BRD4 PROTAC Degradation Agent GNE-987 Inhibits Acute Myeloid Leukemia by Targeting Super Enhancers

2021 ◽  
Author(s):  
Xu Sang ◽  
Yongping Zhang ◽  
Fang Fang ◽  
Li Gao ◽  
Yanfang Tao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Significance ◽  
Xenograft Model ◽  
Rna Seq ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is a common hematological malignancy in children, with poor treatment effect and poor prognosis. Recent studies have shown that bromodomain and terminal protein inhibitors are promising antitumor drugs. As a new type of BRD4 PROTAC degradation agent, GNE-987 can slow down the growth rate of a variety of tumors and cause apoptosis, which has broad clinical prospects. However, the role of GNE-987 in AML is unclear. This study aims to explore the therapeutic effect of GNE-987 in AML and its underlying mechanism.Methods: By studying public databases, the prognostic significance of BRD4 and the correlation between AML were evaluated, and the relationship between BRD4 and the overall survival rate of AML patients was also analyzed. After adding GNE-987 to the AML cell line, cell proliferation slowed down, cycle disorder, and apoptosis increased. In the cells treated with GNE-987, western-blotting was used to detect BRD2, BRD3, BRD4 and PARP proteins. The effect of GNE-987 on AML cells was analyzed in vivo. RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) confirmed the function and molecular pathway of GNE-987 in processing AML. Results: Compared with healthy donors, the expression of BRD4 in children's AML samples was higher than that of healthy donors. The high expression of BRD4 indicates a poor prognosis. GNE-987 inhibits AML cell proliferation by inhibiting the cell cycle and inducing apoptosis. BRD2, BRD3 and BRD4 are consistent with the decreased expression of VHL in AML cells. Compared with JQ1 and ARV-825, GNE-987 has a lower IC50 in AML cells. In the AML xenograft model, GNE-987 significantly reduced the liver and spleen infiltration of leukemia cells, increased the survival time of mice, and caused BRD4, Ki67 dysregulation and caspase3 activation. According to the analysis of RNA-seq and ChIP-seq, GNE-987 can inhibit AML by targeting numerous super-enhancers.Conclusions: GNE-987 has strong anti-tumor activity in AML cell lines and primary child AML samples. GNE-987 works by degrading the BET protein, thereby effectively inhibiting the expression of super enhancers and related oncogenes (such as LYL1). These results indicate that GNE-987 has very broad prospects for the treatment of AML.

scholarly journals Knockdown of Long Noncoding RNA HOXA-AS2 Suppresses Chemoresistance of Acute Myeloid Leukemia via the miR-520c-3p/S100A4 Axis

2018 ◽  
Vol 51 (2) ◽  
pp. 886-896 ◽  
Author(s):  
Xiaoya Dong ◽  
Zhigang Fang ◽  
Mingxue Yu ◽  
Ling Zhang ◽  
Ruozhi Xiao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Luciferase Reporter Assay ◽  
Luciferase Reporter ◽  
Reporter Assay ◽  
Online Programs ◽  
Acute Myeloid

Background/Aims: Among different molecular candidates, there is growing data to support that long noncoding RNAs (lncRNAs) play a significant role in acute myeloid leukemia (AML). HOXA-AS2 is significantly overexpressed in a variety of tumors and associated with anti-cancer drug resistance, however, little is known regarding the expression and function of HOXA-AS2 in the chemoresistance of AML. In this study, we aimed to determine the role and molecular mechanism of HOXA-AS2 in adriamycin-based chemotherapy resistance in AML cells. Methods: Quantitative real-time PCR was used to detect HOXA-AS2 expression in the BM samples and ADR cell lines, U/A and T/A cells. Furthermore, the effects of HOXA-AS2 silencing on cell proliferation and apoptosis were assessed in vitro by CCK8 and flow cytometry, and on tumor growth in vivo. Furthermore, bioinformatics online programs predicted and luciferase reporter assay were used to validate the association of HOXA-AS2 and miR-520c-3p in AML. Results: In this study, we showed that HOXA-AS2 is significantly upregulated in BM samples from AML patients after treatment with adriamycin-based chemotherapy and in U/A and T/A cells. Knockdown of HOXA-AS2 inhibited ADR cell proliferation in vitro and in vivo and promoted apoptosis. Bioinformatics online programs predicted that HOXA-AS2 sponge miR-520c-3p at 3’-UTR with complementary binding sites, which was validated using luciferase reporter assay and anti-Ago2 RIP assay. HOXA-AS2 could negatively regulate the expression of miR-520c-3p in ADR cells. S100A4 was predicted as a downstream target of miR-520c-3p, which was confirmed by luciferase reporter assay. Conclusion: Our results suggest that HOXA-AS2 plays an important role in the resistance of AML cells to adriamycin. Thus, HOXA-AS2 may represent a therapeutic target for overcoming resistance to adriamycin-based chemotherapy in AML.

