive cells, and ectopic expression of ERα rendered ER-negative breast cancer cells more resistant to PAC. In addition, PAC delayed the cell cycle at G2/M phase with a stronger effect on ER-negative cells. Moreover, PAC exhibited strong capacity as an immuno-inducer through reducing the secretion of the two major Th2 cytokines IL-4 and IL-10. Importantly, PAC significantly reduced tumour size, and triggered apoptosis in vivo. Furthermore, PAC inhibited survivin, NF-kB and its downstream effectors cyclin D1 and Bcl-2, and strongly up-regulated p21(WAF1) both in vitro and in tumours. Besides, PAC exhibited higher stability in blood and greater biodistribution and bioavailability than curcumin in mice. These results indicate that PAC could constitute a powerful, yet not toxic, new chemotherapeutic agent against ER-negative breast tumours.
我们研究了两种新型姜黄素类似物 EAC 和 PAC 的抗乳腺癌特性。通过 Annexin V/碘化丙啶（PI）检测不同乳腺癌和正常细胞的凋亡情况。免疫印迹分析确定了这些药物对不同凋亡和致癌蛋白的影响。此外，还利用流式细胞术和 Elispot 分别研究了它们对细胞周期和细胞因子产生的影响。在裸鼠中建立了乳腺癌肿瘤异种移植模型。最后，（18）F 标记的 PAC 和姜黄素被用于研究它们在小鼠体内的生物利用度和组织分布。与 curcumin 相比，PAC 诱导凋亡的效率高五倍，主要通过内部线粒体途径。这种作用在 ER 阴性细胞中比 ER 阳性细胞高 10 倍，而 ERα 的异位表达使 ER 阴性乳腺癌细胞对 PAC 更具抵抗力。此外，PAC 使细胞周期在 G2/M 期停滞，对 ER 阴性细胞的作用更强。此外，PAC 通过减少两种主要 Th2 细胞因子 IL-4 和 IL-10 的分泌表现出很强的免疫诱导能力。重要的是，PAC 显著减少肿瘤大小，并在体内引发细胞凋亡。此外，PAC 在体外和肿瘤中均抑制了 survivin、NF-κB 及其下游效应物 cyclin D1 和 Bcl-2，并强烈上调了 p21(WAF1)。此外，PAC 在血液中的稳定性更高，在小鼠中的生物分布和生物利用度也高于 curcumin。这些结果表明，PAC 可能成为针对 ER 阴性乳腺癌的一种强大而无毒的新型化疗药物。
