Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C

The effect of silibinin, an active component of Silybum marianum, on cellul ar differentiation was investigated in the human promyelocytic leukemia HL- 60 cell culture system. Treatment of HL-60 cells with silibinin inhibited c ellular proliferation and induced cellular differentiation in a dose-depend ent manner. Cytofluorometric analysis and morphologic studies indicated tha t silibinin induced differentiation of HL-60 cells predominantly into monoc ytes. Importantly, strongly synergistic induction of differentiation into m onocytes was observed when silibinin was combined with 5 nM 1 alpha ,25-dih ydroxyvitamin D-3 [1,25-(OH)(2)D-3], a well-known differentiation inducer o f HL-60 cells into the monocytic lineage. Silibinin enhanced protein kinase C (PKC) activity and increased protein levels of both PKC alpha and PKC be ta in 1,25-(OH)(2)D-3-treated HL-60 cells. PKC and extracellular signal-reg ulated kinase (ERK) inhibitors significantly inhibited HL-60 cell different iation induced by silibinin alone or in combination with 1,25-(OH)(2)D-3, i ndicating that PKC and ERK may be involved in silibinin-induced HL-60 cell differentiation. (C) 2001 Elsevier Science Inc. All rights reserved.