Lui Vivian W Y, Wentzel Abbey L, Xiao Dong, Lew Karen L, Singh Shivendra V, Grandis Jennifer R
Department of Otolaryngology and 2Pharmacology, University of Pittsburgh School of Medicine and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Carcinogenesis. 2003 Oct;24(10):1705-12. doi: 10.1093/carcin/bgg127. Epub 2003 Aug 1.
Cruciferous vegetable-derived isothiocyanates (ITCs; chemical structure: R-N=C=S) are highly effective in affording protection against chemically induced cancers in animal models. Here, we studied the antitumor effects of benzyl isothiocyanate (BITC; Ph-CH2-N=C=S), the predominant ITC compound in broccoli, on head and neck squamous cell carcinoma (HNSCC) cell lines. Proliferation, apoptosis and immunoblotting assays were used to determine the effects and mechanism of several ITCs on HNSCC cells. The IC50 for BITC (24 h treatment) in two of the HNSCC cell lines was approximately 22 and 17 micro M, respectively. Interestingly, phenyl isothiocyanate (PITC; Ph-N=C=S), which is a close structural analog of BITC but lacks a -CH2- spacer that links the aromatic ring to N=C=S moiety, did not result in significant killing of the HNSCC cells in this dose range. BITC (but not PITC) caused activation of caspase 3 and PARP cleavage. Within 20 min of treatment, BITC (but not PITC) induced a rapid activation of p38 MAPK. In addition, BITC (but not PITC) treatment resulted in the activation of p44/42 MAPK. Co-treatment with a specific p38 MAPK inhibitor, SB203580, or an inhibitor of the MEK/MAPK pathway, U0126, partially rescued cells from BITC-induced killing. Our results show that minor structural differences in ITCs can be crucial for the antiproliferative activity of ITCs and that BITC may be a promising chemopreventive as well as therapeutic agent in HNSCC.
十字花科蔬菜衍生的异硫氰酸盐（ITCs；化学结构：R-N=C=S）在动物模型中对化学诱导的癌症具有高效的预防作用。在此，我们研究了西兰花中主要的ITC化合物苄基异硫氰酸盐（BITC；Ph-CH2-N=C=S）对头颈部鳞状细胞癌（HNSCC）细胞系的抗肿瘤作用。采用增殖、凋亡和免疫印迹分析来确定几种ITC对HNSCC细胞的作用及其机制。在两种HNSCC细胞系中，BITC（处理24小时）的半数抑制浓度（IC50）分别约为22微摩尔和17微摩尔。有趣的是，苯基异硫氰酸盐（PITC；Ph-N=C=S）是BITC的紧密结构类似物，但缺少将芳香环与N=C=S部分相连的-CH2-间隔基团，在该剂量范围内并未导致HNSCC细胞的显著杀伤。BITC（而非PITC）导致半胱天冬酶3激活和聚（ADP-核糖）聚合酶（PARP）裂解。处理20分钟内，BITC（而非PITC）诱导p38丝裂原活化蛋白激酶（MAPK）快速激活。此外，BITC（而非PITC）处理导致p44/42 MAPK激活。用特异性p38 MAPK抑制剂SB203580或MEK/MAPK途径抑制剂U0126共同处理，可部分挽救细胞免受BITC诱导的杀伤。我们的结果表明，ITCs的微小结构差异对于其抗增殖活性可能至关重要，并且BITC在HNSCC中可能是一种有前景的化学预防和治疗剂。
