Interferon-alpha enhances artemisinin-induced differentiation of HL-60 leukemia cells via a PKC alpha/ERK pathway

Abstract

Interferon-alpha (IFN-alpha) has been used in the treatment of several cancers, including chronic myeloid leukemia. Artemisinin, a sesquiterpene lactone endoperoxide that exists in several medicinal plants, is a well known anti-malarial agent. We previously reported that artemisinin by itself caused a relatively low level of HL-60 cell differentiation. In this study, we investigated the effects of IFN-alpha in combination with artemisinin on cell growth and differentiation in HL-60 leukemia cells. Combination of IFN-alpha and artemisinin synergistically induced the levels of leukemia cell differentiation, although IFN-alpha by itself did not affect cell proliferation and differentiation. The increased cell differentiation by IFN-alpha and artemisinin was significantly suppressed by the inhibitors for protein kinase C (PKC), extracellular signal-regulated kinase (ERK) and jun N-terminal kinase (JNK), but not by the inhibitors for phosphatidylinositol 3-kinase (PI3-K) and p38 mitogen-activated protein kinase (MAPK). Furthermore, co-treatment with IFN-a increased levels of PKC alpha and phosphorylated ERK. Taken together, these results indicate the enhancement of artemisinin-induced HL-60 cell differentiation by IFN-a through the activation of a PKC alpha/ERK signaling pathway, and suggest a possible use of IFN-alpha and artemisinin in the treatment of leukemic diseases. (c) 2008 Elsevier B.V. All rights reserved.