Abstract
Acute lymphoblastic leukemia (ALL) is a common hematological malignancy characterized by the uncontrolled proliferation of leukemia cells in children. Discovering and developing effective chemotherapeutic drugs are needed for ALL. In this study, we investigated the anti-leukemic activity of butein and its action mechanisms in ALL. Butein was found to significantly suppress the cellular proliferation of ALL cell lines and primary ALL blasts in a dose-dependent manner. It also induced cell cycle arrest by decreasing the expression of cyclin E and CDK2. We also found that butein promoted nuclear Forkhead Class box O3a (FOXO3a) localization, enhanced the binding of FOXO3a on the p27kip1 gene promoter and then increased the expression of p27kip1. Moreover, we showed that FOXO3a knockdown significantly decreased the proliferation inhibition by butein, whereas overexpression of FOXO3a enhanced the butein-mediated proliferation inhibition. However, overexpression of FOXO3a mutation (C-terminally truncated FOXO3a DNA-binding domain) decreased the proliferation inhibition by butein through decreasing the expression of p27kip1. Our results therefore demonstrate the therapeutic potential of butein for ALL via FOXO3a/p27kip1 pathway.
Highlights
The dramatic improvements in diseasefree survival among children with acute lymphoblastic leukemia (ALL) has been achieved, outcomes for those who fail to achieve long-term disease-free survival or relapse are poor [1, 2]
To evaluate the effects of butein on the renal toxicity of human normal proximal tubular cell and the proliferation of Acute lymphoblastic leukemia (ALL) cells, we examined the viability of HK-2 cell line and ALL cells
Our previous study revealed that flavokawain B, one of the flavokawains extracted from kava, exhibited anti-leukemic activity through the activation of the p53 and caspase-dependent pathways in ALL, it may be a promising agent for the treatment of patients with ALL [22]
Summary
The dramatic improvements in diseasefree survival among children with acute lymphoblastic leukemia (ALL) has been achieved, outcomes for those who fail to achieve long-term disease-free survival or relapse are poor [1, 2]. Given that the current chemotherapy regimens have had limited success in improving survival in refractory or relapsed ALL, the efforts to investigate potential application of natural antileukemic agents are necessary [3, 4]. Butein has been shown to exhibit antitumor activity against breast cancer [7], bladder cancer [8], prostate cancer [9] and mesothelioma [10]. Butein has inhibited CXCR4 expression, which is correlated with the inhibition of CXCL12-induced migration and invasion in breast and pancreatic cancer cells [11]. Butein has been found to suppress proliferation, induce apoptosis and overcome gefitinib-resistance in lung cancer via EGFR/MET signaling pathway [12]
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