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Chemopreventive effects of berberine on intestinal tumor development in Apcmin/+ mice.

Cao H, Song S, Zhang H, Zhang Y, Qu R, Yang B, Jing Y, Hu T, Yan F, Wang B - BMC Gastroenterol (2013)

Bottom Line: The prostaglandin E2 level in the small intestine was detected using ELISA.Furthermore, berberine decreased the activation levels of Wnt and EGFR signaling pathways, and down-regulated COX-2 expression in intestinal tumor cells and prostaglandin E2 production in the small intestine.Down-regulation of Wnt and EGFR signaling pathways and COX-2 expression by berberine may be involved in its anti-tumorigenic effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, 154 Anshan Road in Heping District, Tianjin 300052, China. gi.tmuh@yeah.net.

ABSTRACT

Background: Berberine, an isoquinoline alkaloid, has shown inhibitory effects on growth of several tumor cell lines in vitro. The aim of this study was to investigate chemopreventive effects of berberine on intestinal tumor development in Apcmin/+ mice.

Methods: Four-week old Apcmin/+ mice were treated with 0.05% or 0.1% berberine in drinking water for twelve weeks. The number and the size of tumors were measured to evaluate intestinal tumor development. Tissue sections were prepared for PCNA and Ki-67 immunostaining to detect cell proliferation, and TUNEL assay and cleaved caspase-3 immunostaining for apoptosis. Western blot analysis and immunostaining were performed to detect the activation of Wnt and epidermal growth factor receptor (EGFR) signaling pathways and COX-2 expression in the intestinal tumor cells. The prostaglandin E2 level in the small intestine was detected using ELISA.

Results: Compared with untreated Apcmin/+ mice, the total numbers of tumors in the small intestine and the colon were reduced by 39.6% and 62.5% in 0.05% and 0.1% berberine-treated mice, respectively. The numbers of tumors in proximal, middle, and distal segments of the small intestine in 0.1% berberine-treated mice were significantly reduced by 53.7%, 55.3%, and 76.5% respectively. Berberine treatment also decreased the numbers of all sizes of tumors (>2 mm, 1-2 mm, and <1 mm) in the small intestine. Berberine suppressed tumor cell proliferation and increased apoptosis. Furthermore, berberine decreased the activation levels of Wnt and EGFR signaling pathways, and down-regulated COX-2 expression in intestinal tumor cells and prostaglandin E2 production in the small intestine.

Conclusions: Berberine inhibits intestinal tumor development, which is correlated with its activity to suppress tumor cell proliferation and increase apoptosis in Apcmin/+ mice. Down-regulation of Wnt and EGFR signaling pathways and COX-2 expression by berberine may be involved in its anti-tumorigenic effects.

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Berberine inhibits intestinal tumor development in Apcmin/+ mice. (A)Apcmin/+ mice (age, 4 weeks) were treated with berberine, and sacrificed after 12 weeks. The representative gross appearance of the intestinal tumors from untreated and 0.1% berberine-treated Apcmin/+ mice was shown under an Olympus SZX7 stereo dissecting microscope. (B) The number of tumors/mouse in the small intestine and colon in 0.05% and 0.1% berberine-treated groups were compared with the untreated Apcmin/+ mice. (C-D) Tumor numbers in each section of the small intestine, and size distribution in each group were also listed. Columns, mean from the ten mice in each group; bars, standard deviation. *, P < 0.01 and #, P < 0.05, 0.05% berberine-treated vs untreated Apcmin/+ mice; $, P < 0.01 and ※, P < 0.05, 0.1% berberine-treated vs untreated Apcmin/+ mice; &, P < 0.01 and §, P < 0.05, 0.1% berberine vs 0.05% berberine-treated Apcmin/+ mice.
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Figure 1: Berberine inhibits intestinal tumor development in Apcmin/+ mice. (A)Apcmin/+ mice (age, 4 weeks) were treated with berberine, and sacrificed after 12 weeks. The representative gross appearance of the intestinal tumors from untreated and 0.1% berberine-treated Apcmin/+ mice was shown under an Olympus SZX7 stereo dissecting microscope. (B) The number of tumors/mouse in the small intestine and colon in 0.05% and 0.1% berberine-treated groups were compared with the untreated Apcmin/+ mice. (C-D) Tumor numbers in each section of the small intestine, and size distribution in each group were also listed. Columns, mean from the ten mice in each group; bars, standard deviation. *, P < 0.01 and #, P < 0.05, 0.05% berberine-treated vs untreated Apcmin/+ mice; $, P < 0.01 and ※, P < 0.05, 0.1% berberine-treated vs untreated Apcmin/+ mice; &, P < 0.01 and §, P < 0.05, 0.1% berberine vs 0.05% berberine-treated Apcmin/+ mice.

