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,尽管偶尔会出现激素抗性克隆,但使用他莫昔芬等拮抗剂来治疗乳腺肿瘤的激素依赖性。另一种化疗策略使用微管抑制剂,如紫杉烷。不幸的是,这些药物会引起毒性,例如白细胞减少,腹泻,脱发和周围神经病变,并且还与耐药性的出现有关。我们先前已经描述了一种微管蛋白结合的天然化合物noscapine,它是无毒的,并在许多癌症类型中触发了凋亡,尽管浓度为10 mumol/L或更高,具体取决于细胞类型。我们现在显示,在激素不敏感的人类乳腺癌 (MDA-MB-231) 中,诺司卡平的合成类似物9-溴单司卡平在抑制细胞增殖和诱导G2-M停滞后的凋亡方面比诺司卡平有效约10倍至15倍。此外,线粒体膜电位的明显丧失,细胞色素c的释放,末端caspase-3的激活以及其底物 (例如聚 (ADP-核糖) 聚合酶) 的裂解提示了内在的凋亡机制。综合起来,这些数据指出了激素不敏感的乳腺癌细胞的线粒体介导的凋亡。裸鼠的人类肿瘤异种移植物显示出显着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,证明9-溴单可用于激素难治性乳腺癌的治疗。

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