Cytotoxicity of apigenin on leukemia cell lines: implications for prevention and therapy

R R Ruela-De-Sousa,H Aoyama,G M Fuhler,M P Peppelenbosch,C V Ferreira,N Blom

doi:10.1038/cddis.2009.18

Abstract

Natural-food-based compounds show substantial promise for prevention and biotherapy of cancers including leukemia. In general, their mechanism of action remains unclear, hampering rational use of these compounds. Herein we show that the common dietary flavonoid apigenin has anticancer activity, but also may decrease chemotherapy sensitivity, depending on the cell type. We analyzed the molecular consequences of apigenin treatment in two types of leukemia, the myeloid and erythroid subtypes. Apigenin blocked proliferation in both lineages through cell-cycle arrest in G2/M phase for myeloid HL60 and G0/G1 phase for erythroid TF1 cells. In both cell lines the JAK/STAT pathway was one of major targets of apigenin. Apigenin inhibited PI3K/PKB pathway in HL60 and induced caspase-dependent apoptosis. In contrast, no apoptosis was detected in TF1 cells, but initiation of autophagy was observed. The block in cell cycle and induction of autophagy observed in this erythroleukemia cell line resulted in a reduced susceptibility toward the commonly used therapeutic agent vincristine. Thus, this study shows that although apigenin is a potential chemopreventive agent due to the induction of leukemia cell-cycle arrest, caution in dietary intake of apigenin should be taken during disease as it potentially interferes with cancer treatment.

Highlights

Apigenin (40,5,7-trihydroxyflavone), a common dietary flavonoid abundantly present in fruits and vegetables, shows promising biological effects such as prevention and therapy of prostate cancer, suppression of tumorigenesis and angiogenesis in melanoma[1] and breast, skin, and colon carcinomas.[2]
Studies in breast cancer cells have identified some of the potential key protein kinases potentially responsible for apigenin effects, in particular PI3K, PKB and ERK1/2, and other upstream kinases involved in cancer development and progression.[8]
Leukemia cells and human peripheral blood lymphocytes were treated with apigenin (Figure 1a) in concentrations up to 200 mM, for 24 h

Summary

Introduction

Apigenin (40,5,7-trihydroxyflavone), a common dietary flavonoid abundantly present in fruits and vegetables, shows promising biological effects such as prevention and therapy of prostate cancer, suppression of tumorigenesis and angiogenesis in melanoma[1] and breast, skin, and colon carcinomas.[2]. The promise of apigenin urgently calls for investigations as to its molecular mode of action in leukemia cellular physiology. This consideration prompted us analyze the molecular pathways activated by apigenin treatment on the leukemic cell. To this end we established the induction of cell-cycle arrest and cell death in two models of leukemic disease, myeloid (HL60 cells) and erythroid (TF1 cells)

Methods

Results

Conclusion