Muscone derivative ZM-32 inhibits breast tumor angiogenesis by suppressing HuR-mediated VEGF and MMP9 expression.

Inhibition of tumor angiogenesis is a highly effective strategy for cancer treatment. Human antigen R (HuR), an RNA-binding protein, is overexpressed in many cancers and regulates the mRNAs of multiple angiogenic factors by binding to the adenylate-uridylate-rich element in their 3' untranslated region. HuR protein has been demonstrated to be an important regulatory factor in macrophage-mediated angiogenesis, a process in which macrophages are critical for tumor progression. Muscone is a synthetic equivalent of musk, and recent studies have shown that it has a regulatory effect on angiogenesis. In this study, we synthesized five series of muscone derivatives and discovered that compound ZM-32 was effective in preventing HuR RRM1/2-Vegf-a mRNA complex formation. ZM-32 bound to HuR RRM1/2 protein with a KD value of 521.7 nmol/L. Furthermore, ZM-32 inhibited endothelial cell proliferation, migration, and tubule formation, and suppressed the VEGF/VEGFR2/ERK1/2 signaling axis mediated by macrophages in vitro. We also demonstrated that ZM-32 effectively prevented the proliferation and migration of breast cancer cells and inhibited the growth and angiogenesis of MDA-MB-231 xenograft tumors without any obvious toxicity in vivo. Mechanistically, exposure to ZM-32 influenced the mRNA stability of Vegf-a and Mmp9 in a HuR-dependent manner in both macrophages and MDA-MB-231 cells. Thus, in this study we identified a new muscone derivative, ZM-32, with anti-angiogenesis effects mediated via targeting HuR in breast cancer, that may become a potentially valuable lead compound for anti-cancer angiogenesis.

Co-administration of Shexiang Baoxin Pill and Chemotherapy Drugs Potentiated Cancer Therapy by Vascular-Promoting Strategy.

Effective delivery of chemotherapeutic agents to tumors is a critical objective of improved cancer therapy. Traditional antiangiogenic therapy aims at eradicating tumor blood vessels, but the subsequently reduced blood perfusion may limit the drug amount delivered into the tumor and potentially lead to tumor hypoxia, which has been proved to be unable to meet the therapeutic expectations. "Shexiang Baoxin Pill" (SBP) is a well-known traditional Chinese medicine (TCM) used in clinical treatment of cardiovascular diseases, which has the pharmacological effect of pro-angiogenesis demonstrated recently. In this study, we disclosed our finding that SBP could enhance the effective treatment performance of gemcitabine (GEM) while minimizing the toxic side effects caused by GEM. Mechanistically, SBP increased tumor angiogenesis, blood perfusion, vascular permeability, and vessel dilation, which subsequently favored the delivery of GEM to the tumor lesion. Moreover, combined treatment with SBP and GEM could modify tumor microenvironment and consequently overcome multidrug resistance, and this combination therapy is also suitable for combination of SBP with some other chemotherapeutic drugs as well. These results suggest that combining SBP with chemotherapeutic agents achieves better treatment efficiency, which can open an avenue for expanding the combined treatment of anti-cancer chemotherapeutic drugs with TCM.

Lung Endothelial MicroRNA-1 Regulates Tumor Growth and Angiogenesis.

RATIONALE: Vascular endothelial growth factor down-regulates microRNA-1 (miR-1) in the lung endothelium, and endothelial cells play a critical role in tumor progression and angiogenesis. OBJECTIVES: To examine the clinical significance of miR-1 in non-small cell lung cancer (NSCLC) and its specific role in tumor endothelium. METHODS: miR-1 levels were measured by Taqman assay. Endothelial cells were isolated by magnetic sorting. We used vascular endothelial cadherin promoter to create a vascular-specific miR-1 lentiviral vector and an inducible transgenic mouse. KRASG12D mut/Trp53-/- (KP) mice, lung-specific vascular endothelial growth factor transgenic mice, Lewis lung carcinoma xenografts, and primary endothelial cells were used to test the effects of miR-1. MEASUREMENTS AND MAIN RESULTS: In two cohorts of patients with NSCLC, miR-1 levels were lower in tumors than the cancer-free tissue. Tumor miR-1 levels correlated with the overall survival of patients with NSCLC. miR-1 levels were also lower in endothelial cells isolated from NSCLC tumors and tumor-bearing lungs of KP mouse model. We examined the significance of lower miR-1 levels by testing the effects of vascular-specific miR-1 overexpression. Vector-mediated delivery or transgenic overexpression of miR-1 in endothelial cells decreased tumor burden in KP mice, reduced the growth and vascularity of Lewis lung carcinoma xenografts, and decreased tracheal angiogenesis in vascular endothelial growth factor transgenic mice. In endothelial cells, miR-1 level was regulated through phosphoinositide 3-kinase and specifically controlled proliferation, de novo DNA synthesis, and ERK1/2 activation. Myeloproliferative leukemia oncogene was targeted by miR-1 in the lung endothelium and regulated tumor growth and angiogenesis. CONCLUSIONS: Endothelial miR-1 is down-regulated in NSCLC tumors and controls tumor progression and angiogenesis.

