Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer.
Antitumor and Antiangiogenic Effects of Aspirin-PC in Ovarian Cancer.
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DOI：
10.1158/1535-7163.mct-16-0074
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发表时间：
2016-12
影响因子：
5.7
通讯作者：
Sood AK
中科院分区：
文献类型：
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作者：
Huang Y;Lichtenberger LM;Taylor M;Bottsford-Miller JN;Haemmerle M;Wagner MJ;Lyons Y;Pradeep S;Hu W;Previs RA;Hansen JM;Fang D;Dorniak PL;Filant J;Dial EJ;Shen F;Hatakeyama H;Sood AK
为了确定一种新的和更安全的（用于胃肠道）阿司匹林（阿司匹林-PC）在卵巢癌临床前模型中的疗效，进行了体外剂量反应研究，以比较阿司匹林-PC与阿司匹林对3种人（A2780，SKOV 3 ip 1，HeyA 8）和小鼠（ID 8）卵巢癌细胞系在8天培养期内的生长抑制作用。在体内研究中，由于抗血管生成治疗后血小板在肿瘤生长中的新作用，单独和在VEGF-A抑制剂（贝伐单抗或B20）存在下研究了阿司匹林试验药物，我们研究了其潜在机制。阿司匹林-PC在单层培养中阻断人和小鼠卵巢癌细胞的生长方面更有效（与阿司匹林相比）。使用卵巢癌的体内模型系统，我们发现阿司匹林-PC显著降低卵巢癌生长50-90%（取决于卵巢细胞系/密度）。与贝伐珠单抗或B20联合使用时，疗效进一步增强。对卵巢肿瘤质量和肿瘤结节数量的生长抑制作用是明显的，但阿司匹林和VEGF抑制剂单独使用不太明显。未检测到胃肠道毒性。阿司匹林和阿司匹林-PC也抑制细胞增殖，血管生成和增加卵巢癌细胞的凋亡。总之，在细胞培养和小鼠模型系统中，PC相关阿司匹林显著抑制卵巢癌细胞的生长，其抑制作用超过母体药物。我们还发现，阿司匹林-PC和阿司匹林在VEGF阻断药物的存在下具有强大的抗肿瘤作用。
To determine the efficacy of a novel and safer (for gastrointestinal tract) aspirin (aspirin-PC) in preclinical models of ovarian cancer, in vitro dose-response studies were performed to compare the growth-inhibitory effect of aspirin-PC vs. aspirin on 3 human (A2780, SKOV3ip1, HeyA8), and a mouse (ID8) ovarian cancer cell line over an 8-day culture period. In the in vivo studies, the aspirin test drugs were studied alone and in the presence of a VEGF-A inhibitor (bevacizumab or B20), due to an emerging role for platelets in tumor growth following anti-angiogenic therapy, and we examined their underlying mechanisms. Aspirin-PC was more potent (vs. aspirin) in blocking the growth of both human and mouse ovarian cancer cells in monolayer culture. Using in vivo model systems of ovarian cancer, we found that aspirin-PC significantly reduced ovarian cancer growth by 50–90% (depending on the ovarian cell line/density). The efficacy was further enhanced in combination with Bevacizumab or B20. The growth-inhibitory effect on ovarian tumor mass and number of tumor nodules was evident, but less pronounced for aspirin and the VEGF inhibitors alone. There was no detectable gastrointestinal toxicity. Both aspirin and aspirin-PC also inhibited cell proliferation, angiogenesis and increased apoptosis of ovarian cancer cells. In conclusion, PC-associated aspirin markedly inhibits the growth of ovarian cancer cells, which exceeds that of the parent drug, in both cell culture and in mouse model systems. We also found that both aspirin-PC and aspirin have robust anti-neoplastic action in the presence of VEGF blocking drugs.