Abstract
The molecular and cellular effects of the anti-neoplastic alkylphospholipid hexadecylphosphocholine (Miltefosine, MIL) on parameters associated with growth and differentiation of human myeloid leukaemic cell lines U937, KG1 and KG1a were investigated. On a cellular level, MIL has dose-dependent differentiationinducing, growth-promoting and cytotoxic activities exemplified by induction of respiratory burst activity, stimulation of interleukin-3 (IL-3)/granulocyte-macrophage colony stimulating factor (GM-CSF)-dependent growth of the KG1 cell line in soft agar culture, inhibition of cellular net growth and finally cell death. By northern blot analysis, transcription of functional receptors for IL-3, GM-CSF, G-CSF and FcRI were studied. It was shown that MIL has stimulatory activity on IL-3 and GM-CSF receptor gene transcription. In addition, the transcription of proliferation- and differentiation-associated proteins, namely histone subtypes, c- myc and NF-KB p50, were studied. MIL suppressed c- myc and enhanced NF-κB p50 transcription in the U937 cell line, comparable to the well-characterised differentiation-inducing phorbolester 12- O-tetradecanoylphorbol-13-acetate (TPA). We conclude that the interaction of MIL with its molecular target(s) in myeloid cells induces molecular and cellular effects associated with induction of differentiation, distinct from its cytotoxic activity.
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