scholarly journals Role of Circular RNA DLEU2 in Human Acute Myeloid Leukemia

2018 ◽  
Vol 38 (20) ◽  
Author(s):  
Dong-Mei Wu ◽  
Xin Wen ◽  
Xin-Rui Han ◽  
Shan Wang ◽  
Yong-Jian Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Circular Rna ◽  
Tumor Formation ◽  
Luciferase Reporter ◽  
Proliferation And Apoptosis ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid

ABSTRACT In the current study, we were interested in exploring the molecular mechanism of circular RNA DLEU2 (circRNA-DLEU2) (hsa_circ_0000488) and microRNA 496 (miR-496), as well as PRKACB, in human acute myeloid leukemia (AML) cell activities. The RNA expression levels of circRNA-DLEU2, hsa-miR-496, and PRKACB were assessed by quantitative real-time PCR (qRT-PCR). The proliferation and apoptosis abilities of the cells were determined by CCK8 assay and flow cytometry analysis. Target relationships between circRNA-DLEU2 and miR-496, as well as PRKACB, were analyzed by luciferase reporter assay and probe assay. Immunoblotting assays were used to detect the protein expression level of PRKACB. We also did in vivo experiments to observe tumor formation after overexpression of circRNA-DLEU2. Our data showed that circRNA-DLEU2 was upregulated in AML tissues and cells, which promoted AML cell proliferation and inhibited cell apoptosis. circRNA-DLEU2 promoted AML tumor formation in vivo. miR-496 was inhibited by circRNA-DLEU2 and was downregulated in AML tissues. circRNA-DLEU2 inhibited miR-496 expression and promoted PRKACB expression. miR-496 antagonized the effects of PRKACB on MOLM-13 cell proliferation and apoptosis. Collectively, circRNA-DLEU2 accelerated human AML by suppressing miR-496 and promoting PRKACB expression.

scholarly journals Selective targeting of NAMPT by KPT-9274 in acute myeloid leukemia

2019 ◽  
Vol 3 (3) ◽  
pp. 242-255 ◽  
Author(s):  
Shaneice R. Mitchell ◽  
Karilyn Larkin ◽  
Nicole R. Grieselhuber ◽  
Tzung-Huei Lai ◽  
Matthew Cannon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Options ◽  
Tumor Development ◽  
Xenograft Model ◽  
Nicotinamide Phosphoribosyltransferase ◽  
P21 Activated Kinase ◽  
Induced Apoptosis ◽  
Acute Myeloid

Abstract Treatment options for acute myeloid leukemia (AML) remain extremely limited and associated with significant toxicity. Nicotinamide phosphoribosyltransferase (NAMPT) is involved in the generation of NAD+ and a potential therapeutic target in AML. We evaluated the effect of KPT-9274, a p21-activated kinase 4/NAMPT inhibitor that possesses a unique NAMPT-binding profile based on in silico modeling compared with earlier compounds pursued against this target. KPT-9274 elicited loss of mitochondrial respiration and glycolysis and induced apoptosis in AML subtypes independent of mutations and genomic abnormalities. These actions occurred mainly through the depletion of NAD+, whereas genetic knockdown of p21-activated kinase 4 did not induce cytotoxicity in AML cell lines or influence the cytotoxic effect of KPT-9274. KPT-9274 exposure reduced colony formation, increased blast differentiation, and diminished the frequency of leukemia-initiating cells from primary AML samples; KPT-9274 was minimally cytotoxic toward normal hematopoietic or immune cells. In addition, KPT-9274 improved overall survival in vivo in 2 different mouse models of AML and reduced tumor development in a patient-derived xenograft model of AML. Overall, KPT-9274 exhibited broad preclinical activity across a variety of AML subtypes and warrants further investigation as a potential therapeutic agent for AML.

