Acute myelogenous leukemia is a highly invasiveness hematological malignancies that mainly relies on chemotherapy to improve survival rate at present.Up to now,the application of natural products has been widely accepted as an alternative compared with conventional chemotherapeutic agents due to their relative safety.In our research,we attempted to explore the anti-AML capacity and the potential mechanism of Erianin(Eri), a natural component from Chinese herbal medicine Dendrobium flaviflorum.We verified that Erianin inhibited the proliferation of AML cells and induced their apoptosis.Erianin can block cell cycle of AML cells at G2/M phase thourgh regulation of cell cycle-related proteins and P21,P27,P53 mRNA expression.Mechanistically, we firstly filtered and locked PPARɑ and PIK3R1 through network pharmacology analysis, protein-protein interaction (PPI) network, GO and KEGG pathway enrichment analysis, and further confirmed their good binding with Erianin by molecular docking.Specifically,Erianin inhibited the transcriptional level of PIK3R1 by activating the protein level of PPARɑ, thereby inhibiting the PI3K/AKT pathway.The inhibitory ability of Erianin on AML cells was partially neutralized by GW6471,an inhibitor of PPARɑ.It was also worth noting that Erianin revealed vigoroso coordinate repression with LY294002 on AML cells. Overall, these evidences indicated that Erianin exerted an influence on AML cells at least partially through PPARɑ to regulate PI3K/AKT signaling pathways.In summarize, we demonstrated the potent anti-AML effect and the potential mechanisms of Erianin, which suggested a hopeful strategy that Erianin has the capacity to be developed into a novel anti-AML drug.

该文主要研究在急性早幼粒细胞白血病NB4细胞中,miR-382-5p通过调控靶基因PTEN(phosphatase and tensin homologue)抑制了全反式维甲酸(all-trans retinoic acid,ATRA)诱导的急性早幼粒细胞分化.我们运用ATRA(1 μmol/L)诱导细胞分化;Western blot检测PTEN及髓系分化标志物CDllb的蛋白质水平;实时荧光定量PCR检测miR-382-5p的表达水平;过表达PTEN的慢病毒载体分别感染NB4细胞和HL-60、THP-1细胞;脂质体转染miR-382-5p的模拟剂(mimics)和特异性抑制剂(inhibitors)NB4细胞.结果显示,PTEN促进ATRA诱导的NB4细胞分化,而在HL-60和THP-1细胞中并无明显促分化效应.NB4细胞中,脂质体转染miR-382-5p mimics在mRNA和蛋白水平均抑制了PTEN的表达,并且抑制了ATRA诱导的分化;转染miR-382-5p inhibitors则恢复了PTEN表达,同时促进了ATRA诱导的急性早幼粒细胞NB4细胞的分化.该文结果提示,miR-382-5p靶向抑制了PTEN的表达从而抑制ATRA诱导的NB4细胞分化.

该文探讨了miR-15b在全反式维甲酸(all-trans retinoic acid,ATRA)治疗急性早幼粒细胞白血病(acute promyelocytic leukemia,APL)过程中发挥的作用.采用实时荧光定量PCR检测miR-15b的表达;流式细胞术检测细胞的分化情况;CCK-8实验检测细胞增殖;双荧光素酶报告实验检测miR-15b与CCNE1 3'UTR端的结合能力;Western blot检测下游靶基因CCNE1的表达.结果 显示,ATRA促进miR-15b的表达;过表达miR-15b增强了ATRA对APL细胞的分化作用,而抑制miR-15b表达后则出现相反结果;miR-15b抑制了APL细胞的增殖能力;双荧光素酶报告实验显示miR-15b与CCNE1的3'UTR端结合;Western blot显示miR-15b可以抑制下游靶基因CCNE1的表达.这些结果表明,miR-15b通过抑制CCNE1的表达促进APL细胞分化,抑制细胞增殖.

