Abstract
The objective of this study was to evaluate the cytotoxicity of (+)-cyanidan-3-ol (CD-3) in human hepatocellular carcinoma cell line (HepG2) and chemopreventive potential against hepatocellular carcinoma (HCC) in Balb/c mice. The HepG2 cell line was treated with CD-3 at various concentrations and the proliferation of the HepG2 cells was measure by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT), sulforhodamine B (SRB) and lactate dehydrogenase (LDH) assays. Cell apoptosis was detected by Hoechst 33258 (HO), Acridine orange/ethylene dibromide (AO/EB) staining, DNA fragmentation analysis and the apoptosis rate was detected by flow cytometry. The HCC tumor model was established in mice by injecting N-nitrosodiethylamine/carbon tetrachloride (NDEA/CCl4) and the effect of CD-3 on tumor growth in-vivo was studied. The levels of liver injury markers, tumor markers, and oxidative stress were measured. The expression levels of apoptosis-related genes in in-vitro and in vivo models were determined by RT-PCR and ELISA. The CD-3 induced cell death was considered to be apoptotic by observing the typical apoptotic morphological changes under fluorescent microscopy and DNA fragmentation analysis. Annexin V/PI assay demonstrated that apoptosis increased with increase in the concentration of CD-3. The expression levels of apoptosis-related genes that belong to bcl-2 and caspase family were increased and AP-1 and NF-κB activities were significantly suppressed by CD-3. Immunohistochemistry data revealed less localization of p53, p65 and c-jun in CD-3 treated tumors as compared to localization in NDEA/CCl4 treated tumors. Taken together, our data demonstrated that CD-3 could significantly inhibit the proliferation of HepG2 cells in-vitro and suppress HCC tumor growth in-vivo by apoptosis induction.
Highlights
Hepatocellular carcinoma (HCC) is one of the most frequent tumors representing the fifth commonest malignancy worldwide and the third cause of mortality from cancer
Apoptosis is a genetically programmed cell death mechanism that can be activated by various stimuli, including the activation of specific pro-apoptotic receptors, and cellular stress or injury caused by loss of growth factor signals, heat shock, irradiation, cytotoxic drugs, bacteria, and viruses
This is the first report on the apoptosis induction and chemopreventive effect of CD-3 in hepatocellular carcinoma (HCC)
Summary
Hepatocellular carcinoma (HCC) is one of the most frequent tumors representing the fifth commonest malignancy worldwide and the third cause of mortality from cancer. The number of natural products has acquired a lot of attention because of their ability to provide prevention and therapeutic efficacy against number of cancers [3]. Out of number of different classes of natural products, flavonoids represent a diverse group of low molecular weight polyphenolic compounds that are widely distributed in nature and renewed interest has been observed in recent years in the novel and multiple activities of flavonoids [4]. (Fabaceae) known as ‘Khadira’ has been extensively used as traditional medicine in India/Asia over a long period of time and a rich source of number of polyphenolic compounds. We have reported chemopreventive effect of aqueous extract of Acacia catechu in skin and mammary cancer rodent models [5,6].
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