Histone deacetylase (HDAC) inhibitors and doxorubicin combinations target both breast cancer stem cells and non-stem breast cancer cells simultaneously
Histone deacetylase (HDAC) inhibitors and doxorubicin combinations target both breast cancer stem cells and non-stem breast cancer cells simultaneously
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DOI：
10.1007/s10549-019-05504-5
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发表时间：
2019-11-29
影响因子：
3.8
通讯作者：
Leong, Chee-Onn
中科院分区：
文献类型：
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作者：
Hii, Ling-Wei;Chung, Felicia Fei-Lei;Leong, Chee-Onn
目的乳腺癌干细胞 (CSC) 是癌细胞的一个小亚群，具有很强的自我更新、分化和肿瘤发生能力。 CSC对化疗和放疗具有抵抗力，并且是癌症复发和转移的原因。方法 通过利用一组乳腺癌细胞和乳腺球培养物作为基于细胞的筛选平台，我们进行了高通量化学库筛选，以确定对乳腺 CSC 和非 CSC 有效的药物。将命中分子与常规化疗配对，以评估对乳腺 CSC 和非 CSC 的组合治疗效果。结果我们总共鉴定了 193 种抑制剂，它们可以有效靶向乳腺 CSC 和非 CSC。我们观察到组蛋白脱乙酰酶抑制剂 (HDACi) 协同传统化疗药物（即阿霉素和顺铂）同时靶向乳腺 CSC 和非 CSC。进一步分析显示，quisinostat（I 类和 II 类 HDAC 的有效抑制剂）可增强阿霉素诱导的乳腺 CSC 和源自基底样乳腺癌（MDA-MB-468 和 HCC38）、间质样乳腺癌（MDA-MB-231）和管腔样乳腺癌（MCF-7）的非 CSC 中的细胞毒性。还观察到，与管腔样乳腺癌亚型相比，基底样乳腺 CSC 和非 CSC 对 quisinostat 与阿霉素联合治疗更敏感。结论 总之，这项研究证明了 HDACi 作为治疗选择的潜力，无论是作为单一疗法还是与化疗药物联合治疗难治性乳腺癌。
Purpose Breast cancer stem cells (CSCs) are a small subpopulation of cancer cells that have high capability for self-renewal, differentiation, and tumor initiation. CSCs are resistant to chemotherapy and radiotherapy, and are responsible for cancer recurrence and metastasis. Methods By utilizing a panel of breast cancer cells and mammospheres culture as cell-based screening platforms, we performed high-throughput chemical library screens to identify agents that are effective against breast CSCs and non-CSCs. The hit molecules were paired with conventional chemotherapy to evaluate the combinatorial treatment effects on breast CSCs and non-CSCs. Results We identified a total of 193 inhibitors that effectively targeting both breast CSCs and non-CSCs. We observed that histone deacetylase inhibitors (HDACi) synergized conventional chemotherapeutic agents (i.e., doxorubicin and cisplatin) in targeting breast CSCs and non-CSCs simultaneously. Further analyses revealed that quisinostat, a potent inhibitor for class I and II HDACs, potentiated doxorubicin-induced cytotoxicity in both breast CSCs and non-CSCs derived from the basal-like (MDA-MB-468 and HCC38), mesenchymal-like (MDA-MB-231), and luminal-like breast cancer (MCF-7). It was also observed that the basal-like breast CSCs and non-CSCs were more sensitive to the co-treatment of quisinostat with doxorubicin compared to that of the luminal-like breast cancer subtype. Conclusion In conclusion, this study demonstrates the potential of HDACi as therapeutic options, either as monotherapy or in combination with chemotherapeutics against refractory breast cancer.