Combination of all-trans retinoic acid and paclitaxel-induced differentiation and apoptosis in human glioblastoma U87MG xenografts in nude mice

Cancer ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 596-607 ◽  
Author(s):  
Surajit Karmakar ◽  
Naren L. Banik ◽  
Swapan K. Ray
Keyword(s):  
Retinoic Acid ◽  
Nude Mice ◽  
Induced Differentiation ◽  
Human Glioblastoma ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

scholarly journals Epigenetic Priming of AML Blasts for All-trans Retinoic Acid-Induced Differentiation by the HDAC Class-I Selective Inhibitor Entinostat

PLoS ONE ◽  
2013 ◽  
Vol 8 (10) ◽  
pp. e75258 ◽  
Author(s):  
Nadja Blagitko-Dorfs ◽  
Yi Jiang ◽  
Jesús Duque-Afonso ◽  
Jan Hiller ◽  
Arzu Yalcin ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Selective Inhibitor ◽  
Class I ◽  
Induced Differentiation ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Expression of the Wilms’ Tumor 1 (WT1) Gene Renders Acute Promyelocytic Leukemia Cells Resistant to All-Trans-Retinoic-Acid-Induced Differentiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4385-4385
Author(s):  
Aschwin L. Menke ◽  
Ruth H.J.N. Knops ◽  
Jurgen A.F. Marteijn ◽  
Willemijn Wissink ◽  
Josie Smeets ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Wilms Tumor ◽  
Promyelocytic Leukemia ◽  
Induced Differentiation ◽  
Expression Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Wilms Tumor 1

Abstract Acute myeloid leukemia is characterized by the uncontrolled proliferation of immature cells that have lost their ability to differentiate. In the case of acute promyelocytic leukemia (AML-M3), the cells can be forced to differentiate by pharmacological dosages of all-trans retinoic acid (ATRA), a phenomenon that is successfully used in the treatment of APL patients. About 70% of the patients, suffering from PML-RARa -positive acute promyelocytic leukemia, can be cured with a combination of ATRA and anthracycline - based chemotherapy. However, relapse remains a major problem. The molecular mechanisms by which the retinoic acid receptors mediate their biological functions have been studied extensively and although various retinoic acid-responsive genes have been identified, the target genes that are crucially involved in leukemogenesis are unknown. The Wilms’ Tumor 1 gene, has been implicated in the development of leukemia. WT1 overexpression can be detected in most acute leukemias and is particularly highly expressed in APL cells. Several groups have found an inverse correlation between the expression levels of WT1 and the overall survival of leukemia patients. The underlying mechanism, however, remains to be elucidated. We have shown that the Wilms’ Tumor 1 (WT1) is strongly downregulated in APL cells, during ATRA-induced differentiation. Using a newly developed realtime RT-PCR method we have found that the expression levels of all four major WT1 isoforms are downregulated. To study the biological activity of each WT1-isoform, we have retrovirally transduced the APL cell line NB4, with the 4 major WT1 isoforms and analyzed the effect on ATRA-induced differentiation. Using flowcytometry and NBT staining, we show that ectopic expression of the different WT1-isoform inhibited ATRA-induced differentiation and subsequently, the apoptosis of APL cells, albeit with different potential. WT1-transduced cells survived pharmacological dosages of ATRA for more than 14 days and in some cases even continued to grow. These data indicate that downregulation of WT1 is essential for ATRA-induced differentiation of APL cells and provide an explanation why AML patients with high WT1 expression levels have worse overall survival in comparison to patients with low WT1 expression levels.

Aminopeptidase Inhibitor Bestatin Potentiates the Induced-Differentiation Activity of All-trans-Retinoic Acid in NB4 Cells Possibly through Down-Regulating c-myc Expression.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4443-4443
Author(s):  
Mao-fang Lin ◽  
Xi-jun Qian
Keyword(s):  
Retinoic Acid ◽  
Tumor Therapy ◽  
Expression Level ◽  
Induced Differentiation ◽  
Cd11b Expression ◽  
Nb4 Cells ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Pharmacologic Activity ◽  
Nbt Reduction

