Cell-Type-Specific Effects of Silibinin on Vitamin D-Induced Differentiation of Acute Myeloid Leukemia Cells Are Associated with Differential Modulation of RXRα Levels
Plant polyphenols have been shown to enhance the differentiation of acute myeloid leukemia (AML) cells induced by the hormonal form of vitamin D3 (1α,25-dihydroxyvitamin D3; 1,25D). However, how these agents modulate 1,25D effects in different subtypes of AML cells remains poorly understood. Here, we show that both carnosic acid (CA) and silibinin (SIL) synergistically enhancd 1,25D-induced differentiation of myeloblastic HL60 cells. However, in promonocytic U937 cells, only CA caused potentiation while SIL attenuated 1,25D effect. The enhanced effect of 1,25D+CA was accompanied by increases in both the vitamin D receptor (VDR) and retinoid X receptor alpha (RXRα) protein levels and vitamin D response element (VDRE) transactivation in both cell lines. Similar increases were observed in HL60 cells treated with 1,25D + SIL. In U937 cells, however, SIL inhibited 1,25D-induced VDRE transactivation concomitant with downregulation of RXRα at both transcriptional and posttranscriptional levels. These inhibitory effects correlated with the inability of SIL, with or without 1,25D, to activate the Nrf2/antioxidant response element signaling pathway in U937 cells. These results suggest that opposite effects of SIL on 1,25D-induced differentiation of HL60 and U937 cells may be determined by cell-type-specific signaling and transcriptional responses to this polyphenol resulting in differential modulation of RXRα expression. 1. Introduction Acute myeloid leukemia (AML) is a hematologic cancer which results from blocked differentiation of hematopoietic stem and/or progenitor cells due to various genetic and epigenetic errors and is characterized by the uncontrolled proliferation of myeloid blasts. The standard approach for AML treatment is chemotherapy with cytarabine and anthracyclines; however, even after aggressive chemotherapy about 75% of AML patients relapse within 2 years of remission [1, 2]. Recently, several targeted cytotoxic approaches to treat AML have been developed, for example, the use of kinase and histone deacetylase inhibitors [3], but such strategy is difficult to apply to AML, since the molecular lesions in AML are highly heterogeneous. Differentiation therapy is an alternative or complementary treatment of AML which aims at inducing maturation of poorly differentiated leukemic blasts. The hormonal form of vitamin D3 (1α,25-dihydroxyvitamin D3) is a strong differentiation inducer which has potential for the treatment of AML [4]. However, at concentrations capable of differentiating AML cells in culture 1,25D may cause fatal hypercalcemia in vivo.
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