Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels.
Zoledronic acid produces combinatory anti-tumor effects with cisplatin on mesothelioma by increasing p53 expression levels.
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DOI：
10.1371/journal.pone.0060297
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tagawa M
中科院分区：
文献类型：
--
作者：
Okamoto S;Jiang Y;Kawamura K;Shingyoji M;Fukamachi T;Tada Y;Takiguchi Y;Tatsumi K;Shimada H;Hiroshima K;Kobayashi H;Tagawa M
我们检测了唑来膦酸（ZOL）对携带野生型p53基因的人间皮瘤细胞的抗肿瘤作用，ZOL是临床上用于防止骨量丢失的双磷酸盐药物之一。zol处理的细胞显示caspase-3/7、-8和-9活化，亚g1期分数增加。ZOL与间皮瘤一线抗癌药物之一顺铂（CDDP）联合使用对间皮瘤细胞产生协同或叠加的细胞毒性。此外，与单独使用ZOL或CDDP相比，联合使用对胸膜腔内发生的间皮瘤具有更大的抗肿瘤作用。zol处理的细胞和cddp处理的细胞诱导p53在丝氨酸15位点（p53激活的标志）磷酸化，并上调p53蛋白表达水平。然而，siRNA下调p53水平并不影响ZOL介导的细胞毒性，但会抵消ZOL和CDDP的联合作用。此外，ZOL治疗可增强表达p53基因的腺病毒对间皮瘤的细胞毒性。这些数据表明，ZOL介导的p53增强与ZOL诱导的细胞毒性无关，但在与p53上调剂的联合作用中发挥了作用，这表明ZOL可能与抗癌药物一起用于间皮瘤的临床应用。
We examined anti-tumor effects of zoledronic acid (ZOL), one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.
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影响因子：
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通讯作者：
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