Following surgery, the hormone dependence of breast tumors is exploited for therapy using antagonists such as tamoxifen, although occasional hormone-resistant clones do appear. Another chemotherapeutic strategy uses microtubule inhibitors such as taxanes. Unfortunately, these agents elicit toxicities such as leukocytopenia, diarrhea, alopecia, and peripheral neuropathies and are also associated with the emergence of drug resistance. We have previously described a tubulin-binding, natural compound, noscapine, that was nontoxic and triggered apoptosis in many cancer types albeit at 10 mumol/L or higher concentrations depending on the cell type. We now show that a synthetic analogue of noscapine, 9-bromonoscapine, is approximately 10-fold to 15-fold more potent than noscapine in inhibiting cell proliferation and induces apoptosis following G2-M arrest in hormone-insensitive human breast cancers (MDA-MB-231). Furthermore, a clear loss of mitochondrial membrane potential, release of cytochrome c, activation of the terminal caspase-3, and the cleavage of its substrates such as poly(ADP-ribose) polymerase, suggest an intrinsic apoptotic mechanism. Taken together, these data point to a mitochondrially mediated apoptosis of hormone-insensitive breast cancer cells. Human tumor xenografts in nude mice showed significant tumor volume reduction and a surprising increase in longevity without signs of obvious toxicity. Thus, our data provide compelling evidence that 9-bromonoscapine can be useful for the therapy of hormone-refractory breast cancer.

译文

:手术后,尽管偶尔出现激素抵抗性克隆,但利用他莫昔芬等拮抗剂开发了乳腺肿瘤的激素依赖性疗法。另一种化学治疗策略是使用微管抑制剂,例如紫杉烷类。不幸的是,这些药物引起毒性,例如白细胞减少,腹泻,脱发和周围神经病,并且还与耐药性的出现有关。先前我们已经描述了微管蛋白结合的天然化合物Noscapine,尽管在10μmol/ L或更高的浓度(取决于细胞类型)下,但在许多类型的癌症中均无毒并引发细胞凋亡。我们现在显示,Noscapine的合成类似物9-bromonoscapine在抑制细胞增殖方面比Noscapine的效力高约10倍至15倍,并在激素不敏感的人类乳腺癌(MDA-MB)中引起G2-M阻滞后诱导凋亡-231)。此外,线粒体膜电位的明显损失,细胞色素c的释放,末端caspase-3的活化以及其底物(如聚(ADP-核糖)聚合酶)的裂解表明了内在的凋亡机制。综上所述,这些数据表明了激素不敏感的乳腺癌细胞由线粒体介导的凋亡。裸鼠中的人类肿瘤异种移植物显示出明显的肿瘤体积减少和寿命的惊人增加,而没有明显的毒性迹象。因此,我们的数据提供了令人信服的证据,表明9-溴莫可可碱可用于治疗激素难治性乳腺癌。

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