Discovery and cellular stress pathway analysis of 1,4-naphthoquinone derivatives with novel, highly potent broad-spectrum anticancer activity.
Discovery and cellular stress pathway analysis of 1,4-naphthoquinone derivatives with novel, highly potent broad-spectrum anticancer activity.
复制标题
DOI：
10.1186/s12929-018-0408-6
复制
发表时间：
2018-02-08
影响因子：
11
通讯作者：
Spanjaard RA
中科院分区：
文献类型：
--
作者：
Ghosh SK;Ganta A;Spanjaard RA
化疗和靶向治疗在癌症治疗方面取得了重要进展，但它们经常失败，仍然需要新的治疗方法。在这里，我们使用化学耐药性 A375 黑色素瘤细胞作为模型，采用表型筛选来识别和分析干扰肿瘤细胞生长关键途径的新型小分子的作用机制。细胞培养研究在 ATCC 推荐的培养基中进行。化合物和化合物库获自波士顿大学或商业购买。通过 Celigo 图像细胞仪和活力染色测定对 A375 细胞活力、增殖和形态的影响。在异种移植裸鼠模型中测试了先导化合物的抗癌活性。通过 SDS-PAGE 和免疫印迹和/或荧光显微镜分析信号传导和细胞死亡途径。在评估 4477 种化合物后，鉴定出一种热门化合物 CB533，它会导致 A375 细胞生长显着减少。 CB533 是一种未经开发的 1,4-萘醌 (NQ) 衍生物，与 1,4-NQ 不同，它可诱导快速细胞死亡而不产生活性氧 (ROS)。构效关系分析表明，先导化合物Pyr-1中1,4-NQ核中的吡咯烷产生了最佳活性。 CB533 和 Pyr-1 在纳米到皮摩尔范围内对多种化疗耐药癌细胞系具有生长抑制作用。 Pyr-1 还显着降低了裸鼠 MDA-MB-231 乳腺癌细胞的生长。 Pyr-1 迅速诱导主要应激途径和自噬的激活，这可以被 ERK 有效阻断，并且在一定程度上被 PI3K 抑制剂阻断。 CB533 和铅 Pyr-1 代表新型广谱抗癌化合物，其效力比白花丹素（一种具有已知抗癌活性的天然 1,4-NQ）强 1000 倍。由于CB533和Pyr-1的生长抑制活性不受癌细胞化疗耐药性的影响，因此这些化合物具有良好的治疗潜力。 Pyr-1 1,4-NQ 核 3 位的吡咯烷是药效基团的重要组成部分。 Pyr-1 诱导的细胞应激由 ERK 介导，并在较小程度上由 AKT 依赖性途径介导，不涉及细胞凋亡。我们的数据表明，Pyr-1 通过模仿 ROS 诱导的应激信号而不产生 ROS，从而大大增强了抗肿瘤活性，并且可能使细胞发生自噬。
Chemotherapy and targeted therapies have made important strides in cancer treatment yet they often fail and new therapies are still needed. Here, we employed a phenotypic screen to identify and analyze the mechanism of action of novel small molecules that interfere with critical pathways involved in tumor cell growth, using chemoresistant A375 melanoma cells as a model. Cell culture studies were performed in ATCC-recommended media. Compounds, and compound libraries were obtained from Boston University or purchased commercially. Effects on A375 cell viability, proliferation and morphology were determined by Celigo Image Cytometer and viability staining. Anticancer activity of the lead compound was tested in a xenograft nude mouse model. Signaling and cell death pathways were analyzed by SDS-PAGE and immunoblotting, and/or fluorescence microscopy. After evaluating 4477 compounds, one hit compound CB533 was identified that caused significant reduction of A375 cell growth. CB533 is an unexplored 1,4-naphthoquinone (NQ) derivative which unlike 1,4-NQ, induced rapid cell death without generating reactive oxygen species (ROS). Structure-activity relationship analysis showed that a pyrrolidine in the 1,4-NQ nucleus in lead compound Pyr-1 yielded optimal activity. CB533 and Pyr-1 had growth-suppressing effects on a large variety of chemotherapy-resistant cancer cell lines in the nano to picomolar range. Pyr-1 also significantly reduced growth of MDA-MB-231 breast cancer cells in nude mice. Pyr-1 rapidly induced activation of major stress pathways and autophagy, which was efficiently blocked by ERK, and somewhat by PI3K inhibitors. CB533 and lead Pyr-1 represent novel broad-spectrum, anticancer compounds that are up to 1000-fold more potent than plumbagin, a natural 1,4-NQ with known anticancer activity. Since the growth suppression activities of CB533 and Pyr-1 are unaffected by the chemotherapy resistance of cancer cells, these compounds have promising therapeutic potential. The pyrrolidine in the 3 position of the 1,4-NQ nucleus of Pyr-1 is a critical component of the pharmacophore. Pyr-1-induced cellular stress was mediated by an ERK, and to a lesser extent by an AKT-dependent pathway without involving apoptosis. Our data suggest that Pyr-1 derives its greatly enhanced antitumor activity via mimicking ROS-induced stress signaling without generating ROS, and likely committing cells to autophagy.
登录
查看更多内容
影响因子：
4
作者：
Ahmad, Aamir;Banerjee, Sanjeev;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.
影响因子：
4.6
作者：
Srinivas, P;Gopinath, G;Srinivas, G
通讯作者：
Srinivas, G
影响因子：
2.8
作者：
Sagar S;Esau L;Moosa B;Khashab NM;Bajic VB;Kaur M
通讯作者：
Kaur M
DOI：
10.4137/jcd.s11034
发表时间：
2013
期刊：
Journal of cell death
影响因子：
--
作者：
El-Khattouti A;Selimovic D;Haikel Y;Hassan M
通讯作者：
Hassan M
影响因子：
120.1
作者：
Swinney, David C.;Anthony, Jason
通讯作者：
Anthony, Jason