Apoptosis-resistant phenotype selected by alternating exposure to camptothecin and etoposide.
We selected an apoptosis-resistant subline (VC-33) in a human promyelocytic leukemia cell line, HL-60, by alternating exposure to camptothecin (CPT) and etoposide (VP-16). When wild-type (WT) and VC-33 cells were incubated with various concentrations of either CPT or VP-16 for 4 h, VC-33 showed several-fold resistance to apoptosis induced by these agents in comparison with WT cells. VC-33 cells also exhibited cross-resistance to apoptosis induced by 1-beta-d-arabinofuranosylcytosine, hydroxyurea, a calcium ionophore (A23187), cycloheximide, or UV irradiation. The levels of protein-DNA cross-linking induced by CPT or VP-16, and the amounts of ara-CTP generation, tended to be smaller in VC-33 cells, but the difference was not sufficient to explain the difference in the sensitivity to apoptosis. The initial rise of intracellular calcium ions with A23187 and the expression of P-glycoprotein, Bcl-2, and Bcl-Xl were comparable between WT and VC-33 cells. This mutant may represent a new phenotype of resistance to apoptosis induced by a variety of agents, and may thus be useful in the study of the mechanisms of apoptosis.
Kubota
M
M
Department of Pediatrics, Faculty of Medicine, Kyoto University, Kyoto, Japan.
Usami
I
I
Watanabe
K i
Ki
Sawada
M
M
Kataoka
A
A
Koishi
S
S
Lin
Y W
YW
Akiyama
Y
Y
Furusho
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D001085:Arabinofuranosylcytosine Triphosphate / Q000032:analysis; D000001:Calcimycin / Q000494:pharmacology; D002166:Camptothecin / Q000633:toxicity*; D002999:Clone Cells; D003513:Cycloheximide / Q000494:pharmacology; D003561:Cytarabine / Q000633:toxicity; D053938:DNA Fragmentation; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000633:toxicity*; D018922:HL-60 Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006918:Hydroxyurea / Q000633:toxicity; D007700:Kinetics; D009707:Nucleosomes / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D010641:Phenotype; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D014466:Ultraviolet Rays; D051020:bcl-X Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D009707:Nucleosomes; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D003561:Cytarabine; D001085:Arabinofuranosylcytosine Triphosphate; D000001:Calcimycin; D005047:Etoposide; D003513:Cycloheximide; D006918:Hydroxyurea; D002166:Camptothecin