Nuclear factor-κB signaling inhibitors revert multidrug-resistance in breast cancer cells. (1st May 2021)

• Record Type: Journal Article
• Authors: Abdin, Shifaa M.; Tolba, Mai F.; Zaher, Dana M.; Omar, Hany A.
• Is Part Of: Chemico-biological interactions. Volume 340(2021)
• Publication Date: 2021-05-01
• Subjects: Breast cancer -- Multidrug resistance -- NF-κB -- Doxorubicin -- Apoptosis; ABC Adenosine triphosphate–binding cassette -- ADR Adriamycin -- BTZ Bortezomib -- CI Combination index -- DOX Doxorubicin -- ER Estrogen -- Fa Fraction affect -- HER-2 Human epidermal growth factor receptor 2 -- IL Interleukin -- MDR Multidrug resistance -- MDRP Multi drug resistance proteins -- P-gp P-glycoprotein -- PTX Pentoxifylline -- ROS Reactive oxygen species -- TNBC Triple negative Breast cancer; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2021.109450
• Languages: English
• ISSNs: 0009-2797

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: NF-κB signaling has a major role in breast cancer resistance. The expression of multidrug-resistant proteins is augmented by NF-κB signaling. The inhibition of NF-κB signaling re-sensitize breast cancer cells to chemotherapy. NF-κB inhibitors downregulate multidrug-resistant proteins and induce apoptosis. NF-κB inhibitors could serve as adjuvants in resistant breast cancer treatment protocols.