Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, 11566, Egypt; School of Life and Medical Sciences, University of Hertfordshire hosted by Global Academic Foundation, New Capital City, Egypt.
Chem Biol Interact. 2021 May 1;340:109450. doi: 10.1016/j.cbi.2021.109450. Epub 2021 Mar 26.
The emergence of multidrug resistance (MDR) is among the crucial obstacles to breast cancer therapy success. The transcription factor nuclear factor (NF)-κB is correlated to the pathogenesis of breast cancer and resistance to therapy. NF-κB augments the expression of MDR1 gene, which encodes for the membrane transporter P-glycoprotein (P-gp) in cancer cells. Since NF-κB activity is considered to be relatively high in particular when it comes to breast cancer, in the present work, we proposed that the inhibition of NF-κB activity can augment and enhance the sensitivity of breast cancer cells to chemotherapy such as doxorubicin (DOX) by virtue of MDR modulation. Our results demonstrated that the DOX-resistant MCF-7 and MDA-MB-231 clones exhibit higher NF-κB (p65) activity, which is linked to the upregulated expression of ABCB1 and ABCC1 transporter proteins. Combined treatment with NF-kB inhibitors (pentoxifylline and bortezomib) sensitized the resistant breast cancer cells to DOX. Such synergy was compromised by forced overexpression of p65. The DOX/NF-κB inhibitor combinations hampered NF-κB (p65) activation and downregulated MDR efflux transporters' level. Breast cancer cell migration was sharply suppressed in cells co-treated with DOX/NF-κB inhibitors. The same treatments successfully enhanced DOX-mediated induction of apoptosis, which is reflected by the elevated ratio of annexin-V/PI positively stained cells, along with the activation of other apoptotic markers. In conclusion, the data generated from this study provide insights for future translational investigations introducing the use of the clinically approved NF-κB inhibitors as an adjuvant in the treatment protocols of resistant breast cancer to overcome the multidrug resistance and enhance the therapeutic outcomes.
多药耐药（MDR）的出现是乳腺癌治疗成功的关键障碍之一。转录因子核因子（NF）-κB 与乳腺癌的发病机制和对治疗的耐药性有关。NF-κB 增强了 MDR1 基因的表达，该基因编码癌细胞中的膜转运蛋白 P-糖蛋白（P-gp）。由于 NF-κB 的活性被认为在乳腺癌中相对较高，因此在本研究中，我们提出抑制 NF-κB 活性可以通过调节 MDR 来增强和提高乳腺癌细胞对阿霉素（DOX）等化疗药物的敏感性。我们的结果表明，DOX 耐药的 MCF-7 和 MDA-MB-231 克隆表现出更高的 NF-κB（p65）活性，这与 ABCB1 和 ABCC1 转运蛋白的上调表达有关。NF-κB 抑制剂（己酮可可碱和硼替佐米）联合治疗使耐药乳腺癌细胞对 DOX 敏感。这种协同作用被强制过表达 p65 所破坏。DOX/NF-κB 抑制剂组合抑制了 NF-κB（p65）的激活并下调了 MDR 外排转运蛋白的水平。DOX/NF-κB 抑制剂联合治疗显著抑制了乳腺癌细胞的迁移。相同的治疗方法成功地增强了 DOX 介导的细胞凋亡诱导，这反映在 Annexin-V/PI 阳性染色细胞的比例升高，以及其他凋亡标志物的激活。总之，本研究提供的资料为未来的转化研究提供了启示，即将临床批准的 NF-κB 抑制剂作为耐药乳腺癌治疗方案的辅助手段，以克服多药耐药性并提高治疗效果。