Abstract All-trans-retinoic acid (ATRA) represents the sole example of clinically useful cyto-differentiating agent. ATRA treatment alone results in complete remission of nearly 80% patients with acute promyelocytic leukemia (APL). However, the therapeutic use of this compound is limited by a number of problems, including the systemic toxicity and ATRA resistant leukemia. One way to circumvent these problems is to identify the agents capable of enhancing the pharmacologic activity of ATRA. As we know, an aminopeptidase inhibitor, bestatin, had been used as an immunomodulator in anti-tumor therapy. Recently, we have reported bestatin can induce apoptosis in HL-60 and K562 cells. In the present study, we investigated whether bestatin can potentiate the ATRA induced-differentiation of APL cell line NB4 cells and whether changes of transcription factors expression are involved in this course. The cellular morphology observed by optical microscopy, the expression level of CD11b measured by flow cytometry and the nitroblue-tetrazolium (NBT) reduction assay was performed to determine the cyto-differentiation in NB4 cells. The mRNA expression levels of c-myc and c-EBPε in NB4 cells were detected by RT-PCR. NB4 cells incubated with 10nM ATRA plus 100μg/ml bestatin showed more morphologic character of metamyelocyte and band neutrophil than that of the cells treated by ATRA alone. Compared with 10nM ATRA used alone, after treating NB4 cells for 72 hours, the addition of various concentration of bestatin (50μg/ml, 75μg/ml, 100μg/ml) dose-dependently enhancesd NBT reduction of NB4 cells (17.6±2.5 vs. 12.0±2.2, p<0.05; 23.5±3.2 vs. 12.0±2.2, p<0.01; 36.0±8.3 vs. 12.0±2.2, p<0.01, respectively). 100μg/ml bestatin time-dependently increased 10nM ATRA induced NBT reduction of NB4 cells from 24 to 72 hours (p<0.01). The effect of various concentration of ATRA in combination with 100μg/ml bestatin was statistically different with the sum of the effects of individual drugs after subtracting the value of background (31.2±9.1 vs. 12.7±4.3, p<0.01; 39.5±5.0 vs.16.0±1.8, p<0.001; 49.6±5.3 vs. 22.1±1.6, p<0.001, respectively). Moreover, 10nM ATRA plus 100μg/ml bestatin could prominently elevate CD11b expression in NB4 cells compared with ATRA alone treated NB4 cells group(60.58±9.18% vs. 31.95±5.52%, p<0.01), while 100μg/ml bestatin could not induced significant changes in the expression level of CD11b in NB4 cells after 72 hours incubation. The various concentration (50μg/ml, 75μg/ml, 100μg/ml) of bestatin synergizes with 10nM ATRA to down-regulate the expression level of c-myc mRNA (p<0.01), which was inversely correlated with the NBT reduction activity of NB4 cells induced by 10nM ATRA plus various concentration bestatin (r=−0.917, p=0.028). However, 100μg/ml bestatin plus 10nM ATRA could not induce any significant changes in the expression level of c-EBPε mRNA compared with ATRA treated alone group. In conclusion, an aminopeptidase inhibitor bestatin can potentiate ATRA-induced differentiation of NB4 cells, which may be through down-regulating the expression of c-myc in concert with ATRA. Bestatin would be useful in anti-APL therapy by enhancing the pharmacologic activity of ATRA.

scholarly journals JWA, a novel signaling molecule, involved in all-trans retinoic acid induced differentiation of HL-60 cells

2006 ◽  
Vol 13 (3) ◽  
pp. 357-371 ◽  
Author(s):  
Shu Huang ◽  
Qun Shen ◽  
Wen-Ge Mao ◽  
Ai-Ping Li ◽  
Jian Ye ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Induced Differentiation ◽  
Signaling Molecule ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Altered Expression and Activity of Topoisomerases During All-Trans Retinoic Acid-Induced Differentiation of HL-60 Cells

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2863-2870
Author(s):  
Masako Aoyama ◽  
Dale R. Grabowski ◽  
Richard J. Isaacs ◽  
Kim A. Krivacic ◽  
Lisa A. Rybicki ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Dna Cleavage ◽  
Topoisomerase I ◽  
Human Leukemia ◽  
Induced Differentiation ◽  
Altered Expression ◽  
Protein Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Topo Ii

Regulation of topoisomerase II (TOPO II) isozymes  and β is influenced by the growth and transformation state of cells. Using HL-60 cells induced to differentiate by all-trans retinoic acid (RA), we have investigated the expression and regulation of TOPO II isozymes as well as the levels of topoisomerase I (TOPO I). During RA-induced differentiation of human leukemia HL-60 cells, levels of TOPO I remained unchanged, whereas the levels and phosphorylation of TOPO II and TOPO IIβ proteins were increased twofold to fourfold and fourfold to eightfold, respectively. The elevation of TOPO II ( and β) protein levels and phosphorylation was apparent at 48 hours of treatment with RA and persisted through 96 hours. The increased level of TOPO IIβ protein was also detected in differentiated cells subsequently cultured for 96 hours in RA-free medium. Pulse chase experiments in cells labeled with 35S-methionine showed that the rate of degradation of TOPO IIβ protein in control cells was about twofold faster than that in the differentiated RA-treated cells. The level of decatenation activity of kDNA was comparable in nuclear extracts from control or RA-treated cells. Whereas etoposide (1 to 10 μmol/L) -induced DNA cleavage was not significantly different, apoptosis was significantly lower (P = .012) in RA-treated versus control cells after exposure to 10 μmol/L etoposide. Consistent with unaltered levels of TOPO I, camptothecin (CPT) -induced DNA cleavage was similar in control or RA-treated cells. However, apoptosis after exposure to 1 to 10 μmol/L CPT was significantly lower (P = .003 to P < .001) in RA-treated versus control cells. Results suggest that TOPO IIβ protein levels are posttranscriptionally regulated and that degradation of TOPO IIβ is decreased during RA-induced differentiation. Furthermore, whereas the total level of TOPO II ( + β) is increased with RA, the level of TOPO II catalytic activity and etoposide-stabilized DNA cleavage activity remains unaltered. Thus, TOPO IIβ may have a specific role in transcription of genes involved in differentiation with RA treatment. © 1998 by The American Society of Hematology.

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