Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines
Dicoumarol potentiates cisplatin-induced apoptosis mediated by c-Jun N-terminal kinase in p53 wild-type urogenital cancer cell lines
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DOI：
10.1038/sj.onc.1209162
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发表时间：
2006-04-01
期刊：
影响因子：
8
通讯作者：
Ogawa, O
中科院分区：
文献类型：
--
作者：
Watanabe, J;Nishiyama, H;Ogawa, O
3- 3 '-亚甲基-双[4-羟基香豆素]（双香豆素）是NADPH：醌氧化还原酶1的抑制剂，据报道具有潜在的抑制作用和消除p53蛋白的能力。在本研究中，我们研究了双香豆素联合顺铂（CDDP）的细胞毒性作用，使用四种膀胱癌细胞系（RT 112，253 J，J82和UMUC 3）和两种前列腺癌细胞系（LNCap和PC 3）。100 μ M双香豆素单次处理抑制细胞增殖，但在24小时内没有诱导所有细胞系的凋亡。另一方面，双香豆素预处理增强CDDP在三个细胞系与野生型p53（RT 112，253 J和LNCap）的细胞毒性，但不是在其他三个细胞系与突变型p53或RT 112稳定转染与显性阴性突变的p53。在RT 112和LNCap中，CDDP诱导p53和p21表达，而双香豆素预处理抑制p53/p21的诱导，并导致c-Jun N-末端激酶（JNK）以时间依赖性方式顺序激活。此外，JNK的抑制，使用SP 600125，完全抑制半胱天冬酶和聚-（ADP-核糖）聚合酶裂解的活性，导致抑制增强CDDP介导的细胞凋亡的双香豆素。这些结果表明，双香豆素可以通过p53/p21/JNK途径增强顺铂对p53野生型泌尿生殖道癌细胞的细胞毒性。
3-3'-Methylene-bis [4-hydroxycoumarin] (dicoumarol), an inhibitor of NADPH: quinone oxidoreductase 1, has been reported to possess potential antineoplastic effects and the ability to abrogate p53 protein. In the present study, we investigated the cytotoxic effects of dicoumarol in combination with cisplatin ( CDDP), using four bladder (RT112, 253J, J82 and UMUC3) and two prostate (LNCap and PC3) cancer cell lines. Single treatment with 100 mu M dicoumarol suppressed cell proliferation but did not induce apoptosis at 24 h in all cell lines examined. On the other hand, pretreatment with dicoumarol enhanced cytotoxicity of CDDP in three cell lines with wild type of p53(RT112, 253J and LNCap), but not in three other cell lines with mutant p53 or in RT112 stable transfectants with a dominant-negative mutant of p53. In RT112 and LNCap, CDDP induced p53 and p21 expression, while pretreatment of dicoumarol suppressed induction of p53/p21 and resulted in sequential activation of c-Jun N-terminal kinase (JNK) in a time-dependent manner. Furthermore, inhibition of JNK, using SP600125, completely suppressed activity of caspases and poly-(ADP-ribose) polymerase cleavage, leading to suppression of enhancement of CDDP-mediated apoptosis by dicoumarol. These results suggested that dicoumarol could enhance cytotoxicity of CDDP in urogenital cancer cells with wild-type p53 through the p53/p21/JNK pathways.