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© 1994 Oxford University Press

research-article

HL-60 cell differentiation induced by phorbol- and 12-deoxyphorbol-esters

W.Jonathan Ryves, Sasa Dimitrijevic, Philip. C. Gordge 1 and Fred J. Evans 2

The School of Pharmacy University of London, Department of Pharmacognosy 29–39 Bnrnswick Square, London WCIN lAX
1ICRF Medical Oncology Unit, Department of Clinical Oncology, University of Edinburgh Western General Hospital, Edinburgh EH4 2XU, UK

2To whom corresponde should be addressed

The haman promyelocytlc leukaemia cell (HL-60) under goes differentiation into a macrophage-like form when exposed to both tumour promoting- and non-promoting phorbol esters. We have Investigated the effect of the two non-promoting phorbol esters, 12-deoxyphorbol-13-O-phenylacetate (Dopp) and 12-deoxyphorbol-13-O-phenyl-acetate-20-acetate (Doppa) on HL-60 cultures, and compared them with the twnour promoter 12-O-tetradecanoylphor-bol-13-acetate (TPA). All phorbol esters tested were found to be able to stop HL-60 proliferation and induce cell adherence and morphological changes characteristic of differentiation. TPA, fully differentiating at 1 nM, was more potent than Dopp and Doppa, which required 100 nM for full differentiation effects within the 4 day study. Doppa initially appeared weaker than Dopp at inhibiting incorporation of thymidine, the earliest effect studied, but we were able to detect rapid C-20 deacylation of Doppa, converting It to Dopp, using an HPLC protocol presented here. A detailed study of this thymidine Incorporation Inhibition showed that both TPA (10 nM or greater) and Dopp (500 nM or greater) have very similar time courses, wIth 50% inhibition occurring at {bsim}12 h, in contrast to Doppa which had a significantly delayed time course at all doses tested. Exposure tests Indicated that Dopp and Doppa could be washed from the cells much more easily than TPA. The data presented here strongly support the notion that the metabolic conversion of Doppa to Dopp by HL-60 cells was necessary to mediate Its differentiating effects. Since protein kinase C (PKC)ß1, present in HL-60 cells, has been found to be the only PKC isotype activated so far in vitro by Doppa, our results suggest that activation of this Isotype is not sufficient to drive HL-60 differentiation in vivo.


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