Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubicin
Inhibition of exosome release by ketotifen enhances sensitivity of cancer cells to doxorubicin
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DOI：
10.1080/15384047.2017.1394544
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发表时间：
2018-01-01
影响因子：
3.6
通讯作者：
El-Awady, Raafat
中科院分区：
文献类型：
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作者：
Khan, Farman Matloob;Saleh, Ekram;El-Awady, Raafat
癌细胞释放的外泌体支持受体细胞的转移和生长，并增加其对化疗的抵抗力。外泌体的治疗靶向是癌症研究中一个有前途的领域。我们的目的是测试肥大细胞稳定剂酮替芬对癌细胞释放外泌体的影响，以及这如何改变癌细胞对阿霉素的反应。通过扫描电子显微镜和外泌体定量试剂盒评估三种癌细胞系（MCF7、HeLa 和 BT549）释放的外泌体。通过荧光测定法监测外泌体内的阿霉素输出，并通过磺胺罗丹明-B 和集落形成测定来测量细胞对阿霉素+/-酮替芬的敏感性。三种细胞系释放不同量的外泌体，其中 BT549 释放的外泌体量最高，其次是 MCF7，然后是 HeLa。酮替芬 (10 mu mol L-1) 以不同的效率减少所有三种细胞系中的外泌体释放 (HeLa>MCF7>BT549)。通过外泌体的阿霉素输出在 BT549 中最高，在 HeLa 中较低，在 MCF7 细胞中最低。酮替芬预处理使细胞对阿霉素敏感（HeLa>MCF7>BT549），敏化因子分别为27、8和1.25。酮替芬增加的细胞对阿霉素的敏感性与其对外泌体释放的影响成正比。我们的数据是酮替芬调节癌细胞外泌体释放的第一份报告，并为外泌体靶向癌症治疗开辟了途径。酮替芬对所研究的细胞系中阿霉素外泌体输出的不同影响表明，在一些但不是所有癌症类型中，有可能药理学增强阿霉素的抗肿瘤活性。
Exosomes released from cancer cells support metastasis and growth of recipient cells and increase their resistance to chemotherapy. Therapeutic targeting of exosomes is a promising area in cancer research. Our aim is to test the effect of the mast cell stabilizer ketotifen on exosomes release from cancer cells and how this can modify their response to doxorubicin. Exosomes release from three cancer cell lines (MCF7, HeLa and BT549) was assessed by scan electron microscope and exosomes quantification kit. Doxorubicin export within exosomes was monitored flurometrically and cellular sensitivity to doxorubicin +/- ketotifen was measured by sulphorhodamine-B and colony formation assays. The three cell lines release different amounts of exosomes with the highest quantity released from BT549 followed by MCF7 and then HeLa. Ketotifen (10 mu mol L-1) reduced exosomes release in all three cell lines with different efficiency (HeLa>MCF7>BT549). Doxorubicin export via exosomes was highest in BT549, lower in HeLa and lowest in MCF7 cells. Pretreatment with ketotifen sensitized the cells to doxorubicin (HeLa>MCF7>BT549) with a sensitization factor of 27, 8 and 1.25 respectively. Increased sensitivity of cells to doxorubicin by ketotifen was proportional to its effect on exosomes release. Our data is the first report of ketotifen modulating exosomes release from cancer cells and opens the avenue for exosomes-targeting cancer therapy. The differential effects of ketotifen on doxorubicin exosomal export in the cell lines studied, suggests an opportunity of pharmacological enhancement of doxorubicin anti-tumor activity in some but not all cancer types.