Up-regulation of MDR1 and induction of doxorubicin resistance by histone deacetylase inhibitor depsipeptide (FK228) and ATRA in acute promyelocytic leukemia cells

Abstract

The multidrug resistance 1 (MDR1) gene product P-glycoprotein (P-gp) is frequently implicated in cross-resistance of tumors to chemotherapeutic drugs. In contrast, acute promyelocytic leukemia (APL) cells do not express MDR1 and are highly sensitive to anthracyclines. The combination of ATRA and the novel histone deacetylase inhibitor (HDACI) depsipeptide (FK228) induced P-gp expression and prevented growth inhibition and apoptosis in NB4 APL cells subsequently exposed to doxorubicin (DOX). ATRA/ FK228 treatment after exposure to DOX, however, enhanced apoptosis. Both agents, ATRA or FK228, induced MDR1 mRNA. This effect was significantly enhanced by ATRA/FK228 administered in combination, due in part to increased H4 and H3-Lys9 acetylation of the MDR1 promoter and recruitment of the nuclear transcription factor Y alpha (NFYA) transcription activator to the CCAAT box. Cotreatment with specific P-gp inhibitor PSC833 reversed cytoprotective effects of ATRA/FK228. G 1 cell-cycle arrest and p21 mRNA induction were also observed in response to ATRA/FK228, which may IntroductionAcute promyelocytic leukemia (APL) cells are highly sensitive to anthracyclines in part due to the lack of expression of the multidrug resistance 1 (MDR1) protein P-glycoprotein (P-gp). 1,2 In this study, we investigated the effects of ATRA and FK228, alone and in combination, on the cytotoxicity of doxorubicin (DOX). Pretreatment by ATRA combined with FK228 prevented DOX-induced apoptosis in NB4 APL cells. However, when DOX treatment preceded ATRA/FK228, DOXinduced cell death was enhanced.The MDR1 gene product P-gp functions as a transmembrane efflux pump for a variety of chemotherapeutic drugs, including anthracyclines, [3][4][5][6] and overexpression of the MDR1 gene is a negative prognostic factor in acute myelogenous leukemias (AMLs). 7 Numerous studies have reported the successful inhibition of P-gp function in vitro using cyclosporine A, PSC833, and other compounds. [8][9][10][11] MDR1 gene expression can also be silenced, however, by epigenetic mechanisms involving histone deacetylases (HDACs) and DNA methyltransferases. [12][13][14][15][16] For example, the nuclear transcription factor Y (NF-Y) heteromeric complex binds to the CCAAT core sequence in the promoters of a variety of eukaryotic genes, including human MDR1, 12,[16][17][18] and acts as a histone acetylation regulator and transcription activator. 12,19 APL cells, which do not express MDR1, are associated with the oncogenic transcription factor PML-RAR␣ that represses transcription of the genes encoding the RA receptor targets through histone deacetylation. The PML-RAR␣ chimeric protein, moreover, has been suspected to be the factor suppressing MDR1 through chromatin remodeling. 20 A number of HDAC inhibitors (HDACIs) are currently being tested in clinical trials against a variety of cancers. Recently, there has been strong interest in HDACIs as anti-APL agents because of their synergistic activity with ATRA. [21][22][23][24] In vivo data demonstrated that HDACIs can overcome ...

The histone deacetylase inhibitor trichostatin A downregulates human MDR1 (ABCB1) gene expression by a transcription-dependent mechanism in a drug-resistant small cell lung carcinoma cell line model

“…Changes in H3 and H4 acetylation were rapid (within 8 h) and directly correlated with ABCB1 induction. Similar data have been reported in NB4 cells incubated with FK228 (Tabe et al, 2006), or in CEM-Bcl2 cells treated with daunorubicin (Baker et al, 2005). In TSA-treated H69VP cells, H4 acetylation exhibited the same kinetics than in drug-sensitive cells, in spite of the repression of the ABCB1 gene induced.…”

“…For instance, ABCB1 gene was overexpressed in SW620 colon carcinoma and CEM-Bcl2 cells exposed to TSA (Jin and Scotto, 1998;Baker et al, 2005), or KU812 and NB4 cells exposed to depsipeptide (Tabe et al, 2006;Yamada et al, 2006). In drug-resistant cells, HDAC inhibition also increased ABCB1 expression in CEM-A7R, Kasumi-1, and Kasumi-6 cell lines (El-Osta et al, 2002;Tabe et al, 2006). On the contrary, our results showed a repression of ABCB1 gene expression by TSA and NaB.…”

“…In drug-sensitive cells, several studies have reported an increase in ABCB1 expression by HDAC inhibitors, a phenomenon we also observed in H69WT cells. For instance, ABCB1 gene was overexpressed in SW620 colon carcinoma and CEM-Bcl2 cells exposed to TSA (Jin and Scotto, 1998;Baker et al, 2005), or KU812 and NB4 cells exposed to depsipeptide (Tabe et al, 2006;Yamada et al, 2006). In drug-resistant cells, HDAC inhibition also increased ABCB1 expression in CEM-A7R, Kasumi-1, and Kasumi-6 cell lines (El-Osta et al, 2002;Tabe et al, 2006).…”

Histone deacetylase inhibitors induce the degradation of the t(8;21) fusion oncoprotein

“…Nevertheless, even at these comparatively high levels of DEP, degradation of RUNX1-ETO appeared to be dependent on proteasomal function, as MG132 completely blocked RUNX1-ETO turnover (Figure 2d). DEP triggers cell cycle arrest and subsequent cellular differentiation or apoptosis in various cell systems (Sandor et al, 2000;Sato et al, 2004;Tabe et al, 2005). As 5 nM DEP induced apoptosis within 12 h, we were unable to determine the effects of this compound on cell cycle arrest and subsequent cellular differentiation.…”

Valproic acid enhances tubulin acetylation and apoptotic activity of paclitaxel on anaplastic thyroid cancer cell lines

“…However, recent studies have shown that HDIs increase the expression of MDR1 (Tabe et al 2006) and its product P-glycoprotein (Robey et al 2006).…”