A drug combination targeting hypoxia induced chemoresistance and stemness in glioma cells.
A drug combination targeting hypoxia induced chemoresistance and stemness in glioma cells.
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DOI：
10.18632/oncotarget.24839
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发表时间：
2018-04-06
期刊：
影响因子：
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通讯作者：
Sinha S
中科院分区：
文献类型：
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作者：
Jalota A;Kumar M;Das BC;Yadav AK;Chosdol K;Sinha S
缺氧是实体瘤特别是胶质母细胞瘤的特征，并且是化学抗性的关键。已知存在于缺氧小生境中的癌症干细胞是进展、转移和复发的主要原因。我们试图确定在肿瘤细胞以及癌症干细胞中的缺氧和常氧中有效的药物的协同组合。由于考克斯-2在胶质母细胞瘤亚群中过度表达，并且在缺氧中也被诱导，我们研究了原型环氧合酶（考克斯-2）抑制剂NS-398与各种药物（BCNU、替莫唑胺、2-脱氧-D-葡萄糖和顺铂）的组合，以研究它们在严重缺氧（0.2%O2）和常氧（20%O2）下消除胶质瘤细胞中的化学抗性的能力。唯一有效的组合是NS-398和BCNU，其在缺氧和常氧下均显示出协同作用。这种协同作用在任一单一药剂的亚致死剂量下是明显的。该组合的有效性由增加的促凋亡分子和减少的抗凋亡分子以及增加的半胱天冬酶活性引起。PGE 2水平，考克斯-2活性的一种表现，在缺氧期间增加，但在缺氧和常氧期间的组合降低。该组合降低了上皮-间质转化（EMT）标志物的水平。它还导致细胞迁移的更大减少。虽然单一药物可以减少胶质球的数量，但联合药物成功地消除了它们的形成。该组合还导致癌症干细胞标志物CD 133的更大减少。这种组合可能是高度缺氧肿瘤（如神经胶质瘤）的可能疗法的原型。
Hypoxia is a characteristic of solid tumors especially Glioblastoma and is critical to chemoresistance. Cancer stem cells present in hypoxic niches are known to be a major cause of the progression, metastasis and relapse. We tried to identify synergistic combinations of drugs effective in both hypoxia and normoxia in tumor cells as well as in cancer stem cells. Since COX-2 is over-expressed in subset of glioblastoma and is also induced in hypoxia, we studied combinations of a prototype Cyclooxygenase (COX-2) inhibitor, NS-398 with various drugs (BCNU, Temozolomide, 2-Deoxy-D-glucose and Cisplatin) for their ability to abrogate chemoresistance under both severe hypoxia (0.2% O2) and normoxia (20% O2) in glioma cells. The only effective combination was of NS-398 and BCNU which showed a synergistic effect in both hypoxia and normoxia. This synergism was evident at sub-lethal doses for either of the single agent. The effectiveness of the combination resulted from increased pro- apoptotic and decreased anti-apoptotic molecules and increased caspase activity. PGE2 levels, a manifestation of COX-2 activity were increased during hypoxia, but were reduced by the combination during both hypoxia and normoxia. The combination reduced the levels of epithelial-mesenchymal transition (EMT) markers. It also resulted in a greater reduction of cell migration. While single drugs could reduce the number of gliomaspheres, the combination successfully abrogated their formation. The combination also resulted in a greater reduction of the cancer stem cell marker CD133. This combination could be a prototype of possible therapy in a tumor with a high degree of hypoxia like glioma.