Tumor suppression effects of bilberry extracts and enzymatically modified isoquercitrin in early preneoplastic liver cell lesions induced by piperonyl butoxide promotion in a two-stage rat hepatocarcinogenesis model.

Abstract

To investigate the protective effect of bilberry extracts (BBE) and enzymatically modified isoquercitrin (EMIQ) on the hepatocarcinogenic process involving oxidative stress responses, we used a two-stage hepatocarcinogenesis model in N-diethylnitrosamine-initiated and piperonyl butoxide (PBO)-promoted rats. We examined the modifying effect of co-administration with BBE or EMIQ on the liver tissue environment including oxidative stress responses, cell proliferation and apoptosis, and phosphatase and tensin homolog (PTEN)/Akt and transforming growth factor (TGF)-β/Smad signalings on the induction mechanism of preneoplastic lesions during early stages of hepatocellular tumor promotion. PBO increased the numbers and area of glutathione S-transferase placental form (GST-P)(+) liver cell foci and the numbers of Ki-67(+) proliferating cells within GST-P(+) foci. Co-administration of BBE or EMIQ suppressed these effects with the reductions of GST-P(+) foci (area) to 48.9-49.4% and Ki-67(+) cells to 55.5-61.4% of the PBO-promoted cases. Neither BBE nor EMIQ decreased microsomal reactive oxygen species induced by PBO. However, only EMIQ suppressed the level of thiobarbituric acid-reactive substances to 78.4% of the PBO-promoted cases. PBO increased the incidences of phospho-PTEN(-) foci, phospho-Akt substrate(+) foci, phospho-Smad3(-) foci and Smad4(-) foci in GST-P(+) foci. Both BBE and EMIQ decreased the incidences of phospho-PTEN(-) foci in GST-P(+) foci to 59.8-72.2% and Smad4(-) foci to 62.4-71.5% of the PBO-promoted cases, and BBE also suppressed the incidence of phospho-Akt substrate(+) foci in GST-P(+) foci to 75.2-75.7% of the PBO-promoted cases. These results suggest that PBO-induced tumor promotion involves facilitation of PTEN/Akt and disruptive TGF-β/Smad signalings without relation to oxidative stress responses, but this promotion was suppressed by co-treatment with BBE or EMIQ through suppression of cell proliferation activity of preneoplastic liver cells.

• Authors: Shintaro Hara, Reiko Morita, Takashi Ogawa, Risa Segawa, Norifumi Takimoto, Kazuhiko Suzuki, Naobumi Hamadate, Shim-Mo Hayashi, Ayano Odachi, Isao Ogiwara, Sakae Shibusawa, Toshinori Yoshida, Makoto Shibutani
• Journal: Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie (Exp Toxicol Pathol) Vol. 66 Issue 5-6 Pg. 225-34 (Aug 2014) ISSN: 1618-1433 [Electronic] Germany
• PMID: 24680176 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier GmbH. All rights reserved.

Chemical References

• Anticarcinogenic Agents
• Plant Extracts
• isoquercitrin
• Diethylnitrosamine
• Quercetin
• Piperonyl Butoxide

Topics

• Animals
• Anticarcinogenic Agents (administration & dosage, therapeutic use)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Cocarcinogenesis
• Diethylnitrosamine (toxicity)
• Glycosylation
• Liver Neoplasms, Experimental (chemically induced, metabolism, pathology, prevention & control)
• Male
• Oxidative Stress (drug effects)
• Piperonyl Butoxide (toxicity)
• Plant Extracts (administration & dosage, isolation & purification, therapeutic use)
• Precancerous Conditions (chemically induced, metabolism, pathology, prevention & control)
• Quercetin (administration & dosage, analogs & derivatives, isolation & purification, therapeutic use)
• Rats, Inbred F344
• Vaccinium myrtillus (chemistry)