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: 3.26). 02/2009; 184(3):204-10. DOI: 10.1016/j.toxlet.2008.11.018
Source: PubMed


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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Available from: Chia-Chou Yeh, Mar 09, 2015
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    • "Ling (Mu-Xiang) and other herbs, inhibits cell invasion, migration and adhesion in HCC cells[107]. Hesperidin, a compound can be found in Citrus reticulata Blanco (Chen-Pi) and other herbs, has reported efficacy in inhibiting acetaldehyde-induced MMP-9 expression and cell invasion in HCC cells[108](Table 2). In addition to single compound, multiple herbal ingredients can be combined and used as a formula. "
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    ABSTRACT: Traditional Chinese Medicines, unique biomedical and pharmaceutical resources, have been widely used for hepatocellular carcinoma (HCC) prevention and treatment. Accumulated Chinese herb-derived compounds with significant anti-cancer effects against HCC have been identified. Chinese herbal compounds are effective in preventing carcinogenesis, inhibiting cell proliferation, arresting cell cycle, inducing apoptosis, autophagy, cell senescence and anoikis, inhibiting epithelial-mesenchymal transition, metastasis and angiogenesis, regulating immune function, reversing drug resistance and enhancing the effects of chemotherapy in HCC. This paper comprehensively reviews these compounds and their effects on HCC. Finally, the perspectives and rational application of herbal compounds for HCC management are discussed.
    Preview · Article · Jan 2016 · Molecules
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    • "Hesperidin is one of the most common flavonoids present in Citrus fruits and has been reported to possess anticancer effects on malignant cancer cells such as breast cancer and prostate cancer (Lee, et al., 2010a), colon cancer cells (Park, et al., 2008) and inhibits tumor invasiveness of hepatocellular carcinoma (Lee, et al., 2010b, Yeh, et al., 2009). And recently, we have showed that hesperidin induce paraptosis in HepG2 cells (Yumnam, et al., 2014). "
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    ABSTRACT: Paraptosis is a programmed cell death which is morphologically and biochemically different from apoptosis. In this study, we have investigated the role of Ca(2+) in hesperidin-induced paraptotic cell death in HepG2 cells. Increase in mitochondrial Ca(2+) level was observed in hesperidin treated HepG2 cells but not in normal liver cancer cells. Inhibition of inositol-1,4,5-triphosphate receptor (IP3 ) and ryanodine receptor also block the mitochondrial Ca(2+) accumulation suggesting that the release of Ca(2+) from the endoplasmic reticulum (ER) may probably lead to the increase in mitochondrial Ca(2+) level. Pretreatment with ruthenium red (RuRed), a Ca(2+) uniporter inhibitor inhibited the hesperidin-induced mitochondrial Ca(2+) overload, swelling of mitochondria and cell death in HepG2 cells. It has also been demonstrated that mitochondrial Ca(2+) influxes act upstream of ROS and mitochondrial superoxide production. The increased ROS production further leads to mitochondrial membrane loss in hesperidin treated HepG2 cells. Taken together our results show that IP3 R and ryanodine receptor mediated release of Ca(2+) from the ER and its subsequent influx through the uniporter into mitochondria contributes to hesperidin-induced paraptosis in HepG2 cells. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · Journal of Cellular Physiology
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    • "In addition, Hsd (50 μM) inhibited acetaldehyde-induced activation of IκB (the principal pathway of NF-κB activation), p38 and JNK (MAP kinase signaling manages the AP-1 activity) phosphorylation, dosedependently . Overall, Hsd was able to suppress MMP-9 transcription, secretion and activity in HepG2 cells, diminishing cellular invasiveness [88]. To have a better perspective of the cellular targets of Hsd/Hst in cancer, the mechanisms discussed in this part including cancer chemoprevention through increasing the antioxidant defense system, inducing apoptosis in cancerous cells, the inhibition of inflammation via decreasing inflammatory cytokines and enzymes, and the inhibition of angiogenesis and metastasis are summarized in Fig. 2. "
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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.
    Full-text · Article · Jan 2015 · Life Sciences
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