S. Hatse et al., 9-(2-phosphonylmethoxyethyl)adenine induces tumor cell differentiation or cell death by blocking cell cycle progression through the S phase, CELL GROWTH, 10(6), 1999, pp. 435-446
In addition to its inhibitory activity against viral DNA polymerases and re
verse transcriptase, the acyclic nucleoside phosphonate 9-(2-phosphonyl-met
hoxyethyl)adenine (PMEA) also markedly inhibits the replicative cellular DN
A polymerases cu, 6, and is an element of, We have previously shown that PM
EA is a strong inducer of differentiation in several in vitro tumor cell mo
dels and has marked antitumor potential in vivo. To elucidate the molecular
mechanism of the differentiation-inducing activity of PMEA, we have now in
vestigated the effects of the drug on cell proliferation and differentiatio
n, cell cycle regulation, and oncogene expression in the human erythroleuke
mia K562 cell line. Terminal, irreversible erythroid differentiation of PME
A-treated K562 cells was evidenced by hemoglobin production, increased expr
ession of glycophorin A on the K562 cell membrane, and induction of acetylc
holinesterase activity. After exposure to PMEA, K562 cell cultures displaye
d a marked retardation of S-phase progression, leading to a severe perturba
tion of the normal cell cycle distribution pattern. Whereas no substantial
changes in c-mye mRNA levels and p21, PCNA, cdc2, and CDK2 protein levels w
ere noted in PMEA-treated K562 cells, there was a marked accumulation of cy
clin A and, most strikingly, cyclins E and B1, A similar picture of cell cy
cle deregulation was also observed in PMEA-exposed human myeloid THP-1 cell
s. However, in contrast to the strong differentiation-inducing activity of
PMEA in K562 cells, the drug completely failed to induce monocytic maturati
on of human myeloid THP-1 cells. On the contrary, THP-1 cells underwent apo
ptotic cell death in the presence of PMEA, as demonstrated by prelytic, int
racellular DNA fragmentation and the binding of annexin V to the cell surfa
ce. We hypothesize that, depending on the nature of the tumor cell line, PM
EA triggers a process of either differentiation or apoptosis by the uncoupl
ing of normally integrated cell cycle processes through inhibition of DNA r
eplication during the S phase.