Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road, LL 128A, Box 571465, Washington, DC 20057, USA.
J Med Chem. 2011 Feb 10;54(3):809-16. doi: 10.1021/jm101199t. Epub 2011 Jan 11.
Isothiocyanates (ITCs) derived from cruciferous vegetables induce apoptosis in cancer cells. We demonstrate that certain naturally occurring ITCs selectively deplete mutant p53 but not the wild-type and do so via a transcription-independent mechanism. Direct p53 binding followed by conformational changes appears to be a mechanism by which mutant p53 is depleted. Structure-activity relationship studies (SARs) using naturally occurring and synthetic ITCs show that depletion is influenced by the ITC side-chain moiety. Furthermore, we show that cells with p53 mutations are more sensitive to cytotoxicity induced by phenethyl isothiocyanate (PEITC) than those with the wild-type protein. 2,2-Diphenylethyl ITC, a synthetic ITC, is one of the most potent depletors of mutant p53 studies and induces apoptosis to the greatest extent in mutant p53 breast cancer cells. Collectively, this study shows that mutant p53 depletion may be an important novel target for cancer chemoprevention and therapy by natural and synthetic ITCs.
异硫氰酸酯（ITCs）来源于十字花科蔬菜，可诱导癌细胞凋亡。我们证明，某些天然存在的 ITCs 可选择性耗尽突变型 p53，但不会耗尽野生型 p53，而且这种作用是通过转录非依赖性机制实现的。直接与 p53 结合并随之发生构象改变，似乎是耗尽突变型 p53 的一种机制。利用天然存在的和合成的 ITCs 进行的构效关系研究（SARs）表明，耗尽作用受到 ITC 侧链部分的影响。此外，我们还发现，与野生型蛋白相比，p53 突变的细胞对苯乙基异硫氰酸酯（PEITC）诱导的细胞毒性更为敏感。2,2-二苯乙基异硫氰酸酯是一种合成的 ITC，是研究中对突变型 p53 最具耗尽作用的物质之一，可在突变型 p53 乳腺癌细胞中诱导最大程度的凋亡。总的来说，这项研究表明，通过天然和合成 ITCs 耗尽突变型 p53 可能是癌症化学预防和治疗的一个重要新靶点。
