Hesperidin inhibited acetaldehyde-induced matrix metalloproteinase-9 gene expression in human hepatocellular carcinoma cells.

Department of Chinese Medicine, Buddhist Dalin Tzu Chi General Hospital, Chia-Yi, Taiwan.
Toxicology Letters (Impact Factor: 3.36). 02/2009; 184(3):204-10. DOI: 10.1016/j.toxlet.2008.11.018
Source: PubMed

ABSTRACT Previous studies have revealed that acetaldehyde-induced cell invasion and matrix metalloproteinase-9 (MMP-9) activation and are directly involved in hepatic tumorigenesis and metastasis. Acetaldehyde is an important substance for tumor regression. We designed this study to aid in the development of powerful anti-cancer drugs with specific tumor regression and anti-metastatic potentials. Optimal drugs should possess both specific MMP-9 enzyme and gene transcriptional activities at the molecular level. Hesperidin, a flavonoid present in fruits and vegetables, possess anti-inflammatory and chemopreventive activities. Hesperidin suppressed acetaldehyde-induced cell invasion and inhibited the secreted and cytosolic MMP-9 forms in HepG2 cells with acetaldehyde. Hesperidin suppressed acetaldehyde-induced MMP-9 expression through the inhibition of nuclear factor-kappaB (NF-kappaB) and AP-1, and suppressed acetaldehyde-stimulated NF-kappaB translocation into the nucleus through IkappaB inhibitory signaling pathways. Hesperidin also inhibited acetaldehyde-induced AP-1 activity by the inhibitory phosphorylation of p38 kinase and c-Jun N-terminal kinase (JNK) signaling pathways. Results from our study revealed that hesperidin suppressed both acetaldehyde-activated NF-kappaB and activator protein 1 (AP-1) activity by IkappaB, JNK, and p38 signaling pathways. This resulted in the reduction of MMP-9 expression, secretion, and hepatocarcinoma cellular invasion. Our result confirmed the therapeutic potential of hesperidin an anti-metastatic and its involvement in the acetaldehyde-induced cell invasiveness of hepatocellular carcinoma in alcoholic patients.

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    ABSTRACT: Hesperidin (Hsd) and its aglycone, hesperetin (Hst), are two flavonoids from citrus species that have various biological properties, particularly those for the prevention of cancer and cardiovascular diseases. Studies have shown both anti-cancer and cancer chemopreventive effects for Hsd and Hst. Cancer chemopreventive properties of Hsd and Hst are mainly associated with their antioxidant, radical scavenging and anti-inflammatory activities. In addition, Hsd and Hst interfere at different stages of cancer. Unlike conventional anti-cancer drugs, Hsd and Hst inhibit tumor growth by targeting multiple cellular protein targets at the same time, including caspases, Bcl-2 (B-cell lymphoma 2) and Bax (Bcl-2 associated X protein) for the induction of apoptosis, and COX-2 (cyclooxygenase-2), MMP-2 (matrix metalloproteinase-2) and MMP-9 for the inhibition of angiogenesis and metastasis. The results of the recent basic and clinical studies revealed the beneficial effects for Hst, Hsd and their derivatives in the treatment of heart failure and cardiac remodeling, myocardial ischemia and infarction, and hypertension. In addition, the valuable effects of Hst and Hsd in the treatment of diabetes and dyslipidemia with their anti-platelet and anti-coagulant effects make them good candidates in the treatment of various cardiovascular diseases. In this review, new findings regarding the molecular targets of Hsd and Hst, animal studies and clinical trials are discussed. Copyright © 2015. Published by Elsevier Inc.
    Life Sciences 01/2015; 124. DOI:10.1016/j.lfs.2014.12.030 · 2.30 Impact Factor
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    ABSTRACT: Objective: To study the effect of hesperidin extracted from the peel of Gannan kumquat on cell proliferation and apoptosis of human poorly diferentiated nasopharyongeal carcinoma epithelial cell (CNE-2Z). Methods: Effect of hesperidin on proliferation of CNE-2Z cells was detected by the MTT method. Effect of hesperidin on apoptosis of CNE-2Z cells was utilized by the acridine orange / ethidium bromide staining method. Results: After being treated with different hesperidin for 24, 48 and 72 h respectively, the proliferation of CNE-2Z cells was inhibited in vitro; different time had high significant difference on the proliferation of CNE-2Z cells (F = 1898.865, P <;; 0.001), different pharmacal concentration had had high significant difference on the proliferation of CNE-2Z cells (F = 5454.040, P <;; 0.001). Time and pharmacal concentration had interaction on the proliferation of CNE-2Z cells (F = 118.909, P <;; 0.001). During the concentration of 1μmol/L-100μmol/L, inhibition ratio of CNE-2Z cells increased gradually along with the increment of pharmacal concentration and the extension of time. When the concentration was higher than 100 μmol/L, its inhibition no more reinforced accompanied with the increasement of pharmacal concentration (P> 0.05) and presented the determinate saturability. The aggregation of cellular nuclear chromatin, karyopycnosis, karyorrhexis and apoptotic body was present in CNE-2Z cells detected by acridine orange/ethidium bromide fluorescent staining after the utilization of hesperidin. Conclusion : Hesperidin inhibited the cellular division growth and induced the cell apoptosis of CNE-2Z cells.
    2010 3rd International Conference on Biomedical Engineering and Informatics (BMEI); 10/2010
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    ABSTRACT: Background Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as negative regulators that balance the strength and duration of NF-¿B signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancer remains unclear. The purpose of this study is to investigate the correlation of Cezanne expression with clinicopathological/prognostic value in hepatocellular carcinoma (HCC).Methods The expression levels of Cezanne and matrix metallopeptidase 9 (MMP-9) were assessed by immunohistochemistry in 230 HCC specimens. The correlation between expression of Cezanne and MMP-9, clinicopathological/prognostic value in hepatocellular carcinoma was examined.ResultsCezanne reduction in HCC was significantly associated with larger tumor, satellite nodule, vascular invasion, TNM stage, BCLC stage and early recurrence. Kaplan-Meier analysis showed that Cezanne was a great predictive factor for overall survival (OS) and time to recurrence (TTR). The expression of Cezanne was decreased in TNM and BCLC stage-dependent manner. In addition, Cezanne reduction was associated with poor prognosis in patients subgroups stratified by tumor size, tumor differentiation, TNM stage and BCLC stage. Moreover, Cezanne was negatively associated with MMP-9 among 230 HCC samples. Patients who had Cezanne downregulation, in which cancer cells showed high invasiveness, had shorter TTR and poor OS. Furthermore, the coindex of Cezanne and preoperative serum AFP levels was significantly correlated with OS and TTR.Conclusion Cezanne has a pivotal role in tumor progression and prognosis, and may act as a potential prognostic biomarker for survival in HCC patients.


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Mar 9, 2015