Huang Yi, Hager Erin R, Phillips Dawn L, Dunn Valerie R, Hacker Amy, Frydman Benjamin, Kink John A, Valasinas Aldonia L, Reddy Venodhar K, Marton Laurence J, Casero Robert A, Davidson Nancy E
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Clin Cancer Res. 2003 Jul;9(7):2769-77.
Polyamine analogs have demonstrated considerable activity against many important solid tumor models including breast cancer. However, the precise mechanisms of antitumor activities of polyamine analogs are not entirely understood. The cytotoxicity of a newly developed polyamine analog compound, SL11144, against human breast cancer was assessed. Treatment of human breast cancer cell lines in culture with SL11144 decreased cell proliferation and induced programmed cell death in a time- and dose-dependent manner. SL11144 also profoundly inhibited the growth of MDA-MB-231 xenografts in host nude mice without overt toxic effects. Treatment of MDA-MB-435 cells with SL11144 led to the release of cytochrome c from mitochondria into cytosol, activation of caspase-3, and poly(ADP-ribose) polymerase cleavage. SL11144 decreased Bcl-2 and increased Bax protein levels in MDA-MB-231 cells. Furthermore, activator protein 1 transcriptional factor family member c-Jun was up-regulated by SL11144 in MDA-MB-435 and MDA-MB-231 cells, but not in MCF7 cells. In addition, significant inhibition of ornithine decarboxylase activity and a decrease in polyamine pools were demonstrated. These results demonstrate that the novel polyamine analog SL11144 has effective antineoplastic action against human breast cancer cells in vitro and in vivo and that multiple apoptotic mechanisms are associated with its cytotoxic effect in specific human breast cancer cell lines.
多胺类似物已在包括乳腺癌在内的许多重要实体瘤模型中显示出相当大的活性。然而，多胺类似物抗肿瘤活性的确切机制尚未完全了解。评估了一种新开发的多胺类似物化合物SL11144对人乳腺癌的细胞毒性。用SL11144处理培养中的人乳腺癌细胞系，以时间和剂量依赖性方式降低细胞增殖并诱导程序性细胞死亡。SL11144还能显著抑制宿主裸鼠体内MDA-MB-231异种移植物的生长，且无明显毒性作用。用SL11144处理MDA-MB-435细胞导致细胞色素c从线粒体释放到细胞质中，激活caspase-3，并切割聚（ADP-核糖）聚合酶。SL11144降低了MDA-MB-231细胞中Bcl-2的水平并增加了Bax蛋白的水平。此外，激活蛋白1转录因子家族成员c-Jun在MDA-MB-435和MDA-MB-231细胞中被SL11144上调，但在MCF7细胞中未上调。此外，还证明了鸟氨酸脱羧酶活性受到显著抑制，多胺池减少。这些结果表明，新型多胺类似物SL11144在体外和体内对人乳腺癌细胞具有有效的抗肿瘤作用，并且多种凋亡机制与其在特定人乳腺癌细胞系中的细胞毒性作用相关。
