Drug-resistance in doxorubicin-resistant FL5.12 hematopoietic cells: elevated MDR1, drug efflux and side-population positive and decreased BCL2-family member expression

Content Provider	Semantic Scholar
Author	Steelman, Linda S. Abrams, Steve L. Ruvolo, Peter P. Ruvolo, Vivian R. Cocco, Lucio Ratti, Stefano Martelli, Alberto Maria Neri, Luca M. Candido, Saverio Libra, Massimo McCubrey, James A.
Copyright Year	2017
Abstract	Chemotherapeutic drug treatment can result in the emergence of drug-resistant cells. By culturing an interleukin-3 (IL-3)-dependent cell line, FL5.12 cells in the presence of the chemotherapeutic drug doxorubicin, we isolated FL/Doxo cells which are multi-drug resistant. Increased levels of drug efflux were detected in FL/Doxo cells which could be inhibited by the MDR1 inhibitor verapamil but not by the MRP1 inhibitor MK571. The effects of TP53 and MEK1 were examined by infection of FL/Doxo cells with retroviruses encoding either a dominant negative TP-53 gene (FL/Doxo+ TP53 (DN) or a constitutively-activated MEK-1 gene (FL/Doxo + MEK1 (CA). Elevated MDR1 but not MRP1 mRNA transcripts were detected by quantitative RT-PCR in the drug-resistant cells while transcripts encoding anti-apoptotic genes such as: BCL2, BCLXL and MCL1 were observed at higher levels in the drug-sensitive FL5.12 cells. The percentage of cells that were side-population positive was increased in the drug-resistant cells compared to the parental line. Drug-resistance and side-positive population cells have been associated with cancer stem cells (CSC). Our studies suggest mechanisms which could allow the targeting of these molecules to prevent drug-resistance.
Starting Page	113013
Ending Page	113033
Page Count	21
File Format	PDF HTM / HTML
Alternate Webpage(s)	http://www.oncotarget.com/index.php?journal=oncotarget&op=download&page=article&path%5B%5D=22956&path%5B%5D=72441
PubMed reference number	29348885v1
Alternate Webpage(s)	https://doi.org/10.18632/oncotarget.22956
DOI	10.18632/oncotarget.22956
Journal	Oncotarget
Volume Number	8
Language	English
Access Restriction	Open
Subject Keyword	BCL2L1 gene Cancer Stem Cells Central Serous Chorioretinopathy DN Term Type Dominant-Negative Mutation Doxorubicin Drug Efflux Flumazenil Interleukin-3 MCL1 protein, human Mitogen-Activated Protein Kinase Kinases Retroviridae Reverse Transcriptase Polymerase Chain Reaction Transcript Verapamil cellular targeting
Content Type	Text
Resource Type	Article