Thalidomide alters nuclear architecture without ABCB1 gene modulation in drug-resistant myeloma cells.
ABCB1 gene overexpression has been described as an important mechanism for resistance to conventional chemotherapy in multiple myelomas. In the refractory multiple myelomas, other drug regimens have been successfully applied, including thalidomide treatments. Besides its well-documented anti-angiogenic effects, thalidomide therapy could result in a decrease in ABCB1 gene expression. In this study, we analysed the effects of a 24-h short-term treatment by thalidomide or its active metabolite phthaloyl glutamic acid (PGA) on nuclear chromatin higher-order organisation and ABCB1 gene expression in drug-sensitive and drug-resistant 8226 human myeloma cells. As compared to sensitive cells, 8226-Dox40 drug-resistant cells exhibited an increase in chromatin texture condensation and ABCB1 gene overexpression. At this gene promoter level, the -50 and -100 GC boxes displayed an unmethylated profile in drug-sensitive cells whereas drug-resistant cell promoter GC boxes were fully methylated. Thalidomide and PGA induced significant chromatin textural changes in 8226-Dox40 drug-resistant cells only with neither alteration in ABCB1 gene expression nor methylation profile of its promoter. Conversely thalidomide and PGA induced down-regulation of VEGF gene expression in both drug-sensitive and -resistant myeloma cells. These data suggest that short-term treatments by thalidomide or PGA do not induce any significant change on ABCB1 gene expression though they modulate chromatin supra-organisation in drug-resistant 8226 human myeloma cells.
Trussardi-Regnier
Aurelie
A
Unité MEDyC CNRS UMR 6237, UFR Pharmacie, 1 Avenue Marechal Juin, Reims, France. aurelie.trussardi@univ-reims.fr
Lavenus
Sandrine
S
Gorisse
Marie-Claude
MC
Dufer
Jean
J
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D000107:Acetylation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000473:pathology; D002843:Chromatin / Q000187:drug effects; D019175:DNA Methylation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000187:drug effects; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015151:Immunoblotting; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002843:Chromatin; D006657:Histones; D042461:Vascular Endothelial Growth Factor A; D013792:Thalidomide