TCRab Deficient CAR T-Cells Targeting CD123: An Allogeneic Approach of Adoptive Immunotherapy for the Treatment of Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2555-2555 ◽  
Author(s):  
Roman Galetto ◽  
Céline Lebuhotel ◽  
Agnès Gouble ◽  
Nuria Mencia-Trinchant ◽  
Cruz M Nicole ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Surface Expression ◽  
Car T Cells ◽  
Healthy Donors ◽  
Car T ◽  
Acute Myeloid

Abstract The remissions achieved using autologous T-cells expressing chimeric antigen receptors (CARs) in patients with advanced B cell leukemia and lymphomas have encouraged the use of CAR technology to treat different types of cancers by targeting distinct tumor-specific antigens. Since the current autologous approach utilizes CAR T-cells manufactured on a "per patient" basis, we propose an alternative approach based on the use of a standardized platform for manufacturing T-cells from third-party healthy donors to generate allogeneic "off-the-shelf" CAR T-cell-based frozen products. In the present work we have adapted this allogeneic platform to the production of T-cells targeting CD123, the transmembrane alpha chain of the interleukin-3 receptor, which is expressed on tumor cells from the majority of patients with Acute Myeloid Leukemia (AML). Multiple antigen recognition domains were screened in the context of different CAR architectures to identify candidates displaying activity against cells expressing variable levels of the CD123 antigen. The three lead candidates were tested in an orthotopic human AML cell line xenograft mouse model. From the three candidates that displayed comparable activity in vitro, we found two candidates capable of eradicating tumor cells in vivo with high efficiency. Subsequently, Transcription Activator-Like Effector Nuclease (TALEN) gene editing technology was used to inactivate the TCRα constant (TRAC) gene, eliminating the potential for engineered T-cells to mediate Graft versus Host Disease (GvHD). Editing of the TRAC gene can be achieved at high frequencies, and allows efficient amplification of TCR-deficient T-cells that no longer mediate alloreactivity in a xeno-GvHD mouse model. In addition, we show that TCR-deficient T-cells display equivalent in vitro and in vivo activity to non-edited T-cells expressing the same CAR. We have performed an initial evaluation of the expression of CD123 in AML patients and found an average cell surface expression of CD123 was of 67% in leukemic blasts (95% CI 48-82), 71% in CD34+CD38+ cells (95% CI 56-86), and 64% in CD34+CD38- (95% CI 41-87). Importantly, we have found that CD123 surface expression persists in CD34+CD38-CD90- cells after therapy in at least 20% of patients in remission (n=25), thus emphasizing the relevance of the target. Currently, the sensitivity of primary AML cells to CAR T-cells is being tested. Finally, we will also present our large scale manufacturing process of allogeneic CD123 specific T-cells from healthy donors, showing the feasibility for this off-the-shelf T-cell product that could be available for administration to a large number of AML patients. Disclosures Galetto: Cellectis SA: Employment. Lebuhotel:Cellectis SA: Employment. Gouble:Cellectis SA: Employment. Smith:Cellectis: Employment, Patents & Royalties.

scholarly journals High Expression of PXN Predicts a Poor Prognosis in Acute myeloid leukemia

