caa a22 4500 606235329 CHVBK 20210128101242.0 cr unu---uuuuu 210128e20151001xx s 000 0 eng 10.1007/s11010-015-2485-0 doi (NATIONALLICENCE)springer-10.1007/s11010-015-2485-0 Differential behaviors of trastuzumab-sensitive and -resistant SKBR3 cells treated with menadione reveal the involvement of Notch1/Akt/FOXO1 signaling elements [Elektronische Daten] [Soraya Sajadimajd, Razieh Yazdanparast] Given that HER2 serves as a putative target for therapy in HER2-positive breast cancer, intrinsic and/or acquired resistance to trastuzumab (T) has been proposed to be the major obstacle in treatments. In addition, chemoresistance is commonly attributed to increased antioxidant capacity. In that regard, we evaluated the effect of menadione (M) alone and/or its combination with trastuzumab on proliferation, intracellular GSH and ROS contents as well as HER2 and Notch1 signaling pathways in both trastuzumab-resistant (SKBR3R) and -sensitive SKBR3 (SKBR3S) cells. In spite of increased level of ROS and reduced level of GSH in M-treated SKBR3S cells, M-treated SKBR3R cells showed a decreased content of ROS and GSH compared to untreated cells. However, M/T co-treatment of SKBR3 cells indicated no effect on ROS content, while decreased the level of GSH compared to untreated control cells. Based on the extent of apoptosis, colony formation and wound healing assays, M alone, and/or in combination with T hada stronger inhibitory effect on proliferation of SKBR3Rcells relative to SKBR3S cells. These effects might be due to the stronger effects of M and/or M/T on downregulation of p-Akt, Hes1, NICD, and upregulation of FOXO1 among SKBR3R cells relative to the sensitive SKBR3 cells. These findings would certainly shed light on some of the signaling factors involved in induction of trastuzumab resistance and would be of value in designing more efficient chemosensitization strategies. Springer Science+Business Media New York, 2015 HER2 nationallicence Menadione nationallicence Notch1 nationallicence Oxidative stress nationallicence SKBR3 cells nationallicence Trastuzumab nationallicence DMSO : Dimethyl sulfoxide nationallicence DCFH : 2′,7′-Dichlorofluorescein diacetate nationallicence DTT : Dithiothreitol nationallicence AO/EtBr : Acridine orange/Ethidium bromide nationallicence GSH : Reduced Glutathione nationallicence MCF-7 : Human breast cancer cell line nationallicence M : Menadione nationallicence MTT : 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide nationallicence NAC : N-Acetylcysteine nationallicence NICD : Notch1 intracellular domain nationallicence PMS : Phenazine methosulphate nationallicence ROS : Reactive oxygen species nationallicence R or SKBR3R : Trastuzumab-resistant SKBR3 cells nationallicence S or SKBR3S : Trastuzumab-sensitive SKBR3 cells nationallicence T : Trastuzumab nationallicence T/M : Trastuzumab/menadione combination nationallicence Sajadimajd Soraya Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran aut Yazdanparast Razieh Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran aut Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 408/1-2(2015-10-01), 89-102 0300-8177 408:1-2<89 2015 408 11010 https://doi.org/10.1007/s11010-015-2485-0 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s11010-015-2485-0 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Sajadimajd Soraya Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran aut NATIONALLICENCE 700 1- Yazdanparast Razieh Institute of Biochemistry and Biophysics, University of Tehran, P. O. Box 13145-1384, Tehran, Iran aut NATIONALLICENCE 773 0- Molecular and Cellular Biochemistry Springer US; http://www.springer-ny.com 408/1-2(2015-10-01), 89-102 0300-8177 408:1-2<89 2015 408 11010