Nuclear factor-κB signaling inhibitors revert multidrug-resistance in breast cancer cells.

Autor: Abdin SM; Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates., Tolba MF; 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. Electronic address: tolba.mf@pharma.asu.edu.eg., Zaher DM; Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates; College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates., Omar HA; Sharjah Institute for Medical Research, University of Sharjah, United Arab Emirates; College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62511, Egypt. Electronic address: hanyomar@sharjah.ac.ae.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2021 May 01; Vol. 340, pp. 109450. Date of Electronic Publication: 2021 Mar 26.
DOI: 10.1016/j.cbi.2021.109450
Abstrakt: 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.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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