Cimigenol depresses acute myeloid leukemia cells protected by breaking bone marrow stromal cells via CXCR4/SDF­1α.

The purpose of the present study was to evaluate cimigenol (Cim) treatment effects to cell proliferation by breaking bone marrow stromal cells (BMSCs) through C-X-C chemokine receptor type 4 (CXCR4)/stromal cell-derived factor-1α (SDF-1α) pathway. MV-4-11 and U937 cell lines were used. The present study was divided into two parts. First, the cell lines were divided into normal control (NC), BMSC (cells co-cultured with BMSCs), BMSC + DMSO, BMSC + Low (treated with 5 mg/ml Cim), BMSC + Middle (treated with 10 mg/ml Cim), BMSC + High (treated with 20 mg/ml Cim). In the second step, the cell lines were divided into NC, BMSC, BMSC + BL8040 (treated with BL8040 which inhibits CXCR4), BMSC + Cim and BMSC + Cim + BL8040. EdU positive cell numbers were measured by EdU assay and apoptosis rate by flow cytometry and TUNEL assay. Relative gene and protein expression was measured by reverse transcription-quantitative PCR and western blotting assay. BMSCs were able to protect proliferation of cancer cells and decreased cell apoptosis compared with the NC group (P<0.001, respectively). With Cim supplement, the cell proliferation was decreased with cell apoptosis increasing compared with NC group (P<0.001 respectively). However, the anti-tumor effects of Cim were not significantly different from the BL8040 treated groups (P<0.001, respectively). In conclusion Cim decreased acute myeloid leukemia cells protected by BMSCs through the CXCR4/SDF-1α pathway.

Aqueous Extract of Cimicifuga dahurica Reprogramming Macrophage Polarization by Activating TLR4-NF-κB Signaling Pathway.

PURPOSE: Cimicifuga dahurica (C. dahurica), which has been used in traditional oriental medicine for a long period, was reported to exert extensive antitumor activity, but the effect and molecular biological mechanism of C. dahurica on multiple myeloma (MM) has not been elaborated. Tumor-associated macrophages (TAMs) exhibit a sustained polarization between tumor killing M1 subtype and tumor supporting M2 subtype. And a lower ratio of M1/M2 is associated with tumor angiogenesis, proliferation and invasion. We explored the inhibitory effect of the aqueous extract of the root of C. dahurica (CRAE) on tumor growth by reprogramming macrophage polarization in the tumor microenvironment. METHODS: Mice bearing SP2/0 multiple myeloma were treated with CRAE. Western blotting (WB), immunohistochemistry (IHC) and immunofluorescence staining were utilized to assess tumor growth and TAM populations. Macrophages were depleted by injection of clodronate liposomes to determine and measure the role of CRAE as an anti-tumor agent by targeting macrophages. To simulate tumor microenvironment, MM cells H929 and TAMs were co-cultured using the transwell co-culture system. By using CRAE as an immunoregulator in M2-like macrophages, we analyzed CRAE-treated macrophage-associated surface markers and cytokines by flow cytometry and WB. RESULTS: The results indicated that CRAE treatment could reduce tumor burden of MM mice and a high degree of M1-like macrophages infiltration was detected in tumor tissues. In vitro co-culture system, CRAE significantly promoted the polarization of M2 to M1 phenotype, which led to the increase in apoptosis of myeloma cells. It was found that the M1 polarization induced by CRAE depended on the TLR4-MyD88-TAK1-NF-κB signal transduction. CONCLUSION: This study elucidated the anticancer mechanism of the aqueous extract of C. dahurica (CRAE) through reprogramming macrophage polarization and highlighted that CRAE could act as a potential novel option for cancer immunotherapy.

Is sCD163 a Clinical Significant Prognostic Value in Cancers? A Systematic Review and Meta-Analysis.

BACKGROUND: Tumor associated macrophages (TAMs), a kind of inflammatory cells in the tumor microenvironment, are crucial for the occurrence and development of various tumors which increased the expression of CD163. Nevertheless, not much has been established regarding soluble CD163 and its connection to tumor diagnosis. In this case, a meta-analysis was conducted to determine the tumor diagnostic importance of serum sCD163. METHODS: In order to assess the correlation between sCD163 and the overall survival (OS) or progression-free survival (PFS) among tumor patients, a systematic perusal of literature published until June 2020 was conducted. Relevant data were primarily obtained from papers that have the following qualifications: 1) a confidence interval (CI) of 95%; 2) a report of the hazard ratios; and, 3) pooled by means of the Mantel-Haenszel random-effect representation. RESULTS: For the final meta-analysis, eight papers comprised of 1,236 cases were involved. Through pooled investigation, it was determined that a correlation exists between elevated serum sCD163 and worse OS (HR = 2.24, 95% CI: 1.50-3.35, P < 0.001) and PFS (HR = 3.90, 95% CI: 2.33-6.52, P < 0.001) among tumor cases. Subgroup analysis stratified by medium age at diagnosis demonstrated that patients over 60 years old with high sCD163 had worse OS (HR 2.28, 95% CI: 1.58-3.29, P < 0.001) than under 60 (HR 1.43, 95% CI: 1.15-1.77, P = 0.001). Subgroup analysis revealed that analysis method and medium age at diagnosis were the potential source of heterogeneity. CONCLUSIONS: Overall, diagnosis of tumor cases can be adversely determined through substantial sCD163 levels. Consequently, it is encouraged that extensive researches regarding the rates of cancer survival be accomplished.

Solasonine Suppresses the Proliferation of Acute Monocytic Leukemia Through the Activation of the AMPK/FOXO3A Axis.

Solasonine, the main active ingredient of Solanum nigrum L., has been reported to exert extensive antitumor activity. However, the antitumor effects in acute monocytic leukemia and the exact mechanisms involved are unknown. In this study, we investigated the role of solasonine on inhibiting the progression of acute monocytic leukemia. Our findings showed that solasonine inhibited the proliferation of acute monocytic leukemic cell lines (THP-1 and MV4-11) in vitro. Solasonine promoted apoptosis and induced cell cycle arrest in the G2/M phase. Analysis of RNA-seq data suggested that solasonine correlated with increased expression of genes in the AMPK/FOXO3A pathway. Inhibition of AMPK with compound C followed by treatment with solasonine showed that solasonine reduced apoptosis, caused less cell cycle arrest, and inactivated the AMPK/FOXO3A axis in THP-1 and MV4-11 cells. Solasonine also inhibited tumor growth by the activation of the AMPK/FOXO3A axis. In conclusion, solasonine inhibited the progress of acute monocytic leukemia in vitro and in vivo and triggered the apoptosis and cell cycle arrest in the G2/M phase by upregulating the AMPK/FOXO3A pathway.