2021 ◽  
Author(s):  
xinwen zhang ◽  
Hao Xiong ◽  
Jialin Duan ◽  
Xiaomin Chen ◽  
Yang Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Receive Treatment ◽  
To Receive ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is one of the common malignant diseases of hematopoietic system. Paxillin ( PXN ) is an important part of focal adhesions (FAs), which is related to the poor prognosis of many kinds of malignant tumors. However, no research has focused on the expression of PXN in AML. We aimed to investigate the expression of PXN in AML and its prognostic significance. Methods: Using GEPIA and UALCAN database to analyze the expression of PXN in AML patients and its prognostic significance. Bone marrow samples of newly diagnosed AML patients were collected to extract RNA, and qRT-PCR was used to detect the expression of PXN . The prognosis was followed up. Chi-square test was used to analyze the relationship between PXN expression and clinical laboratory characteristics. Kaplan-Meier analysis was used to draw survival curve, and Cox regression analysis was used to analyze the independent factors affecting the prognosis of patients with AML. The co-expression genes of PXN were analyzed by LinkedOmics to explore its biological significance in AML. Results: Kaplan-Meier analysis showed that the overall survival time of AML patients was related to whether to receive treatment and PXN expression(P<0.05). COX regression analysis showed that whether to receive treatment (HR=0.227，95%CI=0.075-0.689， P =0.009) and high expression of PXN (HR=4.484，95%CI=1.449-13.889， P =0.009) were independent poor prognostic factors in patients with AML. Conclusion: PXN is highly expressed in AML patient, and high PXN expression is an indicator of poor prognosis in AML patient.

scholarly journals Targeted Treatment of FLT3 -Overexpressing Acute Myeloid Leukemia with MiR-150 Nanoparticles Guided By Conjugated FLT3 Ligand Peptides

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3784-3784
Author(s):  
Xi Jiang ◽  
Jason Bugno ◽  
Chao Hu ◽  
Yang Yang ◽  
Tobias Herold ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Impact ◽  
Dependent Manner ◽  
Flt3 Ligand ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is one of the most common and fatal forms of hematopoietic malignancies. With standard chemotherapies, only 30-50% of younger (aged <60) and 5-10% of older patients with AML survive longer than 5 years. Aberrancy of FMS-like tyrosine kinase 3 (FLT3) occurs in the majority cases of AML. Two major classes of constitutively activating mutations of FLT3, i.e. internal-tandem duplications (ITDs) and tyrosine kinase domain (TKD) point mutations are found in more than 30% of AML cases and usually predict poor prognosis. Overexpression of FLT3 has also been reported in more than 70% of AML cases with a variety of AML subtypes, e.g. MLL (Mixed Lineage Leukemia)-rearranged or FLT3 -ITD AML, and may be associated with poor survival in AML patients. Given the disappointing results with FLT3 tyrosine kinase inhibitors (TKIs) in clinical trials in the past decade, decreasing the overall abundance of FLT3 at the RNA and protein levels would be an alternative strategy to treat AMLs with FLT3 overexpression and/or FLT3 -ITD/TKD mutations. MicroRNAs (miRNA) are a class of small, non-coding RNAs that play important roles in post-transcriptional gene regulation. We recently reported that miR-150 functions as a pivotal tumor-suppressor gatekeeper in MLL-rearranged and other subtypes of AML, through targeting FLT3 and MYB directly, and the MYC/LIN28/HOXA9/MEIS1 pathway indirectly. Our data showed that MLL-fusion proteins up-regulate FLT3 level through inhibiting the maturation of miR-150. Therefore, our findings strongly suggest a significant clinical potential of restoration of miR-150 expression/function in treating FLT3 -overexpressing AML. In the present study, we first analyzed FLT3 expression patterns and prognostic impact in a large cohort of AML patients (n=562). We found that FLT3 is aberrantly highly expressed in FAB M1/M2/M5 AML or AML with t(11q23)/MLL -rearrangements, FLT3 -ITD or NPM1 mutations, and that increased expression of FLT3 is an independent predictor of poor prognosis in patients with FLT3 -overexpressing AML. To treat FLT3 -overexpressing AML, we developed a novel targeted nanoparticle system consisting of FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) dendriplexes encapsulating miR-150 oligos (see Figure 1A). In FLT3 -overexpressing cell lines, the uptake ratios of the G7-FLT3L dendrimers were much higher (50.3~97.1%) than the G7-histone 2B (H2B) control nanoparticles (4.3~33.2%). And the uptake only took minutes. By integrating the miR-150 oligo with G7-FLT3L dendrimers, we constructed the G7-FLT3L-miR-150 dendriplexes, which significantly reduced the viability and increased the apoptosis of MONOMAC-6 cells carrying t(9;11) in a dose-dependent manner. To increase the stability of miR-150 oligos, we incorporated a 2'-o -methyl (2'-O Me) modification into the miRNA oligos. Indeed, the G7-FLT3L nanoparticles carrying 2'-O Me modified miR-150 exhibited a more sustained inhibition on cell growth. In order to further investigate the in vivo therapeutic effects of the miR-150 nanoparticles, we used a MLL -rearranged leukemia model. We transplanted wild-type recipient mice with primary mouse leukemic cells bearing the MLL-AF9 fusion. After the onset of leukemia, the mice were treated with G7-Flt3L or G7-NH2 control nanoparticles complexed with 2'-O Me-modified miR-150 oligos. In these treated animals, G7-Flt3L-miR-150 nanoparticles tended to be enriched in the bone marrow. The G7-Flt3L-miR-150 nanoparticles showed the best therapeutic effect (with median survival of 86 days), as compared with the control group (Ctrl; PBS treated; with median survival of 54 days) or the G7-NH2-miR-150 treated group (with median survival of 63 days). Nanoparticles carrying miR-150 mutant oligos showed no anti-leukemia effect at all. Notably, the G7-Flt3L-miR-150 treatment almost completely blocked MLL-AF9 -induced leukemia in 20% of the mice (Fig. 1B). Furthermore, the G7-Flt3L-miR-150 nanoparticles showed a synergistic effect with JQ1, a small-molecule inhibitor of the MYC pathway, in treating AML in vivo (Fig. 1C). Collectively, we have developed a novel targeted therapeutic strategy to treat FLT3-overexpressing AML, such as MLL-rearranged leukemias, which are resistant to currently available therapies, with both high specificity and efficacy. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hsa_circ_0001947 suppresses acute myeloid leukemia progression by sponging hsa-miR-329-5p and regulating CREBRF expression

