Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America.
PLoS One. 2013 Aug 27;8(8):e73607. doi: 10.1371/journal.pone.0073607. eCollection 2013.
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.
尽管近年来乳腺癌的早期检测有所改善，但晚期乳腺癌患者的预后仍然较差，这主要是由于多药耐药（MDR）的发展以及随后的肿瘤复发。具有更高药物外排能力和其他干细胞样特性的癌症干细胞（CSCs）集中在侧群（SP）细胞中，这些细胞被认为是导致 MDR 和肿瘤再增殖的原因，从而使患者屈服于乳腺癌。因此，作为化疗的辅助手段靶向 CSCs 应该能够为这种疾病提供更有效的治疗。在这里，我们使用了 NF-κB 抑制剂 IMD-0354，该抑制剂是为靶向 CSCs 而鉴定的，与靶向纳米颗粒包裹的阿霉素联合治疗。IMD-0354 通过抑制以下物质来靶向 CSCs，从而减少 SP，证明了这一点：染料/药物外排、ABC 转运蛋白减少以及软琼脂和低附着平板中的集落形成。在用该化合物处理后，还观察到干性基因表达 Oct4、Nanog 和 Sox2 的减少以及与 Survivin 基因相关的抗凋亡能力的降低。此外，IMD-0354 还靶向非 CSCs，表现为降低细胞活力和增加细胞凋亡。用组织蛋白酶抑制剂实现的靶向药物递送被证明可增强缺氧（肿瘤微环境的特征）下的药物递送，但在常氧下不行。总之，这使得能够安全、无毒地将两种抗癌剂递送至患有同源转移性乳腺癌的小鼠的肿瘤微环境中。用化疗药物靶向大块肿瘤细胞和用 IMD-0354 靶向 CSCs 应该能够降低 MDR。这最终可能会减少肿瘤复发和/或改善转移性疾病的结果。
