Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China.
Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, PR China; Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, PR China.
Cancer Lett. 2014 Jun 28;348(1-2):146-55. doi: 10.1016/j.canlet.2014.03.017. Epub 2014 Mar 28.
Imperatorin is a small molecule nature compound isolated from the root of Angelica dahurica, and has been shown to exhibit multiple bioeffector functions, including anti-cancer activity. However, the molecular mechanism underlying imperatorin in suppression of tumor growth is unknown. In this study, we aimed at elucidating the molecular mechanisms underlying imperatorin function and determining the efficacy of imperatorin in suppression of drug-resistant human liver cancer. We observed that imperatorin suppresses tumor cell growth through inducing apoptosis, and imperatorin is more effective in induction of multidrug-resistant human liver cancer cells in vitro. We further determined that imperatorin induces apoptosis through both extrinsic and intrinsic apoptosis pathway. At the molecular level, we identified Mcl-1 as the molecular target of imperatorin and determined that imperatorin induces proteosome-dependent Mcl-1 degradation to release Bak and Bax to trigger apoptosis in liver cancer cells. Consistent with its in vitro apoptosis induction activity, imperatorin exhibited potent activity against multidrug-resistant liver cancer xenograft growth in vivo. Taken together, we determined that imperatorin is a Mcl-1 degradation inducer that can effectively suppress multidrug-resistant human liver cancer growth in vivo, and thus holds great promise for development as an effective small molecule anti-cancer agent in human liver cancer therapy to overcome drug resistance.
欧前胡素是一种从白芷根中分离得到的小分子天然化合物，已被证明具有多种生物效应功能，包括抗癌活性。然而，欧前胡素抑制肿瘤生长的分子机制尚不清楚。在本研究中，我们旨在阐明欧前胡素的功能的分子机制，并确定欧前胡素抑制耐药性人肝癌的疗效。我们观察到欧前胡素通过诱导细胞凋亡来抑制肿瘤细胞生长，并且欧前胡素在体外诱导多药耐药性人肝癌细胞的效果更显著。我们进一步确定欧前胡素通过外在和内在凋亡途径诱导细胞凋亡。在分子水平上，我们鉴定出 Mcl-1 是欧前胡素的分子靶标，并确定欧前胡素诱导依赖蛋白酶体的 Mcl-1 降解，从而释放 Bak 和 Bax 引发肝癌细胞凋亡。与体外诱导细胞凋亡的活性一致，欧前胡素在体内对多药耐药性肝癌异种移植的生长具有很强的抑制作用。总之，我们确定欧前胡素是一种 Mcl-1 降解诱导剂，可有效抑制体内多药耐药性人肝癌的生长，因此有望作为一种有效的小分子抗癌药物，用于人类肝癌治疗，以克服耐药性。
