Hemin-induced erythroid differentiation of human myeloleukemia K562 cell line and its modification by bioresponse modifiers.

We have found that protoporphyrin IX, which had been regarded as inactive, induces erythroid differentiation. The differentiation-inducing activities of various hemin-related compounds, including hematoporphyrin IX, mesoporphyrin IX, deuteroporphyrin IX and protoporphyrin IX dimethyl ester, suggested certain structural requirements for the activity: 1) the iron moiety of hemin is not essential, and 2) the propionic acid side chains of hemin play an important role. In addition, we have examined the influence of some bioactive factors on hemin/protoporphyrin IX-induced differentiation of K562 cell line. Retinoids and tubulin-disruptors dose-dependently enhanced hemin/protoporphyrin IX-induced differentiation of K562 cells, though they did not themselves induce differentiation. Retinoid antagonists suppressed hemin-induced differentiation. The effects of hemin and/or retinoids on the mRNA expressions of oncogenes (c-myc and c-myb) and retinoic acid receptor genes (rar alpha and rar beta) of K562 cells were analyzed. We also examined the possible involvement of peripheral-type benzodiazepine receptor (PBR) in hemin/protoporphyrin IX-induced differentiation of K562 cells by the use of its ligands. Diazepam itself was revealed to possess differentiation-inducing activity on K562 cells. The PBR-specific ligands modified hemin-induced differentiation. These results suggest a requirement for retinoids (or retinoid-like cofactors) for hemin/protoporphyrin IX-induced differentiation of K562 cells and the involvement of PBR in erythroid differentiation of K562 cell line.