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There is a correlation between oxidative stress generated by diethylnitrosamine (DEN) metabolism and liver cancer development. Quercetin is a flavonoid with anti-carcinogenic and antioxidant properties. This study demonstrates the mechanism of action for the chemopreventive effect of quercetin. A 10 mg/kg dose of quercetin produced drastic effect, when it is administrated 2 h before DEN; at 24 days post-DEN, a 70.3% and 66.2% decrease in total area and number of preneoplastic lesions were observed, respectively. At 12 h post-DEN, quercetin inhibited levels of lipid peroxidation by 40%. Quercetin increased the levels of both GSH and of total glutathione, it increased the GSH/GSSG index and it caused a rapid and simultaneous elevation in the activities of superoxide dismutase, glutathione peroxidase and catalase. In conclusion, the quercetin mechanism of action is due to promote the enzymatic and non-enzymatic antioxidant defense system during the initiation of hepatocarcinogenesis.

Caffeic acid phenethyl ester (CAPE), a natural honeybee product exhibits a spectrum of biological activities including anti-microbial, anti-inflammatory, antioxidant and anti-tumoral actions. CAPE is also chemopreventive against intestinal, colon and skin cancer. Our aim was to extend the study of its chemoprotective features to the promotion of hepatocarcinogenesis. Male Wistar rats were subjected to a protocol under a modified promotion regimen of the resistant hepatocyte model. The altered hepatic foci (AHF) were quantitatively analyzed by histochemistry and image processing. When given during promotion, CAPE (20 mg/kg) decreased the expression of number and area ␥-glutamyl transpeptidase (GGT) positive AHF by 91% and 97%, respectively. When GGT expression was analyzed by RT-PCR, CAPE drastically decreased and prevented expression of almost all GGT transcripts at this stage of the carcinogenic process. Glutathione S-transferase placental form (GST-P), another protein marker for preneoplastic lesions was measured by Western blot and a decrease of 82% was observed. Additionally, we evaluated the effect of CAPE on the expression of nuclear factor NF-B and found an 85% decrease in nuclear localization of the p65 subunit of NF-B; however, their repressor, I B␣ was not modified. Our results showed that CAPE given during promotion in hepatocarcinogenesis protects against induction of GGT-positive AHF, GST-P protein, GGT mRNA expression and translocation of p65. This phenomenon was independent of I B␣ degradation.

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Carcinogenic process has been proposed to relay on the capacity to induce local tissue damage and proliferative repair. Liver has a great regeneration capacity and currently, most studies point towards the dominant role of hepatocytes in regeneration at all levels of liver damage. The most frequent liver cancer is hepatocellular carcinoma (HCC). Historical findings originally led to the idea that the cell of origin of HCC might be a progenitor cell. However, current linage tracing studies put the progenitor hypothesis of HCC origin into question. In agreement with their dominant role in liver regeneration, mature hepatocytes are emerging as the cell of origin of HCC, although, the specific hepatocyte subpopulation of origin is yet to be determined. The relationship between the cancer cell of origin (CCO) and cancer-propagating cells, known as hepatic cancer stem cell (HCSC) is unknown. It has been challenging to identify the definitive phenotypic marker of HCSC, probably due to the existence of different cancer stem cells (CSC) subpopulations with different functions within HCC. There is a dynamic interconversion among different CSCs, and between CSC and non-CSCs. Because of that, CSC-state is currently defined as a description of a highly adaptable and dynamic intrinsic property of tumor cells, instead of a static subpopulation of a tumor. Altered conditions could trigger the gain of stemness, some of them include: EMT-MET, epigenetics, microenvironment and selective stimulus such as chemotherapy. This CSC heterogeneity and dynamism makes them out reach from therapeutic protocols directed to a single target. A further avenue of research in this line will be to uncover mechanisms that trigger this interconversion of cell populations within tumors and target it.

The inflammatory condition of malignant tumors continually exposes cancer cells to reactive oxygen species, an oxidizing condition that leads to the activation of the antioxidant defense system. A similar activation occurs with glutathione production. This oxidant condition enables tumor cells to maintain the energy required for growth, proliferation, and evasion of cell death. The objective of the present study was to determine the effect on hepatocellular carcinoma cells of a combination treatment with maleic anhydride derivatives (prooxidants) and quercetin (an antioxidant). The results show that the combination of a prooxidant/antioxidant had a cytotoxic effect on HuH7 and HepG2 liver cancer cells, but not on either of two normal human epithelial cell lines or on primary hepatocytes. The combination treatment triggered apoptosis in hepatocellular carcinoma cells by activating the intrinsic pathway and causing S phase arrest during cell cycle progression. There is also clear evidence of a modification in cytoskeletal actin and nucleus morphology at 24 and 48 h posttreatment. Thus, the current data suggest that the combination of two anticarcinogenic drugs, a prooxidant followed by an antioxidant, can be further explored for antitumor potential as a new treatment strategy.

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