Nuclear DNA content and chromatin texture in multidrug-resistant human leukemic cell lines.
Nuclear morphological alterations associated with multidrug resistance (MDR) were evaluated by image cytometry in various human leukemic cell sub-lines: 3 cell lines with P-gp-mediated resistance (CEM-VLB, HL60/Vinc, K562-Dox), the non-Pgp-mediated MDR HL60/AR leukemic cell line with over-expression of MRP, and the at-MDR CEM-VMI leukemic cell line with alteration of topoisomerase II. All these MDR cell sub-lines were obtained by drug selection and were compared with their sensitive counterparts and with the hamster LR73-R cell line obtained by transfection of mouse mdrl cDNA. All MDR cell sub-lines obtained by drug selection displayed decreased DNA Feulgen stainability as compared with their respective sensitive parental cell line, a phenomenon not observed in the transfected LR73-R cells. Nuclear texture analysis on G0/G1-selected cell nuclei revealed 2 types of textural phenotype. The first phenotype was characterized by chromatin decondensation with small but compact chromatin clumps, and was observed in drug-selected P-gp-mediated MDR cells (CEM-VLB, HL60-Vinc, K562-Dox) and in the non-P-gp-mediated MDR HL60/AR cell line. The second phenotype was characterized by a condensed and homogeneous chromatin pattern, and was observed in the at-MDR CEM-VMI cell line. LR73-R cells transfected with mdrl cDNA did not display any significant changes in textural phenotype as compared with sensitive LR73 cells, suggesting that P-gp over-expression alone cannot account for the cytological modifications observed in MDR cells. These data suggest that multidrug resistance could be associated with specific nuclear morphological changes which appeared to be a consequence of alterations occurring during selection by cytotoxic drugs rather than of P-gp over-expression.
Dufer
J
J
GIBSA, Department of Biology, Institut Jean-Godinot, Reims, France.
Millot-Broglio
C
C
Oum'Hamed
Z
Z
Liautaud-Roger
F
F
Joly
P
P
Desplaces
A
A
Jardillier
J C
JC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D002467:Cell Nucleus / Q000737:chemistry; D002843:Chromatin / Q000737:chemistry*; D006224:Cricetinae; D003412:Cricetulus; D004273:DNA, Neoplasm / Q000032:analysis*; D018432:Drug Resistance, Multiple / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D010641:Phenotype; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002843:Chromatin; D004273:DNA, Neoplasm