Satyan K S, Swamy Narasimha, Dizon Don S, Singh Rakesh, Granai Cornelius O, Brard Laurent
Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI 02905, USA.
Gynecol Oncol. 2006 Oct;103(1):261-70. doi: 10.1016/j.ygyno.2006.03.002. Epub 2006 Apr 19.
Epithelial ovarian cancer has the highest mortality rate among gynecologic cancers. Chemotherapy is an essential component of its treatment. While isothiocyanates are known to possess chemopreventive effects against various cancers, yet little is known about their chemotherapeutic potential in ovarian cancer (OC). In the present study, we examined the antiproliferative and apoptotic effect of phenethyl isothiocyanate (PEITC), a naturally occurring isothiocyanate on OVCAR-3 cells.
Cytotoxic activity of PEITC on OVCAR-3 cells was determined using cell proliferation, apoptosis (DNA fragmentation and TUNEL assay) and caspase-activation studies. The role of PARP-1, Bax, and Bcl-2 in apoptosis was analyzed by Western blotting. Activation of JNK1/2, p38, Akt, ERK1/2, and c-Myc was examined by immunoblotting. Specific inhibitors of caspases, JNK1/2, p38, and MEK were used to corroborate these data.
PEITC was cytotoxic to OVCAR-3 cells, and inhibited proliferation in a dose-dependent fashion (IC(50) = 23.2 microM). PEITC induced apoptosis by activating caspase-3 and -9, without capsase-8 activation. Anti-apoptotic Bcl-2 levels were suppressed while pro-apoptotic Bax levels were enhanced. PEITC suppressed activation of Akt, ERK1/2, and the expression of transcription factor c-Myc, while simultaneously activating pro-apoptotic p38 and JNK1/2. Specific inhibitors of caspase-3 and -9, JNK1/2, and p38 reversed the cytotoxic effect of PEITC.
These findings demonstrate that PEITC exhibits cytotoxicity towards OVCAR-3 cells and induces apoptosis via caspase-9 and -3 pathways. PEITC inhibits Akt, ERK1/2 survival signaling, and c-Myc while simultaneously activating pro-apoptotic p38 and JNK1/2. Systematic preclinical and clinical trials with PEITC in ovarian cancer are indicated.
上皮性卵巢癌在妇科癌症中死亡率最高。化疗是其治疗的重要组成部分。虽然异硫氰酸盐已知对多种癌症具有化学预防作用，但关于它们在卵巢癌（OC）中的化疗潜力却知之甚少。在本研究中，我们检测了天然存在的异硫氰酸盐苯乙基异硫氰酸酯（PEITC）对OVCAR-3细胞的抗增殖和凋亡作用。
使用细胞增殖、凋亡（DNA片段化和TUNEL检测）和半胱天冬酶激活研究来确定PEITC对OVCAR-3细胞的细胞毒性活性。通过蛋白质印迹分析PARP-1、Bax和Bcl-2在凋亡中的作用。通过免疫印迹检测JNK1/2、p38、Akt、ERK1/2和c-Myc的激活情况。使用半胱天冬酶、JNK1/2、p38和MEK的特异性抑制剂来证实这些数据。
PEITC对OVCAR-3细胞具有细胞毒性，并以剂量依赖性方式抑制增殖（IC(50)=23.2 microM）。PEITC通过激活半胱天冬酶-3和-9诱导凋亡，而不激活半胱天冬酶-8。抗凋亡的Bcl-2水平受到抑制，而促凋亡的Bax水平升高。PEITC抑制Akt、ERK1/2的激活以及转录因子c-Myc的表达，同时激活促凋亡的p38和JNK1/2。半胱天冬酶-3和-9、JNK1/2和p38的特异性抑制剂可逆转PEITC的细胞毒性作用。
这些发现表明，PEITC对OVCAR-3细胞表现出细胞毒性，并通过半胱天冬酶-9和-3途径诱导凋亡。PEITC抑制Akt、ERK1/2存活信号和c-Myc，同时激活促凋亡的p38和JNK1/2。表明需要对PEITC在卵巢癌中进行系统的临床前和临床试验。
