Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Department of Infection and Immunity, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Mol Carcinog. 2018 Mar;57(3):333-346. doi: 10.1002/mc.22758. Epub 2017 Nov 24.
Triple-negative breast tumors are very aggressive and contain relatively high proportion of cancer stem cells, and are resistant to chemotherapeutic drugs including cisplatin. To overcome these limitations, we combined eugenol, a natural polyphenolic molecule, with cisplatin to normalize cisplatin mediated toxicity and potential drug resistance. Interestingly, the combination treatment provided significantly greater cytotoxic and pro-apoptotic effects as compared to treatment with eugenol or cisplatin alone on several triple-negative breast cancer cells both in vitro and in vivo. Furthermore, adding eugenol to cisplatin potentiated the inhibition of breast cancer stem cells by inhibiting ALDH enzyme activity and ALDH-positive tumor initiating cells. We provide also clear evidence that eugenol potentiates cisplatin inhibition of the NF-κB signaling pathway. Indeed, the binding of NF-κB to its cognate binding sites present in the promoters of IL-6 and IL-8 was dramatically reduced, which led to potent down-regulation of the IL-6 and IL-8 cytokines upon combination treatment relative to the single agents. Similar effects were observed on proliferation, inhibition of epithelial-to-mesenchymal transition and stemness markers in tumor xenografts. These results provide strong preclinical justification for combining cisplatin with eugenol as therapeutic approach for triple-negative breast cancers through targeting the resistant ALDH-positive cells and inhibiting the NF-κB pathway.
三阴性乳腺癌肿瘤非常具有侵袭性，并且含有相对较高比例的癌症干细胞，对包括顺铂在内的化疗药物具有耐药性。为了克服这些局限性，我们将天然多酚分子丁香酚与顺铂联合使用，使顺铂介导的毒性和潜在耐药性正常化。有趣的是，与单独使用丁香酚或顺铂相比，联合治疗在体外和体内对几种三阴性乳腺癌细胞均表现出显著更大的细胞毒性和促凋亡作用。此外，丁香酚与顺铂联合使用通过抑制 ALDH 酶活性和 ALDH 阳性肿瘤起始细胞来增强对乳腺癌干细胞的抑制作用。我们还提供了明确的证据表明，丁香酚增强了顺铂对 NF-κB 信号通路的抑制作用。事实上，NF-κB 与其在 IL-6 和 IL-8 启动子中存在的同源结合位点的结合显著减少，这导致与单一药物相比，联合治疗时 IL-6 和 IL-8 细胞因子的表达水平显著下调。在肿瘤异种移植物中的增殖、上皮-间充质转化和干细胞标志物的抑制方面也观察到了类似的效果。这些结果为通过靶向耐药性 ALDH 阳性细胞和抑制 NF-κB 通路，将顺铂与丁香酚联合作为治疗三阴性乳腺癌的方法提供了强有力的临床前依据。