Mentions: We first evaluated tumor development in 16-week old Apcmin/+ mice with or without 12-week berberine treatment. Berberine significantly reduced the multiplicity of intestinal tumor in Apcmin/+ mice in a dose-dependent manner (Table 1, Figure 1). Compared with the total number of tumor in the small intestine and the colon in untreated Apcmin/+ mice (30.63 ± 1.69), 0.05% and 0.1% berberine treatment significantly decreased the number of tumor by 39.6% (18.50 ± 1.51, P < 0.01), and 62.5% (11.50 ± 2.05, P < 0.01, Figure 1B), respectively. Berberine reduced 62.0% and 31.2% of the number of colon tumor in 0.05% and 0.1% treatment groups (Figure 1B). In addition, tumor numbers in proximal, middle, and distal portions of the small intestine in 0.1% berberine-treated group were reduced by 53.7%, 55.3%, and 76.5%, respectively, while those in 0.05% group were reduced by 37.4%, 41.5%, and 42.0%, respectively. The numbers of all sizes of tumors (>2 mm, 1–2 mm, and <1 mm) in the small intestine were significantly reduced (Figure 1D). Adenomas with or without low-grade dysplasia were found in the small intestine and colon in untreated and berberine-treated Apcmin/+ mice, and we did not find the difference regarding tumor stage in these two groups (data not shown).


Chemopreventive effects of berberine on intestinal tumor development in Apcmin/+ mice.

Cao H, Song S, Zhang H, Zhang Y, Qu R, Yang B, Jing Y, Hu T, Yan F, Wang B - BMC Gastroenterol (2013)

Berberine inhibits intestinal tumor development in Apcmin/+ mice. (A)Apcmin/+ mice (age, 4 weeks) were treated with berberine, and sacrificed after 12 weeks. The representative gross appearance of the intestinal tumors from untreated and 0.1% berberine-treated Apcmin/+ mice was shown under an Olympus SZX7 stereo dissecting microscope. (B) The number of tumors/mouse in the small intestine and colon in 0.05% and 0.1% berberine-treated groups were compared with the untreated Apcmin/+ mice. (C-D) Tumor numbers in each section of the small intestine, and size distribution in each group were also listed. Columns, mean from the ten mice in each group; bars, standard deviation. *, P < 0.01 and #, P < 0.05, 0.05% berberine-treated vs untreated Apcmin/+ mice; $, P < 0.01 and ※, P < 0.05, 0.1% berberine-treated vs untreated Apcmin/+ mice; &, P < 0.01 and §, P < 0.05, 0.1% berberine vs 0.05% berberine-treated Apcmin/+ mice.
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Figure 1: Berberine inhibits intestinal tumor development in Apcmin/+ mice. (A)Apcmin/+ mice (age, 4 weeks) were treated with berberine, and sacrificed after 12 weeks. The representative gross appearance of the intestinal tumors from untreated and 0.1% berberine-treated Apcmin/+ mice was shown under an Olympus SZX7 stereo dissecting microscope. (B) The number of tumors/mouse in the small intestine and colon in 0.05% and 0.1% berberine-treated groups were compared with the untreated Apcmin/+ mice. (C-D) Tumor numbers in each section of the small intestine, and size distribution in each group were also listed. Columns, mean from the ten mice in each group; bars, standard deviation. *, P < 0.01 and #, P < 0.05, 0.05% berberine-treated vs untreated Apcmin/+ mice; $, P < 0.01 and ※, P < 0.05, 0.1% berberine-treated vs untreated Apcmin/+ mice; &, P < 0.01 and §, P < 0.05, 0.1% berberine vs 0.05% berberine-treated Apcmin/+ mice.
Mentions: We first evaluated tumor development in 16-week old Apcmin/+ mice with or without 12-week berberine treatment. Berberine significantly reduced the multiplicity of intestinal tumor in Apcmin/+ mice in a dose-dependent manner (Table 1, Figure 1). Compared with the total number of tumor in the small intestine and the colon in untreated Apcmin/+ mice (30.63 ± 1.69), 0.05% and 0.1% berberine treatment significantly decreased the number of tumor by 39.6% (18.50 ± 1.51, P < 0.01), and 62.5% (11.50 ± 2.05, P < 0.01, Figure 1B), respectively. Berberine reduced 62.0% and 31.2% of the number of colon tumor in 0.05% and 0.1% treatment groups (Figure 1B). In addition, tumor numbers in proximal, middle, and distal portions of the small intestine in 0.1% berberine-treated group were reduced by 53.7%, 55.3%, and 76.5%, respectively, while those in 0.05% group were reduced by 37.4%, 41.5%, and 42.0%, respectively. The numbers of all sizes of tumors (>2 mm, 1–2 mm, and <1 mm) in the small intestine were significantly reduced (Figure 1D). Adenomas with or without low-grade dysplasia were found in the small intestine and colon in untreated and berberine-treated Apcmin/+ mice, and we did not find the difference regarding tumor stage in these two groups (data not shown).

