Cinnamic aldehyde suppresses hypoxia-induced angiogenesis via inhibition of hypoxia-inducible factor-1α expression during tumor progression

Bae, Woom-Yee; Choi, Jae-Sun; Kim, Ja Eun; Jeong, Joo‐Won

doi:10.1016/j.bcp.2015.08.095

Cited by 27 publications

(20 citation statements)

References 52 publications

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“…Here, we found little effect of procyanidins on VEGF expression when cells were treated with trimeric (MW = 864) and tetrameric (MW = 1,152) procyanidins isolated from CE using HPLC (Figure A). In contrast, cinnamaldehyde was found to suppress VEGF reporter gene expression, VEGF mRNA and protein expression (Figures B–D), consistent with the results from a very recently published study . Taken together, our study implicated the potential of cinnamaldehyde as one major component in CE suppressing VEGF expression by cancer cells.…”

Section: Resultssupporting

confidence: 92%

Cinnamon extract reduces VEGF expression via suppressing HIF‐1α gene expression and inhibits tumor growth in mice

Zhang

Han

Dellinger

et al. 2016

Molecular Carcinogenesis

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Although many anti-VEGF agents are available for cancer treatment, side effects of these agents limit their application for cancer treatment and prevention. Here we studied the potential use of a diet-based agent as an inhibitor for VEGF production. Using a VEGF reporter assay, our data showed that an extract from cinnamon (CE) was a potent inhibitor of VEGF production in human cancer cells and suggested inhibition might be mediated through the suppression of HIF-1α gene expression and protein synthesis. Furthermore, CE treatment was found to inhibit expression and phosphorylation of STAT3 and AKT, which are key factors in the regulation of HIF-1α expression, and significantly reduce angiogenesis potential of cancer cells by migration assay. Consistent with these results, we observed significant suppression of VEGF expression, blood vessel formation, and tumor growth in a human ovarian tumor model in mice treated with CE. Cinnamaldehyde, a major component in cinnamon, was identified as one active component in CE that inhibits VEGF expression. Taken together, our findings provide a novel mechanism underlying anti-angiogenic and anti-tumor actions of CE and support the potential use of CE in cancer prevention and treatment. © 2016 Wiley Periodicals, Inc.

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Section: Resultssupporting

confidence: 92%

Cinnamon extract reduces VEGF expression via suppressing HIF‐1α gene expression and inhibits tumor growth in mice

Zhang

Han

Dellinger

et al. 2016

Molecular Carcinogenesis

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“…Because angiogenesis is an essential event for tumor progression, we examined the effect of zingerone on tumor angiogenesis. When we analyzed the hemoglobin contents of the tumor using Drabkin's reagent [19], we found that the concentration of hemoglobin in zingerone-administered mice was decreased (Figure 2A), suggesting that zingerone inhibits tumor angiogenesis. To explore vessel formation inside tumors, we further examined the level of CD31, a specific marker for endothelial cells, using immunohistochemistry.…”

Section: Resultsmentioning

confidence: 99%

Zingerone suppresses angiogenesisviainhibition of matrix metalloproteinases during tumor development

et al. 2016

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Angiogenesis is an essential step for tumor survival and progression, and the inhibition of angiogenesis is a good strategy for tumor therapeutics. In this study, we investigated the therapeutic effect of zingerone in a mouse tumor model. Zingerone suppressed tumor progression and tumor angiogenesis. Moreover, we found that zingerone inhibited the angiogenic activities of endothelial cells by both direct and indirect means. A mechanistic study showed that the activities of MMP-2 and MMP-9 in tumor cells were decreased by treatment with zingerone. Interestingly, zingerone-mediated inhibition of MMP-2 and MMP-9 was involved in the JNK pathway. In conclusion, zingerone showed strong anti-angiogenic activity via the inhibition of MMP-2 and MMP-9 during tumor progression, suggesting that zingerone may be a potential therapeutic drug for human cancers.

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“…In this regard, a few dietary flavonoids such as chrysin and cinnamaldehyde (CA) have been proposed to inhibit the master regulator HIF thereby reducing angiogenesis and metastasis. However, the detailed mechanism underlying the inhibitory effect of these phytochemicals on HIF and its regulation is yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

The inhibition of hypoxia‐induced angiogenesis and metastasis by cinnamaldehyde is mediated by decreasing HIF‐1α protein synthesis via PI3K/Akt pathway

et al. 2019

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Tumor hypoxia is positively correlated with tumor aggressiveness and hence is a negative prognostic factor in cancer. As normal cells usually do not experience such low oxygen levels, hypoxic cell signaling has attracted significant attention for the development of tumor-selective treatment strategies. In response to hypoxia, the master transcriptional regulator, HIF-1α plays central role in cellular adaptation by transactivating several crucial downstream target genes, which are involved in angiogenesis, metastasis, and EMT. In this study, we investigated the effect of cinnamaldehyde (CA), the main active ingredient of Cinnamon cassia bark extract, on hypoxia-induced angiogenesis and metastasis. The study in vitro comprised two cell lines, viz, sarcoma 180 and B16F10 melanoma, which were further confirmed in their respective transplantable in vivo models. Results show that CA administration inhibited tumor angiogenesis, EMT, and metastasis. At the molecular level, this was accompanied by a reduction in VEGF secretion, VEGF receptor (FLK) phosphorylation, matrix metalloproteinase (MMP) expression, and activity as well as a reduction in the EMT-related factors TWIST and ZEB1. Next, we focused our study particularly on the modulation of HIF-1 α by CA, which revealed that CA decreased HIF-1 α protein level by inhibiting its synthesis without affecting its proteasomal degradation. Furthermore, the PI3/Akt/m-TOR pathway, which plays an important role in HIF-1α transcription and translation, was also inhibited by CA both in vitro and in vivo. Thus, it can be concluded that CA decreased angiogenesis and metastasis in tumor cells by inhibiting HIF-1α protein accumulation probably by targeting the PI3/Akt/mTOR pathway. © 2019 BioFactors, 45(3):401-415, 2019

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Cinnamic aldehyde suppresses hypoxia-induced angiogenesis via inhibition of hypoxia-inducible factor-1α expression during tumor progression

Cited by 27 publications

References 52 publications

Cinnamon extract reduces VEGF expression via suppressing HIF‐1α gene expression and inhibits tumor growth in mice

Cinnamon extract reduces VEGF expression via suppressing HIF‐1α gene expression and inhibits tumor growth in mice

Zingerone suppresses angiogenesisviainhibition of matrix metalloproteinases during tumor development

The inhibition of hypoxia‐induced angiogenesis and metastasis by cinnamaldehyde is mediated by decreasing HIF‐1α protein synthesis via PI3K/Akt pathway

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