VEGF controls lung Th2 inflammation via the miR-1-Mpl (myeloproliferative leukemia virus oncogene)-P-selectin axis.

Asthma, the prototypic Th2-mediated inflammatory disorder of the lung, is an emergent disease worldwide. Vascular endothelial growth factor (VEGF) is a critical regulator of pulmonary Th2 inflammation, but the underlying mechanism and the roles of microRNAs (miRNAs) in this process have not been defined. Here we show that lung-specific overexpression of VEGF decreases miR-1 expression in the lung, most prominently in the endothelium, and a similar down-regulation occurs in lung endothelium in Th2 inflammation models. Intranasal delivery of miR-1 inhibited inflammatory responses to ovalbumin, house dust mite, and IL-13 overexpression. Blocking VEGF inhibited Th2-mediated lung inflammation, and this was restored by antagonizing miR-1. Using mRNA arrays, Argonaute pull-down assays, luciferase expression assays, and mutational analysis, we identified Mpl as a direct target of miR-1 and showed that VEGF controls the expression of endothelial Mpl during Th2 inflammation via the regulation of miR-1. In vivo knockdown of Mpl inhibited Th2 inflammation and indirectly inhibited the expression of P-selectin in lung endothelium. These experiments define a novel VEGF-miR-1-Mpl-P-selectin effector pathway in lung Th2 inflammation and herald the utility of miR-1 and Mpl as potential therapeutic targets for asthma.

Evaluation of apparent diffusion coefficient mappings in amnestic mild cognitive impairment using an image analysis software brain search.

BACKGROUND: The apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI) can quantify alterations in water diffusivity resulting from microscopic structural changes from amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). PURPOSE: To investigate the ADC value for aMCI and AD using Brain Search (BS) software based on anatomical volumes of interest (AVOI). MATERIAL AND METHODS: In total, 174 aged people were screened, and 25 patients with AD, 26 patients with aMCI, and 18 normal controls (NCs) were recruited. DWI was performed at 1.5 T with a fluid-attenuated inversion recovery (FLAIR), and the independent ADC mapping was generated after imaging acquisition. Ninety regional parcellations were adopted in a Brain Search (BS) based on the automated anatomic labeling atlas. The gray scale intensities (water diffusivity) from the collected ADC mappings were analyzed with BS. The mean value of each anatomical brain region was compared among aMCI, AD, and NC. The statistically significant (P < 0.05) group differences are displayed in color. RESULTS: During the pathological process of AD, the changes of water diffusivity appeared first in the left hippocampus, then gradually progressed to the bilateral sides and eventually displayed right lateralization. The ADC values from aMCI were obviously elevated compared to the values from the NC group in the left limbic cortex. Between the AD and NC groups, the significantly different brain areas included the bilateral hippocampus, the Cingulum_Mid, the ParaHippocampal_R, and the Temporal and Frontal lobes. There was a negative correlation between the ADC values and the scores from MMSE, MoCA, the Digit test, Raven's IQ, and WAIS IQ. Additionally, the ADC values were positively correlated with the scores from CDR, ADL, and ADAS-Cog. CONCLUSION: The water diffusivity for aMCI and AD displays asymmetric anatomical lateralization. The water diffusivity alterations can be analyzed and visualized with our newly designed analytic imaging software, BS, which can be used as a good reference for examining and diagnosing aMCI and AD patients.