Bottom Line: The prostaglandin E2 level in the small intestine was detected using ELISA.Furthermore, berberine decreased the activation levels of Wnt and EGFR signaling pathways, and down-regulated COX-2 expression in intestinal tumor cells and prostaglandin E2 production in the small intestine.Down-regulation of Wnt and EGFR signaling pathways and COX-2 expression by berberine may be involved in its anti-tumorigenic effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, 154 Anshan Road in Heping District, Tianjin 300052, China. gi.tmuh@yeah.net.

ABSTRACT

Background: Berberine, an isoquinoline alkaloid, has shown inhibitory effects on growth of several tumor cell lines in vitro. The aim of this study was to investigate chemopreventive effects of berberine on intestinal tumor development in Apcmin/+ mice.

Methods: Four-week old Apcmin/+ mice were treated with 0.05% or 0.1% berberine in drinking water for twelve weeks. The number and the size of tumors were measured to evaluate intestinal tumor development. Tissue sections were prepared for PCNA and Ki-67 immunostaining to detect cell proliferation, and TUNEL assay and cleaved caspase-3 immunostaining for apoptosis. Western blot analysis and immunostaining were performed to detect the activation of Wnt and epidermal growth factor receptor (EGFR) signaling pathways and COX-2 expression in the intestinal tumor cells. The prostaglandin E2 level in the small intestine was detected using ELISA.

Results: Compared with untreated Apcmin/+ mice, the total numbers of tumors in the small intestine and the colon were reduced by 39.6% and 62.5% in 0.05% and 0.1% berberine-treated mice, respectively. The numbers of tumors in proximal, middle, and distal segments of the small intestine in 0.1% berberine-treated mice were significantly reduced by 53.7%, 55.3%, and 76.5% respectively. Berberine treatment also decreased the numbers of all sizes of tumors (>2 mm, 1-2 mm, and <1 mm) in the small intestine. Berberine suppressed tumor cell proliferation and increased apoptosis. Furthermore, berberine decreased the activation levels of Wnt and EGFR signaling pathways, and down-regulated COX-2 expression in intestinal tumor cells and prostaglandin E2 production in the small intestine.

Conclusions: Berberine inhibits intestinal tumor development, which is correlated with its activity to suppress tumor cell proliferation and increase apoptosis in Apcmin/+ mice. Down-regulation of Wnt and EGFR signaling pathways and COX-2 expression by berberine may be involved in its anti-tumorigenic effects.

Show MeSH
Related in: MedlinePlus