Background: The aim of our study was to assess the value of serum human epididymis protein 4 (HE4) to diagnose lung cancer and provide reliable scientific conclusions to guide clinical practice. Methods: A systematic search of the PubMed, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature, and WANFANG databases was conducted to identify all studies examining serum HE4 in the diagnosis of lung cancer published up to June, 2017. The Quality Assessment of Diagnostic Accuracy Studies tool was used to evaluate the methodological quality of each trial. The meta-analysis was performed using STATA software and Review Manager 5.3. Results: There were 21 studies involving 1883 cases and 1696 controls included in our meta-analysis. The pooled sensitivity and specificity of HE4 for diagnosing lung cancer were 0.73 (95% confidence interval [CI] 0.68-0.78) and 0.86 (95% CI 0.81-0.91), respectively. The positive likelihood ratio and negative likelihood ratio were 5.4 (95% CI 3.8-7.5) and 0.31 (95% CI 0.26-0.37), respectively. The diagnostic odds ratio was 17 (95% CI 12-26). The area under the curve of the summary receiver-operating characteristic curve was 0.86 (95% CI 0.83-0.89). Race, assay method, type of cancer, sample size, and publication date might be sources of heterogeneity in our meta-analysis. Subgroup analyses showed that the sensitivity in Caucasians was higher than that in Asians (0.81, 95% CI 0.71-0.91; and 0.71, 95% CI 0.66-0.77, respectively), but the specificity in Asians was better than that in Caucasians (0.87, 95% CI 0.81-0.92; and 0.85, 95% CI 0.73-0.97, respectively). The chemiluminescent microparticle immunoassay had the highest sensitivity, with 0.79 (95% CI 0.73-0.97), and the enzyme-linked immunosorbent assay had the highest specificity, with 0.87 (95% CI 0.79-0.94). HE4 had high diagnostic efficacy when screening for small cell lung cancer with the highest specificity (0.90, 95% CI 0.77-1.00). Conclusions: HE4 is a relatively promising and effective biomarker for the diagnosis of lung cancer. Furthermore, given the limitations of our study, additional large-scale and well-designed studies are needed in the future.

RAS-responsive element-binding protein 1 (RREB1) is a transcription factor that is implicated in RAS signaling and multiple tumors. However, the role of RREB1 in acute myeloid leukemia has not been studied. We found that RREB1 is overexpressed in AML patients and myeloid leukemia cell lines (NB4 and HL-60), and RREB1 expression was significantly decreased during granulocytic differentiation of myeloid leukemia cells induced by all-trans retinoic acid (ATRA). Then we performed a RREB1 knockdown assay in NB4 and HL-60 cells; the results showed that knockdown of RREB1 upregulated expression of CD11b, CEBPβ, and microRNA-145 (miR-145), which hinted that knockdown of RREB1 enhanced granulocytic differentiation of myeloid leukemia cells. In addition, inhibitor of miR-145 can offset the enhanced effect on granulocytic differentiation mediated by downregulation of RREB1. These collective findings demonstrated that RREB1 blocks granulocytic differentiation of myeloid leukemia cells by inhibiting the expression of miR-145 and downstream targets of the RAS signal pathway. These may provide a promising therapeutic target for AML patients.

MicroRNAs have been shown to be involved in various cell processes, including proliferation, apoptosis and differentiation. However, little is known about their function in granulopoiesis. In the present study, overexpression and knockdown experiments revealed that miR-15b was required to block the proliferation of NB4 and HL60 cells and induce them differentiated to granulocyte lineage. Moreover, we identified CCNE1 as a direct target of miR-15b, and demonstrated that CCNE1 was involved in cell differentiation and proliferation in acute promyelocytic leukemia cells. In addition, we demonstrated a novel pathway in which miR-15b regulated cells arrested in the G0/G1 phase and promoted terminal differentiation of cells by targeting CCNE1, which could modulate the cell cycle effort pRb in APL cells. These events blocked cell proliferation and promoted granulocyte differentiation. In conclusion, our data highlighted, for the first time, the important role of miR-15b in myeloid differentiation and suggested the potential role of miR-15b in cancer therapy.

