Targeting cancer stem cells with p53 modulators.
Targeting cancer stem cells with p53 modulators.
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DOI：
10.18632/oncotarget.8650
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发表时间：
2016-07-19
期刊：
影响因子：
--
通讯作者：
DeLeo AB
中科院分区：
文献类型：
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作者：
Zhang Z;Liu L;Gomez-Casal R;Wang X;Hayashi R;Appella E;Kopelovich L;DeLeo AB
癌症干细胞（CSC）通常过表达醛脱氢酶（ALDH）。因此，ALDHbright肿瘤细胞代表了开发新的癌症预防/治疗干预措施的靶点。p53功能的丧失是癌症发展期间的常见遗传事件，其中已经鉴定了恢复p53功能和逆转肿瘤生长的小分子量化合物（SMWC）。在这里，我们专注于两个广泛研究的p53 SMWC，CP-31398和PRIMA-1，在表达突变型或野生型（WT）p53的人乳腺癌，子宫内膜癌和胰腺癌细胞系中靶向ALDHbright CSC。CP-31398和PRIMA-1在体外显著降低这些细胞系的CSC含量和球体形成。此外，与顺铂和吉西他滨（两种常用的化疗药物）相比，这些药物在体外对CSC更有效。我们还测试了甲基胆蒽（MCA）治疗的小鼠组成的p53 SMWC和p53为基础的疫苗的组合治疗。然而，使用生存终点分析，与单独的疫苗相比，在单独的p53 SMWC或与疫苗一起存在下没有观察到增加的功效。这些结果可能部分归因于免疫细胞的存在，例如以与一些肿瘤细胞相当的水平表达WT p53的活化淋巴细胞，其中通过p53 SMWC进一步增加p53表达可能改变这些免疫细胞的存活并负面影响有效的免疫应答。小鼠连续暴露于MCA也可能干扰这些p53 SMWC的作用，包括与MCA的潜在直接相互作用。尽管如此，p53 SMWC对CSC和癌症治疗的作用仍然非常令人感兴趣。
Cancer stem cells (CSC) typically over-express aldehyde dehydrogenase (ALDH). Thus, ALDHbright tumor cells represent targets for developing novel cancer prevention/treatment interventions. Loss of p53 function is a common genetic event during cancer development wherein small molecular weight compounds (SMWC) that restore p53 function and reverse tumor growth have been identified. Here, we focused on two widely studied p53 SMWC, CP-31398 and PRIMA-1, to target ALDHbright CSC in human breast, endometrial and pancreas carcinoma cell lines expressing mutant or wild type (WT) p53. CP-31398 and PRIMA-1 significantly reduced CSC content and sphere formation by these cell lines in vitro. In addition, these agents were more effective in vitro against CSC compared to cisplatin and gemcitabine, two often-used chemotherapeutic agents. We also tested a combinatorial treatment in methylcholantrene (MCA)-treated mice consisting of p53 SMWC and p53-based vaccines. Yet using survival end-point analysis, no increased efficacy in the presence of either p53 SMWC alone or with vaccine compared to vaccine alone was observed. These results may be due, in part, to the presence of immune cells, such as activated lymphocytes expressing WT p53 at levels comparable to some tumor cells, wherein further increase of p53 expression by p53 SMWC may alter survival of these immune cells and negatively impact an effective immune response. Continuous exposure of mice to MCA may have also interfered with the action of these p53 SMWC, including potential direct interaction with MCA. Nonetheless, the effect of p53 SMWC on CSC and cancer treatment remains of great interest.