Enhanced phosphatidylserine-selective cancer therapy with irradiation and SapC-DOPS nanovesicles.
Enhanced phosphatidylserine-selective cancer therapy with irradiation and SapC-DOPS nanovesicles.
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DOI：
10.18632/oncotarget.26615
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发表时间：
2019-01-25
期刊：
影响因子：
--
通讯作者：
Qi, Xiaoyang
中科院分区：
文献类型：
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作者：
Davis, Harold W;Vallabhapurapu, Subrahmanya D;Qi, Xiaoyang
正常活细胞主要在质膜的细胞内小叶内显示磷脂酰丝氨酸（PS）。相反，活的癌细胞在外表面上具有高水平的PS，并且即使在特定类型的癌症中也表现出广泛的表面PS。靶向表面PS的药物最近已被开发用于治疗肿瘤，并且预期在较高的表面PS水平下更有效。在这种情况下，我们研究了表面PS是否随着照射而增加。在体外照射的癌细胞系选择存活的细胞，具有较高的表面PS的剂量和时间依赖性的方式。如果表面PS最初在癌细胞的较低范围内，则这一点更加明显。放射线还增加了裸鼠皮下移植瘤中肿瘤细胞的表面PS。我们发现癌细胞系的稳态表面PS水平与其对辐射诱导的细胞死亡的敏感性之间存在反比关系。此外，选择具有较高表面PS的存活细胞的连续照射也增加了对辐射和某些化疗药物的抗性，这表明对治疗的抗性发展的PS依赖性机制。另一方面，分次辐射增强了一种新型抗癌药物SapC-DOPS在某些癌细胞系中的作用。我们的数据表明，我们可以将癌细胞分为对辐射敏感的低表面PS细胞和对SapC-DOPS敏感的高表面PS细胞。这些干预措施的组合可能提供一种潜在的新的联合治疗。
Normal living cells exhibit phosphatidylserine (PS) primarily within the intracellular leaflet of the plasma membrane. In contrast, viable cancer cells have high levels of PS on the external surface, and exhibit a broad range of surface PS, even within specific types of cancer. Agents that target surface PS have recently been developed to treat tumors and are expected to be more effective with higher surface PS levels. In this context, we examined whether surface PS is increased with irradiation. In vitro irradiation of cancer cell lines selected surviving cells that had higher surface PS in a dose- and time-dependent manner. This was more pronounced if surface PS was initially in the lower range for cancer cells. Radiation also increased the surface PS of tumor cells in subcutaneous xenografts in nude mice. We found an inverse relationship between steady state surface PS level of cancer cell lines and their sensitivity to radiation-induced cell death. In addition, serial irradiation, which selected surviving cells with higher surface PS, also increased resistance to radiation and to some chemotherapeutic drugs, suggesting a PS-dependent mechanism for development of resistance to therapy. On the other hand, fractionated radiation enhanced the effect of a novel anti-cancer, PS-targeting drug, SapC-DOPS, in some cancer cell lines. Our data suggest that we can group cancer cells into cells with low surface PS, which are sensitive to radiation, and high surface PS, which are sensitive to SapC-DOPS. Combination of these interventions may provide a potential new combination therapy.