Concentration-dependent variable effects of etoposide on the cell cycle of CML cells.
BACKGROUND
Etoposide, a DNA-topoisomerase II inhibitor, is used for a broad spectrum of cancers with various therapeutic strategies. But the molecular mechanisms of its concentration-dependent effects are not clearly defined.


METHODS
Chronic myelogenous leukemia K562 cells were treated with low (5 microM) or high (100 microM) concentrations of this drug and the changes of cell cycle progression, expression of cell cycle regulating genes and cyclin B1-dependent histone H1 kinase activity were studied.


RESULTS
In the presence of 5 microM etoposide, K562 cells continued to synthesize DNA and most cells showed progress into G2 phase until 24 hours. In contrast, 100 microM etoposide rapidly inhibited DNA synthesis by around 6 hours and most cells remained in their initial phase, while the incorporation of bromodeoxyuridine was partially resumed from 12 hours. The histone H1 kinase activity was only down-regulated in the early phase of 100 microM treated cells. Among the cell cycle controlling genes, c-Myc and P21Cip1/WAF1 showed impressive responses to the two etoposide concentrations. At 100 microM, c-Myc protein rapidly vanished at 3 hours, while p21Cip1/WAF1 was inversely induced from 3 hours. These changes were also observed at 5 microM, but they occurred slowly and weakly.


CONCLUSIONS
The present findings indicate that two concentrations of etoposide functioned as an anticancer agent through modulating the genes related in cell cycle progression. Differing responses of c-Myc and p21Cip1/WAF1 at two concentrations may govern the antiproliferative effects of etoposide.
Fukumi
S
S
Department of Oncology, Jikei University School of Medicine, Tokyo, Japan.
Horiguchi-Yamada
J
J
Iwase
S
S
Ohno
T
T
Yamada
H
H
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D019384:Nucleic Acid Synthesis Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D011494:Protein Kinases; C102333:histone H1 kinase