Kim Jung-Hwan, Xu Changjiang, Keum Young-Sam, Reddy Bandaru, Conney Allan, Kong Ah-Ng Tony
Center for Cancer Prevention Research, Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Carcinogenesis. 2006 Mar;27(3):475-82. doi: 10.1093/carcin/bgi272. Epub 2005 Nov 19.
Many naturally occurring compounds, including beta-phenylethyl isothiocyanate (PEITC) and curcumin, exhibit significant anti-cancer chemopreventive effects. In this study, we investigated the combined effects of PEITC and curcumin in PC-3 human prostate cancer cells and in PC-3 cells that were stably transfected with an NF-kappaB luciferase plasmid (PC-3 C4). We found an additive effect of PEITC and curcumin for the induction of apoptosis. To elucidate the potential mechanisms of this effect, we studied several critical cellular signaling pathways, including the critical NF-kappaB cell survival signal that is hyper-activated in PC-3 cells and many other cancers. PEITC and curcumin additively inhibited NF-kappaB luciferase activity. Furthermore, the combined treatment significantly increased the activity of poly(ADP-Ribose) polymerase and cleavage of caspase-3 in correlation with apoptotic cell death. Studying upstream signaling events, we found that the phosphorylations of IkappaBalpha and Akt (Ser473, Thr308) were significantly attenuated by the combination of PEITC and curcumin. As these events can be downstream of the activation of epidermal growth factor receptor (EGFR), we pretreated PC-3 cells with PEITC and curcumin and then stimulated them with EGF. EGFR phosphorylations (Y845 and Y1068) were dramatically suppressed by PEITC or curcumin, and more so by the combination. Importantly, the degree of Akt and PI3K phosphorylations induced by EGF were also significantly suppressed. We conclude that the simultaneous targeting of EGFR, Akt and NF-kappaB signaling pathways by PEITC and curcumin could be the molecular targets by which PEITC and curcumin exert their additive inhibitory effects on cell proliferation and ultimately lead to programmed cell death of tumor cells.
许多天然存在的化合物，包括β-苯乙基异硫氰酸酯（PEITC）和姜黄素，都具有显著的抗癌化学预防作用。在本研究中，我们调查了PEITC和姜黄素对PC-3人前列腺癌细胞以及稳定转染了NF-κB荧光素酶质粒的PC-3细胞（PC-3 C4）的联合作用。我们发现PEITC和姜黄素在诱导细胞凋亡方面具有相加作用。为了阐明这种作用的潜在机制，我们研究了几个关键的细胞信号通路，包括在PC-3细胞和许多其他癌症中过度激活的关键NF-κB细胞存活信号。PEITC和姜黄素相加抑制NF-κB荧光素酶活性。此外，联合处理显著增加了聚（ADP-核糖）聚合酶的活性以及半胱天冬酶-3的切割，这与凋亡性细胞死亡相关。研究上游信号事件时，我们发现PEITC和姜黄素的联合使用显著减弱了IκBα和Akt（Ser473，Thr308）的磷酸化。由于这些事件可能是表皮生长因子受体（EGFR）激活的下游事件，我们先用PEITC和姜黄素预处理PC-3细胞，然后用表皮生长因子（EGF）刺激它们。PEITC或姜黄素可显著抑制EGFR的磷酸化（Y845和Y1068），联合使用时抑制作用更强。重要的是，EGF诱导的Akt和PI3K磷酸化程度也被显著抑制。我们得出结论，PEITC和姜黄素同时靶向EGFR、Akt和NF-κB信号通路可能是PEITC和姜黄素对细胞增殖发挥相加抑制作用并最终导致肿瘤细胞程序性死亡的分子靶点。
