Prolonged low-dose administration of the cyclooxygenase-2 inhibitor celecoxib enhances the antitumor activity of irinotecan against neuroblastoma xenografts
Prolonged low-dose administration of the cyclooxygenase-2 inhibitor celecoxib enhances the antitumor activity of irinotecan against neuroblastoma xenografts
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DOI：
10.1111/j.1349-7006.2009.01280.x
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发表时间：
2009-11-01
期刊：
影响因子：
5.7
通讯作者：
Suzuki, Kenshi
中科院分区：
文献类型：
--
作者：
Kaneko, Michio;Kaneko, Setsuko;Suzuki, Kenshi
环氧合酶(COX)-2在包括神经母细胞瘤(NB)在内的许多人类肿瘤中过表达，并促进肿瘤的发展。我们评价了伊立替康(CPT-11)联合超低剂量选择性COX-2抑制剂塞来昔布对TNB9、TS-N-2NU和TS-N-5NU三种人NB移植瘤的抗肿瘤作用。此外，还观察了塞来昔布联合治疗对移植瘤细胞增殖、凋亡、血管生成及血管内皮生长因子和凋亡相关蛋白表达的影响。塞来昔布每日给药5 mg/kg体重，不能阻止任何NB异种移植物的生长。然而，每日低剂量的CPT-11(5.9 mg/kg体重/天)和同时极低剂量的塞来昔布联合使用，不仅与低剂量的CPT-11单独治疗相比，而且与间歇常规剂量的CPT-11(59 mg/kg体重)和塞来昔布的联合治疗相比，对所有三种异种移植瘤的肿瘤生长都有非常显著的抑制作用(P<；0.001)，同时伴随着肿瘤细胞增殖减少和诱导凋亡的增加。CPT-11与塞来昔布联合应用诱导细胞凋亡与上调Bax表达和下调Bcl2表达有关。这两种药物联合应用对移植瘤的抗肿瘤作用可能部分不依赖于COX-2，并可能通过多种因素发挥作用，包括下调血管内皮生长因子的表达和激活依赖于caspase的线粒体凋亡通路。这些发现表明，长期低剂量的CPT-11联合极低剂量的塞来昔布通过阻断与NB肿瘤细胞生存和增殖相关的多个关键靶点而显示出良好的抗肿瘤活性。(《癌症科学》2009；00：000-000)。
Cyclooxygenase (COX)-2 is overexpressed in many human tumors including neuroblastoma (NB) and promotes tumor progression. We evaluated the antitumor effect of irinotecan (CPT-11) treatment combined with prolonged very low-dose administration of celecoxib, a selective COX-2 inhibitor, against three human NB xenografts, TNB9, TS-N-2nu, and TS-N-5nu. In addition, the effects of the celecoxib-combined treatment were examined on tumor cell proliferation, apoptosis, angiogenesis, and expression of vascular endothelial growth factor and apoptosis-related proteins in xenografts. Celecoxib administered daily at 5 mg/kg body weight/day could not prevent the growth of any of the NB xenografts. However, the combination of daily low-dose CPT-11 (5.9 mg/kg body weight/day) and simultaneous very low-dose celecoxib resulted in highly significant suppression of tumor growth in all three xenografts (P < 0.001) compared not only with low-dose CPT-11 therapy alone but also with the combination therapy of intermittent conventional-dose CPT-11 (59 mg/kg body weight) and celecoxib accompanied by decreased proliferation and increased induction of apoptosis in tumor cells. Induction of apoptosis by CPT-11 with and without celecoxib was associated with the up-regulation of Bax expression and the down-regulation of Bcl-2 expression. The enhanced antitumor effect of the combination of the two drugs against the NB xenografts might be partially COX-2-independent and was probably mediated through multiple factors including diminished expression of VEGF and activation of the caspase-dependent mitochondrial apoptosis pathway. These findings demonstrate that prolonged low-dose CPT-11 treatment combined with very low-dose celecoxib shows promising antitumor activity through the blockage of multiple critical targets related to NB tumor cell survival and proliferation. (Cancer Sci 2009; 00: 000-000).