2019 ◽  
Author(s):  
Fengjiao Han ◽  
Chaoqin Zhong ◽  
Wei Li ◽  
Ruiqing Wang ◽  
Chen Zhang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Rearrangements ◽  
Gene Mutations ◽  
In Vivo Studies ◽  
Circular Rnas ◽  
Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a heterogeneous group of diseases resulting from clonal transformation of hematopoietic precursors through the acquisition of chromosomal rearrangements and multiple gene mutations. Accumulating evidence has indicated that aberrantly expressed circular RNAs (circRNAs) are involved in cancer development and progression. However, their clinical values and biological roles in AML remain unclear. In this study, we identified the aberrantly down-regulated profile of hsa_circ_0001947 in AML through microarray analysis and validated it with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Then, we explored the clinical significance, biological functions and regulatory mechanisms of hsa_circ_0001947 in AML patients. The results showed that lower hsa_circ_0001947 expression was positively correlated with higher leukemia cells in bone marrow or peripheral blood, indicating poor prognosis. Further, bioinformatics analysis demonstrated hsa_circ_0001947-hsa-miR-329-5p-CREBRF network. Down-regulation of hsa_circ_0001947 by siRNA promoted cell proliferation, inhibited apoptosis, reduced drug resistance of AML cells, and also decreased the expression of its targeted gene, CREBRF. The mimics of hsa-miR-329-5p reduced drug resistance and decreased the expression of CREBRF, while its inhibitor manifested anti-leukemia effects and increased CREBRF expression. In vivo studies revealed that silencing hsa_circ_0001947 promoted the tumor growth in BALB/c nude mice. Collectively, our findings suggest that hsa_circ_0001947 functions as a tumor inhibitor to suppress AML cell proliferation through hsa-miR-329-5p/CREBRF axis, which would be a novel target for AML therapy.

Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia

2013 ◽  
Vol 31 (31) ◽  
pp. 3898-3905 ◽  
Author(s):  
Tilmann Bochtler ◽  
Friedrich Stölzel ◽  
Christoph E. Heilig ◽  
Christina Kunz ◽  
Brigitte Mohr ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Clonal Evolution ◽  
Prognostic Significance ◽  
Genomic Diversity ◽  
Prognostic Information ◽  
Clonal Heterogeneity ◽  
Landmark Analyses ◽  
Acute Myeloid

