Liang Fong-Pin, Lien Jin-Cherng, Wu Yu-Hua, Chen Chien-Shu, Juang Shin-Hun
Graduate Institute of Pharmaceutical Chemistry, China Medical University Hospital, Taichung, Taiwan.
School of Pharmacy and Department of Pediatrics, Children's Hospital, China Medical University Hospital, Taichung, Taiwan.
Drug Des Devel Ther. 2015 Mar 12;9:1499-510. doi: 10.2147/DDDT.S66647. eCollection 2015.
Expression of ErbB2 protein is inversely correlated with the prognosis in cancer patients. Consequently, strategies targeting ErbB2 remain an attractive option in treating several types of malignancies, including oral cancer. In addition, many studies have shown that emodin and emodin derivatives are able to inhibit growth of ErbB2-overexpressing tumor cells. In this study, a series of computer modeling-generated emodin analogues were synthesized and tested for their antiproliferative activity against oral cancer cell lines overexpressing ErbB2. Among these analogues, em08red (1,8-dihydroxy-9(10H)-anthracenone) demonstrated potent antiproliferative activity against all three tested ErbB2-overexpressing cell lines, ie, FaDu, HSC3, and OECM1. Treatment with em08red significantly downregulated activation of ErbB2 as well as the ErbB2 protein expression level in the tested cell lines and induced G2 arrest. Antiapoptosis protein (Bcl-xl and Bcl-2) expression levels were also downregulated, and active caspase-3 and caspase-9 was detected in cells after treatment with em08red. Moreover, treatment with em08red stimulated production of cytotoxic reactive oxygen species in treated cells, and this could be partially reversed by pretreatment with N-acetylcysteine. Overall, we demonstrated inhibition of ErbB2 function and induction of reactive oxygen species in tumor cells by em08red, which prevented proliferation of tumor cells and induced apoptotic cell death.
ErbB2蛋白的表达与癌症患者的预后呈负相关。因此，靶向ErbB2的策略仍是治疗包括口腔癌在内的多种恶性肿瘤的一个有吸引力的选择。此外，许多研究表明，大黄素及其衍生物能够抑制过表达ErbB2的肿瘤细胞的生长。在本研究中，合成了一系列计算机模拟生成的大黄素类似物，并测试了它们对过表达ErbB2的口腔癌细胞系的抗增殖活性。在这些类似物中，em08red（1,8 - 二羟基 - 9(10H)-蒽酮）对所有三种测试的过表达ErbB2的细胞系，即FaDu、HSC3和OECM1，均表现出强大的抗增殖活性。用em08red处理显著下调了测试细胞系中ErbB2的激活以及ErbB2蛋白表达水平，并诱导G2期阻滞。抗凋亡蛋白（Bcl-xl和Bcl-2）的表达水平也下调，在用em08red处理后的细胞中检测到活性caspase-3和caspase-9。此外，用em08red处理刺激了处理细胞中细胞毒性活性氧的产生，而用N-乙酰半胱氨酸预处理可部分逆转这种情况。总体而言，我们证明了em08red对肿瘤细胞中ErbB2功能的抑制和活性氧的诱导，这阻止了肿瘤细胞的增殖并诱导了凋亡性细胞死亡。
