Feng Chen, Xia Yiqun, Zou Peng, Shen Miaoshan, Hu Jie, Ying Shilong, Pan Jialing, Liu Zhiguo, Dai Xuanxuan, Zhuge Weishan, Liang Guang, Ruan Yeping
Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Mol Carcinog. 2017 Jul;56(7):1765-1777. doi: 10.1002/mc.22633. Epub 2017 Mar 10.
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 bearing human 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.
肺癌是癌症相关死亡的主要原因。姜黄素是一种具有抗癌能力的知名天然产物，然而，其较差的生物利用度和药代动力学特性限制了其在抗癌治疗中的应用。此前，我们报道了L48H37，一种具有更高生物利用度的新型姜黄素类似物，可改善脂多糖诱导的炎症，但L48H37的抗癌作用仍不清楚。在本研究中，我们研究了L48H37对人肺癌细胞的影响。我们的结果表明，L48H37可降低肺癌细胞的生长和集落形成。这些改变是通过诱导肺癌细胞的G2/M期细胞周期阻滞和凋亡介导的。L48H37处理后，内质网应激相关蛋白增加，p-STAT3的表达呈剂量依赖性降低。L48H37还可诱导肺癌细胞中活性氧（ROS）的积累，用NAC预处理可完全逆转L48H37诱导的活性氧增加。阻断ROS能够逆转L48H37诱导的内质网（ER）应激、细胞周期阻滞和凋亡。最后，我们表明L48H37可抑制肺癌异种移植瘤的生长而不表现出毒性。用L48H37处理携带人肺癌异种移植瘤的小鼠也与内质网应激激活指标有关。总之，我们的结果为一种治疗肺癌的新型抗肿瘤候选药物提供了证据。
