IMD-0354 targets breast cancer stem cells: a novel approach for an adjuvant to chemotherapy to prevent multidrug resistance in a murine model.
IMD-0354 targets breast cancer stem cells: a novel approach for an adjuvant to chemotherapy to prevent multidrug resistance in a murine model.
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DOI：
10.1371/journal.pone.0073607
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Reisfeld RA
中科院分区：
文献类型：
--
作者：
Gomez-Cabrero A;Wrasidlo W;Reisfeld RA
尽管近年来乳腺癌的早期发现有所改善，但晚期乳腺癌患者的预后仍然很差，这主要是由于肿瘤复发后出现多药耐药(MDR)所致。肿瘤干细胞(CSCs)具有更高的药物外排能力和其他类似干细胞的特性，集中在一群细胞(SP)中，这些细胞被认为是导致MDR和肿瘤再繁殖的原因，导致患者死于乳腺癌。因此，靶向CSCs作为化疗的辅助手段应该能够提供一种更有效的治疗方法。在这里，我们使用了一种核因子-κB的抑制剂IMD-0354，它被确定为靶向CSCs，与包裹在靶向纳米粒中的阿霉素联合治疗。IMD-0354确实以CSCs为靶点，其证据是SP的减少，表现为对以下方面的抑制：染料/药物外流，ABC转运蛋白的减少以及在软琼脂和低附着平板上的集落形成。与Survivin基因相关的干细胞样基因Oct4、Nanog和Sox2的表达也明显降低，并具有抗细胞凋亡作用。此外，IMD-0354靶向非肿瘤干细胞，表现为降低存活率和增加细胞凋亡率。通过豆类抑制剂实现的靶向药物传递被证明在低氧条件下增强了药物传递，这是肿瘤微环境的一个标志，但在常氧条件下不能。总之，这使得这两种抗癌剂能够安全、无毒地输送到携带同基因转移性乳腺癌的小鼠的肿瘤微环境中。用化疗药物靶向肿瘤细胞和用IMD-0354靶向CSCs应该能够减少MDR。这最终可能导致降低肿瘤复发和/或改善转移性疾病的结局。
Although early detection of breast cancer improved in recent years, prognosis of patients with late stage breast cancer remains poor, mostly due to development of multidrug resistance (MDR) followed by tumor recurrence. Cancer stem cells (CSCs), with higher drug efflux capability and other stem cell-like properties, are concentrated in a side population (SP) of cells, which were proposed to be responsible for MDR and tumor repopulation that cause patients to succumb to breast cancer. Therefore, targeting of CSCs as an adjuvant to chemotherapy should be able to provide a more effective treatment of this disease. Here, we used IMD-0354, an inhibitor of NF-κB, identified for targeting CSCs, in a combination therapy with doxorubicin encapsulated in targeted nanoparticles. IMD-0354 did target CSCs, evidenced by a decrease in the SP, demonstrated by the inhibition of the following: dye/drug efflux, reduction in ABC transporters as well as in colony formation in soft agar and low attachment plates. Decrease of stem-like gene expression of Oct4, Nanog and Sox2, and apoptosis resistance related to the Survivin gene also was observed after treatment with this compound. In addition, IMD-0354 targeted non-CSCs as indicated by reducing viability and increasing apoptosis. Targeted drug delivery, achieved with a legumain inhibitor, proved to enhance drug delivery under hypoxia, a hallmark of the tumor microenvironment, but not under normoxia. Together, this allowed a safe, non-toxic delivery of both anticancer agents to the tumor microenvironment of mice bearing syngeneic metastatic breast cancer. Targeting both bulk tumor cells with a chemotherapeutic agent and CSCs with IMD-0354 should be able to reduce MDR. This could eventually result in decreasing tumor recurrences and/or improve the outcome of metastatic disease.
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