Curcumin analog L48H37 induces apoptosis through ROS-mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells
Curcumin analog L48H37 induces apoptosis through ROS-mediated endoplasmic reticulum stress and STAT3 pathways in human lung cancer cells
复制标题
姜黄素类似物 L48H37 通过 ROS 介导的内质网应激和 STAT3 途径诱导人肺癌细胞凋亡
DOI：
10.1002/mc.22633
复制
发表时间：
2017-07-01
影响因子：
4.6
通讯作者：
Ruan, Yeping
中科院分区：
文献类型：
--
作者：
Feng, Chen;Xia, Yiqun;Ruan, Yeping
肺癌是癌症相关死亡的主要原因。姜黄素是一种具有抗肿瘤活性的天然产物，但其生物利用度和药代动力学特性较差，限制了其在抗肿瘤治疗中的应用。以前，我们报道了L48 H37，一种具有更高生物利用度的姜黄素的新型类似物，改善LPS诱导的炎症，但L48 H37的抗癌作用仍然未知。在本研究中，我们研究了L48 H37在人肺癌细胞中的作用。我们的结果表明L48 H37可以减少肺癌细胞的生长和集落形成。这些变化是通过诱导肺癌细胞G2/M期细胞周期阻滞和凋亡介导的。L48 H37处理后，ER应激相关蛋白表达增加，p-STAT 3表达降低，且呈剂量依赖性。L48 H37还可诱导肺癌细胞内活性氧的积累，NAC预处理可完全逆转L48 H37诱导的活性氧（ROS）增加。阻断ROS能够逆转L48 H37诱导的内质网（ER）应激、细胞周期阻滞和凋亡。最后，我们表明L48 H37抑制肺癌异种移植物的生长而不表现出毒性。用L48 H37治疗携带人肺癌异种移植物的小鼠也与ER应激激活的指数相关。总之，我们的研究结果提供了一种新的抗肿瘤候选物用于治疗肺癌的证据。
Lung cancer is the leading cause of cancer-related deaths. Curcumin is a well-known natural product with anticancer ability, however, its poor bioavailability and pharmacokinetic profiles have limited its application in anticancer therapy. Previously, we reported that L48H37, a novel analog of curcumin with higher bioavailability, ameliorated LPS-induced inflammation, but the anticancer effect of L48H37 is still unknown. In the present study, we have investigated the effects of L48H37 in human lung cancer cells. Our results show that L48H37 decreases lung cancer cell growth and colony formation. These alterations were mediated through induction of G2/M cell cycle arrest and apoptosis in lung cancer cells. After L48H37 treatment, ER stress-related proteins were increased, and the expression of p-STAT3 was decreased in a dose-dependent manner. L48H37 also induced the accumulation of ROS in lung cancer cells, and pretreatment with NAC could fully reverse L48H37-induced reactive oxygen species (ROS) increase. Blocking ROS was able to reverse L48H37-induced endoplasmic reticulum (ER) stress, cell cycle arrest, and apoptosis. Finally, we show that L48H37 inhibits the growth of lung cancer xenografts without exhibiting toxicity. Treatment of mice bearinghuman lung cancer xenografts with L48H37 was also associated with indices of ER stress activation. In summary, our results provide evidence for a novel anti-tumor candidate for the treatment of lung cancer.