Purpose In acute myeloid leukemia (AML), studies based on whole-genome sequencing have shown genomic diversity within leukemic clones. The aim of this study was to address clonal heterogeneity in AML based on metaphase cytogenetics. Patients and Methods This analysis included all patients enrolled onto two consecutive, prospective, randomized multicenter trials of the Study Alliance Leukemia. Patients were newly diagnosed with non-M3 AML and were fit for intensive chemotherapy. Results Cytogenetic subclones were detected in 418 (15.8%) of 2,639 patients from the whole study population and in 418 (32.8%) of 1,274 patients with aberrant karyotypes. Among those, 252 karyotypes (60.3%) displayed a defined number of distinct subclones, and 166 (39.7%) were classified as composite karyotypes. Subclone formation was particularly frequent in the cytogenetically adverse group, with subclone formation in 69.0%, 67.1%, and 64.8% of patients with complex aberrant, monosomal, and abnl(17p) karyotypes (P < .001 each). Two-subclone patterns typically followed a mother-daughter evolution, whereas for ≥ three subclones, a branched pattern prevailed. In non–core binding factor AML, subclone formation was associated with inferior event-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariate analysis. Subgroup analysis showed that subclone formation adds prognostic information particularly in the cytogenetic adverse-risk group. Allogeneic stem-cell transplantation improved the prognosis of patients with subclone karyotypes as shown in landmark analyses. Conclusion Cytogenetic subclones are frequent in AML and permit tracing of clonal evolution and architecture. They bear prognostic significance with clonal heterogeneity as an independent adverse prognostic marker in cytogenetically adverse-risk AML.

scholarly journals Emodin and Its Combination with Cytarabine Induce Apoptosis in Resistant Acute Myeloid Leukemia Cells in Vitro and in Vivo

2018 ◽  
Vol 48 (5) ◽  
pp. 2061-2073 ◽  
Author(s):  
Yingyu Chen ◽  
Donghui Gan ◽  
Qinghua Huang ◽  
Xiaofeng Luo ◽  
Donghong Lin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Xenograft Model ◽  
Erk Signaling ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model ◽  
Acute Myeloid

Background/Aims: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor survival and a high risk of relapse, which is mainly caused by the emergence of multidrug resistance (MDR). The identification of novel agents to improve therapeutic strategies becomes important priority for AML treatment. It has been shown that emodin has therapeutic effects on many kinds of human malignant tumors. In this study, we investigated the anti-leukemia effects of emodin alone or in combination with cytarabine (Ara-C) on multidrug-resistant AML HL-60/ADR cells and in a mouse xenograft model of human highly tumorigenic AML HL-60/H3 cells. The underlying mechanism was also addressed. Methods: Cell viability after treatment was measured by MTT assay. The DNA fragmentation assay, Annexin V-PE/7-AAD, AO/EB staining, and electron microscopy were introduced to assess the apoptotic induction effects. Changes in protein expression in the Akt and ERK signaling pathways were determined by western blotting. In vivo antileukemia effects on HL-60/H3 xenograft model and overall mouse survival outcomes were further analyzed in this study. Results: Emodin dose-dependently induced growth inhibition and apoptotic effects in resistant HL-60/ADR cells in vitro as well as in the HL-60/H3 xenograft models in vivo. Moreover, emodin significantly enhanced chemosensitivity of AML cells to Ara-C, inhibited leukemic cell growth, and improved survival in the mouse xenograft model of AML. Dual targeting of Akt and ERK signaling pathways might contribute to the anti-leukemia effects on AML cells in vitro and in vivo. Conclusion: Emodin and its combination with Ara-C may be considered a promising therapeutic approach in AML and worthy of further investigation.

Pre-Clinical Activity of Amino-Alcohol Dimeric Naphthoquinones as Potential Therapeutics for Acute Myeloid Leukemia

2021 ◽  
Vol 21 ◽  
Author(s):  
Dana Ferraris ◽  
Rena Lapidus ◽  
Phuc Truong ◽  
Dominique Bollino ◽  
Brandon Carter-Cooper ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Amino Alcohol ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Lead Compound ◽  
Acute Myeloid

Background: The clinical outcomes of patients with acute myeloid leukemia (AML) remain unsatisfactory, therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported the anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. Objective: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate the anti-leukemic activity of the lead compound in vitro and in a human AML xenograft mouse model. Methods: We designed, synthesized, and performed structure-activity relationship of several rationally designed BiQ analogues that possess amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. Results: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. Conclusion: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML.

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