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首页> 外文期刊>International journal of oncology >RL66 a second-generation curcumin analog has potent in?vivo and in?vitro anticancer activity in ER?negative breast cancer models
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RL66 a second-generation curcumin analog has potent in?vivo and in?vitro anticancer activity in ER?negative breast cancer models

机译：第二代姜黄素类似物RL66在ER阴性乳腺癌模型中具有有效的体内和体外抗癌活性

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There is a need for the development of new safe and efficacious drug therapies for the treatment of estrogen receptor (ER)?negative breast cancers. 1-Methyl-3,5-bis[(E)-4-pyridyl)methylidene]-4-piperidone (RL66) is a second generation curcumin analog that exhibits potent cytotoxicity towards a variety of ER-negative breast cancer cells. Therefore, we have further examined the mechanism of this novel drug in in?vitro and in?vivo models of ER-negative breast cancer. The mechanistic studies demonstrated that RL66 (2?μM) induced cell cycle arrest in the G2/M phase of the cell cycle. Moreover, RL66 (2?μM) caused 40% of SKBr3 cells to undergo apoptosis after 48?h and this effect was time-dependent. This correlated with an increase in cleaved caspase-3 as shown by western blot analysis. RL66 (2?μM) also decreased HER2eu phosphorylation and increased p27 in SKBr3 cells, while in MDA-MB-231 and MDA-MB-468 cells RL66 (2?μM) significantly decreased Akt phosphorylation and transiently increased the stress kinases JNK1/2 and MAPK p38. In addition, RL66 exhibited anti-angiogenic potential in?vitro as it inhibited HUVEC cell migration 46% and the ability of these cells to form tube?like networks. RL66 (8.5?mg/kg) suppressed the growth of MDA-MB-468 xenograft tumors by 48% compared to vehicle control following 10?weeks of daily oral administration. Microvessel density in the tumors from treated mice was also decreased 57% compared to control. Thus our findings demonstrate that RL66 has potent proapoptotic and anti-angiogenic properties in?vivo and in?vitro and has the potential to be further developed as a drug for the treatment of ER?negative breast cancer.
机译：需要开发用于治疗雌激素受体（ER）阴性乳腺癌的新的安全有效的药物疗法。 1-甲基-3,5-双[（E）-4-吡啶基）亚甲基] -4-哌啶酮（RL66）是第二代姜黄素类似物，对多种ER阴性乳腺癌细胞均表现出强大的细胞毒性。因此，我们在ER阴性乳腺癌的体外和体内模型中进一步研究了该新药的作用机理。机理研究表明，RL66（2？M）诱导细胞周期停滞在G2 / M期。此外，RL66（2？μM）在48？h后引起40％的SKBr3细胞凋亡，这种作用是时间依赖性的。如蛋白印迹分析所示，这与裂解的caspase-3的增加相关。 RL66（2？μM）还可降低SKBr3细胞的HER2 / neu磷酸化并增加p27，而在MDA-MB-231和MDA-MB-468细胞中，RL66（2？μM）显着降低Akt磷酸化并短暂增加应激激酶JNK1。 / 2和MAPK p38。另外，RL66在体外表现出抗血管生成的潜力，因为它抑制了46％的HUVEC细胞迁移以及这些细胞形成管样网络的能力。每天口服10周后，与媒介物对照相比，RL66（8.5？mg / kg）抑制了MDA-MB-468异种移植瘤的生长，增幅为48％。与对照相比，来自治疗小鼠的肿瘤中的微血管密度也降低了57％。因此，我们的发现表明RL66在体内和体外具有有效的促凋亡和抗血管生成特性，并有可能被进一步开发为治疗ER阴性乳腺癌的药物。

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