In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic differentiation and maturation. MicroRNAs play pivotal roles in formation of the leukemic phenotype. Previously, microRNA-382-5p (miR-382-5p) was upregulated in acute myeloid leukemia (AML) with t(15;17). In the present study, we found that miR-382-5p expression was elevated with ATRA-induced differentiation of APL. To investigate the potential functional role of miR-382-5p in APL differentiation, an APL cell line was transfected with miR-382-5p mimics, inhibitors, or negative control (NC). The results showed in APL cell line NB4 that miR-382-5p downregulation upon ATRA treatment was a key event in the drug response. Mechanistic investigations revealed that miR-382-5p targeted the ATRA-regulated tumor suppressor gene PTEN through direct binding to its 3′ UTR. Enforced expression of miR-382-5p or specific PTEN inhibitors inhibited ATRA-induced granulocytic differentiation via regulation of the cell cycle regulator cyclinD1. Conversely, PTEN overexpression promoted differentiation and enhanced sensitivity of NB4 cell line to physiological levels of ATRA. Finally, we found that PTEN overexpression restored PML nuclear bodies (NBs). Taken together, these results demonstrated that up-regulated miR-382-5p in NB4 cell line inhibited granulocytic differentiation through the miR-382-5p/PTEN axis, uncovering PTEN as a critical element in the granulocytic differentiation program induced by ATRA in APL.

This study aimed to discuss the effect of verteporfin on cell viability, apoptosis, and its mechanism in human leukemia NB4 cells. CCK-8 assay was used to test the proliferation of verteporfin on NB4 cells. Colony forming assay was used to detect the colony forming ability of NB4 cells. Cell cycle and apoptosis were examined by flow cytometry. Hoechst33342 staining was used to observe the morphology of apoptotic cells. The protein expression levels were detected byWestern blot. The colony forming assay showed that the number of colony units decreased and colony size decreased after treatment with verteporfin (p＜0.05). The CCK-8 results indicated that verteporfin inhibited NB4 cells proliferation in dose- and time-dependent manner (p <0.05).In addition, the morphology of apoptotic cells was observed by Hoechst33342 staining. The percentage of NB4 cells in G0/G1 phase and apoptosis in verteporfin treatment group were higher than that of control group (p＜0.05).Meanwhile, the expression levels of YAP, p-AKT, GSK3β, cyclinD1, and Bcl-2 decreased, while Bax, p-GSK3β, and cleaved PARP increased(p＜0.05). Therefore, this study suggested that verteporfin inhibited proliferation and induced apoptosis by inhibition of YAP, and AKT/GSK3β signaling molecules were involved.

Actin-like 6A (ACTL6A), a component of BAF chromatin remodeling complexes, is important for cell differentiation. Nevertheless, its role and mechanism in acute promyelocytic leukemia (APL) has not been reported. To identify the genes that may participate in the development of APL, we analyzed data from an APL cDNA microarray (GSE12662) in the NCBI database, and found that ACTL6A was up-regulated in APL patients. Subsequently, we investigated the function and mechanisms of ACTL6A in myeloid cell development. The expression of ACTL6A was gradually decreased during granulocytic differentiation in all-trans retinoic acid-treated NB4 and HL-60 cells, and phorbol myristate acetate-treated HL-60 cells. We also found that knockdown of ACTL6A promoted differentiation in NB4 and HL-60 cells, and decreased the levels of Sox2 and Notch1. Mechanistically, ACTL6A interacted with and was co-localized with Sox2 and p53. Meanwhile, CBL0137, an activator of p53, decreased the expression of ACTL6A and promoted differentiation in NB4 and HL-60 cells. These findings suggest that the inhibition of ACTL6A promotes differentiation via the Sox2 and Notch1 signaling pathways. Furthermore, the differentiation promoted by inhibiting ACTL6A could be regulated by p53 via its physical interaction with ACTL6A.

This study aimed to investigate the effects of PTEN in EGCG enhanced ATRA induced differentiation in acute promyelocytic leukemia cells. After treated with ATRA and EGCG in combination for 72 h, morphological changes of the nucleus were observed in NB4 and HL-60 cells the expression of PTEN and myeloid differentiation markers CD11b were detected by Western blotting; the level and redistribution of PTEN was examined using Indirect immunofluorescence assay; CCK-8 assay was used to examine the proliferation. We consistently observed that the increased expression of PTEN was closely related to the CD11b expression in ATRA and the combined treatment. PTEN inhibitor SF1670, inhibited the expression of PTEN and decreased the level of CD11b; PI3K inhibitor LY294002, the level of PTEN and CD11b were increased. These results suggest that EGCG can promotes ATRA-induced maturation of acute promyelocytic leukemia cells via PTEN.

At present, acute promyelocytic leukemia (APL) is the most curable form of acute myeloid leukemia and can be treated using all-trans retinoic acid and arsenic trioxide. However, the current treatment of APL is associated with some issues such as drug toxicity, resistance and relapse. Therefore, other strategies are necessary for APL treatment. In the present study, we investigated the effects of salinomycin (SAL) on APL cell lines NB4 and HL-60 and determined its possible mechanisms. We observed that SAL inhibited cell proliferation, as determined by performing Cell Counting Kit-8 (CCK-8) assay, promoted cell apoptosis, as determined based on morphological changes, and increased Annexin V/propidium iodide (PI)-positive apoptotic cell percentage. Treatment with SAL increased Bax/Bcl-2 and cytochrome c expression and activated caspase-3 and -9, thus leading to poly(ADP-ribose) polymerase (PARP) cleavage and resulting in cell apoptosis. These results revealed that SAL induced cell apoptosis through activation of the intrinsic apoptosis pathway. The present study is the first to show that SAL induced the differentiation of APL cells, as determined based on mature morphological changes, increased NBT-positive cell and CD11b-positive cell percentages and increased CD11b and C/EBPβ levels. Furthermore, SAL decreased the expression of β-catenin and its targets cyclin D1 and C-myc. Results of immunofluorescence analysis revealed that SAL markedly decreased the β-catenin level in both the nucleus and cytoplasm. Combination treatment with SAL and IWR-1, an inhibitor of Wnt signaling, synergistically triggered SAL-induced differentiation of APL cells. These findings demonstrated that SAL effectively inhibited cell proliferation accompanied by induction of apoptosis and promotion of cell differentiation by inhibiting Wnt/β-catenin signaling. Collectively, these data revealed that SAL is a potential drug for treatment of APL.

Background: Acute myeloid leukaemia (AML) is a highly heterogeneous disease that commonly occurs in elderly cohorts. To date, there is still no standard induction therapy for elderly AML patients, and they experience low complete remission rates and short survival time. Methods: We retrospectively analysed the clinical data of 86 AML patients aged ≥50 years admitted at the First Affiliated Hospital of Chongqing Medical University and the Second Affiliated Hospital of Chongqing Medical University. The patients were divided into three groups, idarubicin plus cytarabine (IA) group; decitabine, cytarabine, aclarubicin, and granulocyte stimulating factor (D-CAG) group; and daunorubicin plus cytarabine (DA) group. Patients’ adverse reactions, complete remission (CR) rates, overall response (OR) rates, and long-term survival conditions were compared. Results: The CR rates of the IA group, D-CAG group, and DA group were 47.4%, 54.3%, and 42.9%, respectively (P=0.659), and the OR rates were 52.6%, 71.4%, and 71.4%, respectively (P=0.311). The median survival time of the IA group was 12.47 months, while that of the D-CAG group was 28.6 months (P=0.180). All of the above results had no statistical difference. However, the D-CAG group had lower incidence of haematological adverse reactions, fever, and gastrointestinal response of grade II or above than the DA Group and IA group. Conclusions: This study showed that IA regimen, D-CAG regimen and DA regimen have similar therapeutic effect on patients aged ≥50 years with newly diagnosed AML while D-CAG regimen shows fewer adverse reactions. Age and bone marrow blasts at initial diagnosis are risk factors for prognostic.

Background: Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a candidate oncoprotein and participates in the progression of various malignancies. However, few reports have examined the effect of YAP inhibition in human leukemia HL-60 cells.Methods: We examined the effects of YAP knockdown or inhibition using short hairpin RNA (shRNA) or verteporfin (VP), respectively. Western blot assays were used to determine the expression levels of YAP, Survivin, cyclinD1, PARP, Bcl-2, and Bax. Cell proliferation was assessed using the cell counting kit (CCK- 8) assay. Cell cycle progression and apoptosis were evaluated by flow cytometry, and apoptotic cell morphology was observed by Hoechst 33342 staining.Results: Knockdown or inhibition of YAP led to cell cycle arrest at the G0/G1 phase and increased apoptosis, inhibited cell proliferation, increased levels of Bax and cleaved PARP, and decreased levels of PARP, Bcl-2, Survivin, and cyclinD1. Moreover, Hoechst 33342 staining revealed increased cell nuclear fragmentation.Conclusion: Collectively, these results show that inhibition of YAP inhibits proliferation and induces apoptosis in HL-60 cells. Therefore, a novel treatment regime involving genetic or pharmacological inhibition of YAP could be established for acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is a distinctive subtype of acute myeloid leukemia (AML) in which the hybrid protein promyelocytic leukemia protein/retinoic acid receptor α (PML/RARα) acts as a transcriptional repressor impairing the expression of genes that are critical to myeloid cell mutation. We aimed at explaining the molecular mechanism of green tea polyphenol epigallocatechin-3-gallate (EGCG) enhancement of ATRA-induced APL cell line differentiation. Tumor suppressor phosphatase and tensin homolog (PTEN) was found downregulated in NB4 cells and rescued by proteases inhibitor MG132. A significant increase of PTEN levels was found in NB4, HL-60 and THP-1 cells upon ATRA combined with EGCG treatment, paralleled by increased myeloid differentiation marker CD11b. EGCG in synergy with ATRA promote degradation of PML/RARα and restores PML expression, and increase the level of nuclear PTEN. Pretreatment of PTEN inhibitor SF1670 enhances the PI3K signaling pathway and represses NB4 cell differentiation. Moreover, the induction of PTEN attenuated the Akt phosphorylation levels, pretreatment of PI3K inhibitor LY294002 in NB4 cells, significantly augmented the cell differentiation and increased the expression of PTEN. These results therefore indicate that EGCG targets PML/RARα oncoprotein for degradation and potentiates differentiation of promyelocytic leukemia cells in combination with ATRA via PTEN.

Background and Aims: Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has recently been proven a suppressor of yes-associated protein (YAP) and has shown potential in anticancer treatment. However, its anti-human leukemia effects in NB4 cells remain unclear. In this study, we investigated the effects of VP on proliferation and apoptosis in human leukemia NB4 cells. Methods: NB4 cells were treated with VP for 24 h. The effects of VP on cell proliferation were determined using a Cell-Counting Kit-8 assay (CCK-8) assay and colony forming assay. Apoptosis and cell cycle were evaluated by flow cytometry (FCM). The protein levels were detected by western blot. Results: We found that VP inhibited the proliferation of NB4 cells in a concentration and time-dependent manner. FCM analysis showed that VP induced apoptosis in a concentration dependent manner and that VP treatment led to cell cycle arrest at G0/G1 phase. Moreover, VP significantly decreased the protein expression of YAP, p-YAP, Survivin, c-Myc, cyclinD1, p-ERK, and p-AKT. In addition, VP increased the protein expression of cleaved caspase3, cleaved PARP, Bax, and p-p38 MAPK. Conclusions: VP inhibited the proliferation and induced apoptosis in NB4 cells.

This study is aimed to investigate the effects of salinomycin (SAL) on cell proliferation and differentiation in acute promyelocytic leukemia cell line NB4 and its potential mechanisms.In this study,cell proliferation was determined by cell counting kit-8 (CCK-8) assay,and cell morphological changes was evaluated by performing Wright Giemsa staining.The expression of cell surface differentiation marker CD11b was detected by flow cytometry.The protein levels of CD11b,C/EBPβ,β-catenin,C-myc and Cyclin D1 were detected by Western blot.The results indicated that SAL significantly inhibited cell proliferation,cells displayed morphological features of differentiation after treated with SAL for 72 h.SAL treatment significantly increased the percentage of CD1 1b-positive cells and protein levels of CD11b and C/EBPβ in a dose-dependent manner.In addition,SAL decreased the protein levels of β-catenin,C-myc and Cyclin D1.This study also investigated the effect of combined treatment of IWR-1,which was an inhibitor of the Wnt/β-catenin signaling pathway,and SAL on cell differentiation.Compared with SAL treatment alone,the combination with SAL and IWR-1 promoted NB4 cell differentiation induced by SAL.These results suggest that SAL effectively inhibits cell proliferation and promotes cell differentiation possibly by blocking of Wnt/β-catenin signaling.

This study was aimed to investigate the effect of lapatinib on cell proliferation and apoptosis in NB4 cells,and its related mechanisms.NB4 cells were treated with p38MAPK inhibitor and different concentrations of lapatinib for 24 h.The proliferation of NB4 cells was detected by CCK-8 (cell counting kit-8) assay.Apoptosis was determined by Annexin V/PI double binding assay and Hoechst 33258 fluorescent staining.Morphological changes were observed under optical microscope.The protein levels of Bcl-2 (B cell leukemia-2),Bax (Bcl-2 associated X protein),caspase-3,PARP (poly-ADP-ribose polymerase),PML-RARα (promyelocytic leukemiaretinoic acid receptor alpha),p38MAPK (p38 mitongen-activated protein kinase) and p-p38MAPK (phosphorylated p38 mitongen-activated protein kinase) were detected by Western blot.The results showed that lapatinib significantly inhibited proliferation and induced apoptosis of NB4 cells.Chromatin condensation and fragmentation were observed in lapatinib treated group.Lapatinib decreased the levels of Bcl-2 and PML-RARα,increased the levels of Bax,cleaved caspase-3,cleaved PARP and p-p38MAPK.Meanwhile,SB203580 partially increase the viability of NB4 cells and reduced apoptosis induced by lapatinib;and decreased the levels of p-p38MAPK,Bax,cleaved caspase-3 and cleaved PARP.These results suggested that lapatinib inhibited proliferation and induced apoptosis in NB4 cells,and p38MAPK signal pathway may be involved in these processes.

Objective To investigate the effect of lapatinib on cell proliferation and apoptosis in acute myeloid leukemia HL60 cells in vitro and the related molecular mechanisms. Methods The HL60 cells were treated with 5, 10, 15 μmol/L lapatinib for 24 hours, and then morphological changes of the cells were observed under optical microscope. CCK-8 assay was used to assess the cell viability. Colony formation assay was performed to detect the cell proliferation ability. Cell apoptosis labeled by annexinV-FITC/PI were analyzed by flow cytometry. Wright modified LIU's staining and Hoechst33342 fluorescent staining were used to observe the morphology of the nucleus. Western blotting was utilized to detect the expressions of Bax, Bcl2, caspase-3, caspase-9, cleaved caspase-3, cleaved caspase-9, cleaved poly-ADP-ribose polymerase (cleaved PARP), cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A), c-MYC, AKT and p-AKT. Results Compared with the control group, lapatinib inhibited cell proliferation and promoted apoptosis, induced nuclear fragmentation, chromatin condensation of HL60 cells in a dose-dependent manner. Meanwhile, it down-regulated the expression of Bcl2, up-regulated the levels of Bax, cleaved caspase-3, cleaved caspase-9 and cleaved PARP, and decreased the levels of CIP2A, p-AKT and c-MYC. Conclusion Lapatinib could inhibit cell proliferation and promote apoptosis in HL60 cells by inhibiting the CIP2A/AKT/c-MYC signal pathway.

Bestatin has been known as an immunomodulating agent in anti-leukemia treatment. The mechanism by which Bestatin enhances all-trans retinoic acid (ATRA)-induced cell differentiation of acute promyelocytic leukemia (APL) cells is generally attributed to inhibition of cell surface CD13/aminopeptidase N activity. Bestatin also exerts its biological activities besides its ability to inhibit aminopeptidase N enzymatic activity. This article provides data to support an alternative mechanism regarding an important role of inhibition of p38 mitogen-activated protein kinase (MAPK) signal pathway in Bestatin's anti-leukemia effect. Bestatin enhanced ATRA-induced differentiation and inhibited ATRA-driven phosphorylation of p38 MAPK in ATRA-sensitive APL NB4 cells. In contrast, Bestatin could not reverse the differentiation block in ATRA-resistant APL MR2 cells, in which ATRA was unable to induce phosphorylation of p38 MAPK. Moreover, CD13 ligation with anti-CD13 antibody WM-15 resulted in phosphorylation of p38 MAPK, reduced the inhibition of Bestatin on the phosphorylation of p38 MAPK, and completely abolished the enhancement of Bestatin on ATRA-inducing differentiation in NB4 cells. This study shows that inhibition of p38 MAPK phosphorylation is critical for Bestatin to enhance ATRA-induced cell differentiation in ATRA-sensitive APL NB4 cells. Results suggested that pharmacological inhibition of the p38 MAPK pathway might enhance ATRA-dependent differentiation.