Lien Jin-Cherng, Hung Chao-Ming, Lin Yi-Jing, Lin Hui-Chang, Ko Ting-Chia, Tseng Li-Chung, Kuo Sheng-Chu, Ho Chi-Tang, Lee Jang-Chang, Way Tzong-Der
School of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.
Department of General Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan; School of Medicine, I-Shou University, Kaohsiung, Taiwan.
Chem Biol Interact. 2015 Jun 25;235:17-26. doi: 10.1016/j.cbi.2015.04.005. Epub 2015 Apr 10.
Amplification of the HER2 gene (also known as neu or ErbB2) or overexpression of HER2 protein has become a solicitous therapeutic target in metastatic and clinical drug-resistance cancer. In our present work, a new series of curcumin derivatives were designed and synthesized using curcumin as model. Here, we evaluated whether curcumin derivatives have better efficiency to degrade HER2 than curcumin. Among these test compounds, pculin02H had better efficiency to inhibit the expression of HER2 than curcumin. Moreover, pculin02H preferentially suppressed the growth of HER2-overexpressing cancer cell lines. Pculin02H induced G2/M cell cycle arrest followed by apoptosis. Interestingly, our results suggested that a posttranslational mechanism contributed to pculin02H-induced HER2 depletion in HER2-overexpressing cancer cells. We found that pculin02H significantly enhanced the antitumor efficacy of clinical drugs on HER2-overexpressing cancer cells as well as efficiently reduced HER2-induced drug resistance. These findings may provide an alternative preventive or therapeutic strategy against HER2-overexpressing cancer cells.
HER2基因（也称为neu或ErbB2）的扩增或HER2蛋白的过表达已成为转移性和临床耐药性癌症中备受关注的治疗靶点。在我们目前的工作中，以姜黄素为模型设计并合成了一系列新的姜黄素衍生物。在此，我们评估了姜黄素衍生物降解HER2的效率是否比姜黄素更高。在这些测试化合物中，pculin02H抑制HER2表达的效率比姜黄素更高。此外，pculin02H优先抑制HER2过表达癌细胞系的生长。Pculin02H诱导G2/M期细胞周期阻滞，随后发生凋亡。有趣的是，我们的结果表明，一种翻译后机制导致了pculin02H诱导HER2过表达癌细胞中HER2的消耗。我们发现，pculin02H显著增强了临床药物对HER2过表达癌细胞的抗肿瘤疗效，并有效降低了HER2诱导的耐药性。这些发现可能为针对HER2过表达癌细胞提供一种替代性的预防或治疗策略。
