Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs
Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs
复制标题
DOI：
10.1093/jnci/djh305
复制
发表时间：
2004-11-17
影响因子：
10.3
通讯作者：
Fais, S
中科院分区：
文献类型：
--
作者：
Luciani, F;Spada, M;Fais, S
背景：抗肿瘤药物耐药是癌症患者治疗失败的主要原因。肿瘤对细胞毒性药物的耐药性的一些机制可能涉及细胞外区室的酸化增加。我们研究了目前用于消化系统疾病抗酸治疗的质子泵抑制剂（PPI）是否可以抑制肿瘤微环境的酸化并增加肿瘤细胞对细胞毒性药物的敏感性。研究方法：我们用PPI奥美拉唑、埃索美拉唑或泮托拉唑预处理人黑色素瘤、腺癌和淋巴瘤细胞系，并在细胞死亡试验中检测其对细胞毒性药物的反应。我们还评估了细胞外和细胞内的pH值和vacuolar-H+-ATPase（V-H+-ATPase）的表达，分布，并通过使用蛋白质印迹分析，免疫细胞化学，激光扫描共聚焦分析，和生物发光测定在PPI预处理的细胞活性。最后，我们在异种移植的SCID/SCID小鼠中评估了有或没有奥美拉唑预处理的人黑色素瘤生长和顺铂敏感性。结果如下：PPI预处理使肿瘤细胞系对顺铂、5-氟尿嘧啶和长春碱的作用敏感，IC 50值降低高达2 log。PPI预处理与V-H+-ATP酶活性的抑制和细胞外pH和溶酶体细胞器pH的增加有关。PPI预处理诱导细胞毒性药物的细胞质滞留显著增加，在阿霉素的情况下具有明确的细胞核靶向。在体内实验中，口服奥美拉唑预处理能够诱导人实体瘤对顺铂的敏感性。结论：我们的研究结果为通过基于使用耐受性良好的pH调节剂（如PPI）的联合策略治疗耐药肿瘤开辟了新的可能性。
Background: Resistance to antitumor agents is a major cause of treatment failure in patients with cancer. Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. We investigated whether proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents. Methods: We pretreated cell lines derived from human melanomas, adenocarcinomas, and lymphomas with the PPIs omeprazole, esomeprazole, or pantoprazole and tested their response to cytotoxic drugs in cell death assays. We also evaluated extracellular and intracellular pH and vacuolar-H+-ATPase (V-H+-ATPase) expression, distribution, and activity in PPI-pretreated cells by using western blot analyses, immunocytochemistry, laser scanning confocal analysis, and bioluminescence assays. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice. Results: PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles. PPI pretreatment induced a marked increase in the cytoplasmic retention of the cytotoxic drugs, with clear targeting to the nucleus in the case of doxorubicin. In in vivo experiments, oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin. Conclusion: Our results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs.