Homoharringtonine potentiates the antileukemic activity of arsenic trioxide against acute myeloid leukemia cells.

Relapse of minimal residual disease (MRD) is a major problem after conventional chemotherapy in patients with acute myeloid leukemia (AML). The bone marrow stroma can protect AML cells from insults of chemotherapy, partly contributing to AML relapse. Arsenic trioxide (ATO) is the main component of arsenical traditional Chinese medicines and has been widely used for the treatment of hematologic malignancies particularly acute promyelocytic leukemia over the past three decades. ATO acts through a direct arsenic binding to cysteine residues in zinc fingers located in promyelocytic leukemia protein (PML), thus killing the leukemia stem cells (LSCs). Our prior study has demonstrated that adhesion to stroma cells could render AML cells resistant to ATO but the detailed mechanism remains to be explored. Here, we report that the adhesion-induced resistance to ATO is related to the up-regulation of myeloid cell leukemia-1 (Mcl-1). Homoharringtonine (HHT) can potentiate the anti-leukemia effects of ATO on adhered AML cells by suppressing Mcl-1 through glycogen synthase kinase-3ß (GSK3ß). Furthermore, a potentiating effect of HHT on ATO was also observed in primary AML cells and AML xenografted tumors. Thus, these data indicate that HHT could enhance ATO anti-leukemia activity both in vitro and in vivo.

Exosomes derived from acute myeloid leukemia cells promote chemoresistance by enhancing glycolysis-mediated vascular remodeling.

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. AML cells secrete angiogenic factors to remodel vasculature and acquire chemoresistance; however, antiangiogenic drugs are often ineffective in AML treatment. Cancer cell-derived exosomes can induce angiogenesis, but their role in vascular remodeling during AML is unclear. Here, we found that exosomes secreted by AML cells promoted proliferation and migration and tube-forming activity of human umbilical vein endothelial cells (HUVECs), whereas HUVECs conferred chemoresistance to AML cells. AML cell-derived exosomes contained vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) messenger RNA and induced VEGFR expression in HUVECs. Furthermore, they enhanced glycolysis, which correlated with HUVEC proliferation, tube formation, and resistance to apoptosis. Thus, AML cells secrete VEGF/VEGFR-containing exosomes that induce glycolysis in HUVECs leading to vascular remodeling and acquisition of chemoresistance. These findings may contribute to the development of novel therapeutic strategies targeting exosomes in AML.

Polymorphism and plasma levels of apolipoprotein E and the risk of aneurysmal subarachnoid hemorrhage in a Chinese population: a case-control study.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is the most common types of subarachnoid hemorrhage, which is a critical clinical problem with high morbidity, mortality, and economic impact. Recent studies have shown that APOE was a genetic risk factor of aSAH, however, the studies lack consistent conclusions and the evidence from Chinese Han population is rare. OBJECTIVE: To determine the relationship between APOE polymorphism and the incidence of aSAH in Chinese Fujian Han population and explore the possible mechanism of ApoE in the pathogenesis of aSAH. METHODS: A total of 131 patients newly diagnosed with aSAH were selected as aSAH group and 137 healthy subjects were selected as the control group. All the samples were analyzed for blood lipids and serum ApoE levels, and ApoE genotype was determined by a commercial chip and further confirmed with Sanger sequencing. An adjusted multivariate logistic regression analysis was carried out to estimate the effects of APOE polymorphism on the risk of aSAH. RESULTS: Compared with the controls, the serum TC, HDL-C and ApoA1 levels in aSAH were significantly lower: TC (4.52 ± 1.38 vs. 5.11 ± 0.86 mmol/L, P < 0.001), HDL-C (1.23 ± 0.46 vs. 1.44 ± 0.32 mmol/L, P < 0.001) and ApoA1 (1.20 ± 0.32 vs. 1.38 ± 0.25 g/L, P < 0.001). The distribution of ε2/ε3 genotype (19.08% vs. 9.49%, P = 0.038) and ε2 allele frequency (11.07% vs. 5.84%, P = 0.039) was significantly higher in aSAH than the healthy controls. The multivariate logistic regression identified that ApoE ε2 allele was independently associated with aSAH (OR = 2.083; and 95% CI = 1.045-4.153, P = 0.037). The serum ApoE in aSAH were significantly higher than controls (53.03 ± 24.64 vs. 45.06 ± 12.84 mg/L, P = 0.010). CONCLUSION: APOE polymorphism might be associated with the incidence of aSAH in Chinese Fujian Han population. ApoE ε2 may be a risk factor for the incidence of aSAH, which may be related with the impacts of ApoE genotypes for the serum lipids, especially for the plasma levels of ApoE.

The Efficacy of High-Dose Dexamethasone vs. Other Treatments for Newly Diagnosed Immune Thrombocytopenia: A Meta-Analysis.

Objective: To compare the therapeutic efficacies of high dose dexamethasone, prednisone and rituximab in combination with dexamethasone for newly diagnosed ITP (Immune Thrombocytopenia, ITP) patients. Methods and results: Relevant publications for this study were obtained by searching PubMed, Embase, Cochrane, and CNKI (National Knowledge Infrastructure, CNKI) databases following the PRISMA guidelines. A total of, 15 publications were retrieved that contained sufficient data from 1,362 patients for high quality analysis of this study endpoints. Data analysis was carried out using Stata 11.0 software. The primary outcomes were OR (Overall Response, OR) at 1 month after intervention and SR at 6 and 12 months. The secondary outcomes were AEs and relapse. There were no differences in the OR, while the SR was higher at 6 months (p = 0.001) as well as 12 months (p < 0.001) in the rituximab + dexamethasone group. In addition, the incidences of AEs (p = 0.008) were also higher in the rituximab + dexamethasone group. Dexamethasone was superior to prednisone based on OR (p = 0.006). We found no differences in SR at 6 months between dexamethasone and prednisone but SR at 12 months was higher in the dexamethasone group (p = 0.014). The relapse rate was higher in the high dose dexamethasone group compared to the rituximab + dexamethasone group (p = 0.042). Conclusion: This demonstrated that new treatment options such as Rituximab + dexamethasone, could be a good alternative to traditional therapy in improving long-term response and reducing the rate of relapse. However, further studies are required on the increased risk of AEs associated with Rituximab + dexamethasone.

Stromal cells promote chemoresistance of acute myeloid leukemia cells via activation of the IL-6/STAT3/OXPHOS axis.

BACKGROUND: Bone marrow stromal cells (BMSCs) are known to promote chemoresistance in acute myeloid leukemia (AML) cells. However, the molecular basis for BMSC-associated AML chemoresistance remains largely unexplored. METHODS: The mitochondrial oxidative phosphorylation (OXPHOS) levels of AML cells were measured by a Seahorse XFe24 cell metabolic analyzer. The activity of total or mitochondrial signal transducer and transcription activator 3 (STAT3) in AML cells was explored by flow cytometry and Western blotting. Real-time quantitative PCR, Western blotting and enzyme-linked immunosorbent assay (ELISA) were used to analyze expression of interleukin 6 (IL-6) in the human BMSC line HS-5, and IL-6 was knocked out in HS-5 cells by CRISPR/Cas9 system. RESULTS: In this study, we observed that co-culturing with BMSCs heightened OXPHOS levels in AML cells, thus promoting chemoresistance in these cells. HS-5 cell-induced upregulation of OXPHOS is dependent on the activation of STAT3, especially on that of mitochondrial serine phosphorylated STAT3 (pS-STAT3) in AML cells. The relationship among pS-STAT3, OXPHOS, and chemosensitivity of AML cells induced by BMSCs was demonstrated by the STAT3 activator and inhibitor, which upregulated and downregulated the levels of mitochondrial pS-STAT3 and OXPHOS, respectively. Intriguingly, AML cells remodeled HS-5 cells to secrete more IL-6, which augmented mitochondrial OXPHOS in AML cells and stimulated their chemoresistance. IL-6 knockout in HS-5 cells impaired the ability of these cells to activate STAT3, to increase OXPHOS, or to promote chemoresistance in AML cells. CONCLUSIONS: BMSCs promoted chemoresistance in AML cells via the activation of the IL-6/STAT3/OXPHOS pathway. These findings exhibit a novel mechanism of chemoresistance in AML cells in the bone marrow microenvironment from a metabolic perspective.

Melatonin inhibits lung metastasis of gastric cancer in vivo.

AIM: Melatonin shows therapeutic benefits in gastric cancer, but the mechanism underlying its anticancer effects remains elusive. The aim of this study was to determine whether melatonin inhibits lung metastasis in gastric cancer. MAIN METHODS: A lung metastasis model of gastric cancer was established in nude mice injected with human gastric adenocarcinoma MGC80-3 cells. Mice were divided into control, IL-1ß-treated, melatonin-treated, and IL-1ß plus melatonin-treated groups and analyzed for the formation of lung metastatic nodules by flow cytometry and hematoxylin and eosin staining. The mRNA expression of epithelial-mesenchymal transition (EMT) markers was assessed by RT-qPCR. The activities of matrix metalloproteinase (MMP)-2 and MMP-9 were determined by gelatin zymography and their protein expression by western blotting and immunohistochemistry. The levels of NF-κB p65 and phosphorylated (p)-p65 were detected by immunohistochemistry. KEY FINDINGS: The number of lung metastases in the IL-1ß plus melatonin group was significantly lower and the sizes of nodules were smaller than those in the IL-1ß group. Furthermore, melatonin reversed changes in the expression of EMT markers induced by IL-1ß by increasing mRNA levels of ß-catenin and E-cadherin and decreasing those of fibronectin, vimentin, and Snail compared to IL-1ß. Treatment with IL-1ß upregulated the expression and activities of MMP-2 and MMP-9 and expression of NF-κB p65 and phospho-p65 (p-p65), but melatonin alleviated these effects. SIGNIFICANCE: Melatonin inhibited IL-1ß-induced lung metastasis of gastric cancer through downregulation of MMP-2, MMP-9, and NF-κB p65 expression and activities. These findings provide a basis for potential use of melatonin as a supplementary therapy for patients with advanced gastric cancer.