1-beta-D-arabinofuranosylcytosine (Ara-C) enhances mitochondrial activities in human leukaemic cells.
1-beta-D-Arabinofuranosylcytosine (Ara-C) at a concentration which inhibits nuclear-DNA reduplication (0.05 microM), enhances mitochondrial activities like respiration, in cell of a human leukaemic cell line Molt 4. While the specific activity of cytochrome c oxidase doubles in the course of the G1 phase of the cell cycle in control cells, in the presence of Ara-C G1 phase cells begin to increase the enzyme activity earlier and show a 3-fold rise of the enzyme activity in the same period of time. This is explained by an enhanced expression of the mitochondrial genome: the concentration of transcripts for the mitochondrially encoded subunit II of cytochrome c oxidase increases. Inhibition of mitochondrial protein synthesis abolishes the Ara-C induced effect on the specific activity of cytochrome c oxidase activity. The concentration of transcripts of the nuclearly encoded subunit IV of cytochrome c oxidase is the same as in control cells, and also the specific activity of the mitochondrial enzyme citrate synthase, which is exclusively encoded on nuclear-DNA, is not affected by Ara-C. Dysregulation in time and intensity of the expression of the mitochondrial relative to the nuclear genome may impair cell function and reflect a till now neglected mechanism of Ara-C cytotoxicity.
Muus
P
P
Department of Haematology, Nijmegen University Hospital, The Netherlands.
Van den Bogert
C
C
De Vries
H
H
Pennings
A
A
Holtrop
M
M
Haanen
C
C
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D003561:Cytarabine / Q000494:pharmacology*; D015342:DNA Probes; D004273:DNA, Neoplasm / Q000032:analysis; D003576:Electron Transport Complex IV / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016196:S Phase / Q000187:drug effects
D015342:DNA Probes; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D003561:Cytarabine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV