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The anti-tumor properties of two tumstatin peptide fragments in human gastric carcinoma.

Li YJ, Sun LC, He Y, Liu XH, Liu M, Wang QM, Jin XM - Acta Pharmacol. Sin. (2009)

Bottom Line: Each peptide arrested both cell lines at the G(0)/G(1) phase of the cell cycle, and they also synergistically suppressed in vitro and in vivo tumor growth.Decreased expressions of VEGF and bFGF and decreased microvessel density (MVD) in orthotopic tumor tissues were seen in mice treated with peptide 21 alone or in combination with peptide 19.Two tumstatin peptide fragments facilitate two unique antitumor activities.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Second Hospital of Harbin Medical University, Harbin, China.

ABSTRACT

Aim: The aim was to study the anti-tumor activities and mechanisms of two synthetic peptide fragments of tumstatin (alpha3 (IV) NC1 domain) in human gastric carcinoma cells in vitro and in vivo.

Methods: MTT assay and cell cycle assay were used to study the anti-tumor and anti-angiogenic activities of two peptide fragments in vitro. Apoptosis induced by the two peptide fragments was demonstrated by TUNEL assay and morphological observation. The orthotopic tumor model was established to investigate the activities of two peptide fragments in vivo. Intratumor vascularization and the expressions of VEGF, bFGF, Fas, FasL, Bax, Bcl-2, and caspase 3 were determined using immunohistochemistry and Western blot analysis.

Results: Peptide 19 inhibited SGC-7901 proliferation and induced apoptosis both in vitro and in vivo. Notably, peptide 21 suppressed the proliferation of HUVEC-12 cells in vitro. Each peptide arrested both cell lines at the G(0)/G(1) phase of the cell cycle, and they also synergistically suppressed in vitro and in vivo tumor growth. Immunohistochemistry and Western blot analysis revealed the strong expression of Fas, FasL and caspase 3 in orthotopic tumor tissues treated with peptide 19 alone or in combination with peptide 21. Decreased expressions of VEGF and bFGF and decreased microvessel density (MVD) in orthotopic tumor tissues were seen in mice treated with peptide 21 alone or in combination with peptide 19.

Conclusion: Two tumstatin peptide fragments facilitate two unique antitumor activities. Thus, they are drug candidates in the treatment of gastric carcinoma.

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Related in: MedlinePlus

Immunohistochemical expression of Fas; FasL; caspase3; Bcl-2; Bax; VEGF and bFGF in orthotopic gastric carcinoma samples or orthotopic gastric carcinoma treated with peptide 19 and peptide 21. Plasma or membrane staining was frequently observed in tumour cells treated with peptide 19 (A, B, C, D, and E; Fas; FasL; caspase 3; Bcl-2 and Bax, respectively A×400, B×400, C×200, D×400, and E×200). Absent expression of bFGF (F×200) or VEGF (G×200) was observed in tumour cells treated with peptide 21. Expression of bFGF (H×200) and VEGF (I×400) were high in orthotopic gastric carcinoma samples without treatment.
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fig6: Immunohistochemical expression of Fas; FasL; caspase3; Bcl-2; Bax; VEGF and bFGF in orthotopic gastric carcinoma samples or orthotopic gastric carcinoma treated with peptide 19 and peptide 21. Plasma or membrane staining was frequently observed in tumour cells treated with peptide 19 (A, B, C, D, and E; Fas; FasL; caspase 3; Bcl-2 and Bax, respectively A×400, B×400, C×200, D×400, and E×200). Absent expression of bFGF (F×200) or VEGF (G×200) was observed in tumour cells treated with peptide 21. Expression of bFGF (H×200) and VEGF (I×400) were high in orthotopic gastric carcinoma samples without treatment.

Mentions: 26.67%, 13.33%, and 6.67% tumors were positive for Fas, FasL, and caspase 3 in the mouse gastric cancer tissues treated with control peptide. However, 30 days after treatment with peptide 19 or the two peptides together, the expression levels of all three proteins increased in the gastric cancer tissues of mice (Figure 6A–6C). The expression of Fas, FasL, and caspase 3 remained low in animals treated with peptide 21. The expression of Bcl-2 and Bax was similar in the three treated groups and the control peptide group (Figure 6D, 6E). The expression of VEGF and bFGF was high in the control peptide group and the peptide 19 group (Figure 6H, 6I). Treatment with peptide 21 (Figure 6F, 6G) or with the two peptides together decreased the expression of VEGF and bFGF in gastric cancer tissues (Table 4). We further confirmed these findings by Western blot analysis. The data showed that the expression levels of Fas, FasL, and caspase3 were increased in mouse gastric cancer tissues treated with peptide 19 or peptide 19 and peptide 21, whereas the expression of Bcl-2 and Bax was similar in the three treated groups and the control peptide group (Figure 7).


The anti-tumor properties of two tumstatin peptide fragments in human gastric carcinoma.

Li YJ, Sun LC, He Y, Liu XH, Liu M, Wang QM, Jin XM - Acta Pharmacol. Sin. (2009)

Immunohistochemical expression of Fas; FasL; caspase3; Bcl-2; Bax; VEGF and bFGF in orthotopic gastric carcinoma samples or orthotopic gastric carcinoma treated with peptide 19 and peptide 21. Plasma or membrane staining was frequently observed in tumour cells treated with peptide 19 (A, B, C, D, and E; Fas; FasL; caspase 3; Bcl-2 and Bax, respectively A×400, B×400, C×200, D×400, and E×200). Absent expression of bFGF (F×200) or VEGF (G×200) was observed in tumour cells treated with peptide 21. Expression of bFGF (H×200) and VEGF (I×400) were high in orthotopic gastric carcinoma samples without treatment.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4007175&req=5

fig6: Immunohistochemical expression of Fas; FasL; caspase3; Bcl-2; Bax; VEGF and bFGF in orthotopic gastric carcinoma samples or orthotopic gastric carcinoma treated with peptide 19 and peptide 21. Plasma or membrane staining was frequently observed in tumour cells treated with peptide 19 (A, B, C, D, and E; Fas; FasL; caspase 3; Bcl-2 and Bax, respectively A×400, B×400, C×200, D×400, and E×200). Absent expression of bFGF (F×200) or VEGF (G×200) was observed in tumour cells treated with peptide 21. Expression of bFGF (H×200) and VEGF (I×400) were high in orthotopic gastric carcinoma samples without treatment.
Mentions: 26.67%, 13.33%, and 6.67% tumors were positive for Fas, FasL, and caspase 3 in the mouse gastric cancer tissues treated with control peptide. However, 30 days after treatment with peptide 19 or the two peptides together, the expression levels of all three proteins increased in the gastric cancer tissues of mice (Figure 6A–6C). The expression of Fas, FasL, and caspase 3 remained low in animals treated with peptide 21. The expression of Bcl-2 and Bax was similar in the three treated groups and the control peptide group (Figure 6D, 6E). The expression of VEGF and bFGF was high in the control peptide group and the peptide 19 group (Figure 6H, 6I). Treatment with peptide 21 (Figure 6F, 6G) or with the two peptides together decreased the expression of VEGF and bFGF in gastric cancer tissues (Table 4). We further confirmed these findings by Western blot analysis. The data showed that the expression levels of Fas, FasL, and caspase3 were increased in mouse gastric cancer tissues treated with peptide 19 or peptide 19 and peptide 21, whereas the expression of Bcl-2 and Bax was similar in the three treated groups and the control peptide group (Figure 7).

Bottom Line: Each peptide arrested both cell lines at the G(0)/G(1) phase of the cell cycle, and they also synergistically suppressed in vitro and in vivo tumor growth.Decreased expressions of VEGF and bFGF and decreased microvessel density (MVD) in orthotopic tumor tissues were seen in mice treated with peptide 21 alone or in combination with peptide 19.Two tumstatin peptide fragments facilitate two unique antitumor activities.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Second Hospital of Harbin Medical University, Harbin, China.

ABSTRACT

Aim: The aim was to study the anti-tumor activities and mechanisms of two synthetic peptide fragments of tumstatin (alpha3 (IV) NC1 domain) in human gastric carcinoma cells in vitro and in vivo.

Methods: MTT assay and cell cycle assay were used to study the anti-tumor and anti-angiogenic activities of two peptide fragments in vitro. Apoptosis induced by the two peptide fragments was demonstrated by TUNEL assay and morphological observation. The orthotopic tumor model was established to investigate the activities of two peptide fragments in vivo. Intratumor vascularization and the expressions of VEGF, bFGF, Fas, FasL, Bax, Bcl-2, and caspase 3 were determined using immunohistochemistry and Western blot analysis.

Results: Peptide 19 inhibited SGC-7901 proliferation and induced apoptosis both in vitro and in vivo. Notably, peptide 21 suppressed the proliferation of HUVEC-12 cells in vitro. Each peptide arrested both cell lines at the G(0)/G(1) phase of the cell cycle, and they also synergistically suppressed in vitro and in vivo tumor growth. Immunohistochemistry and Western blot analysis revealed the strong expression of Fas, FasL and caspase 3 in orthotopic tumor tissues treated with peptide 19 alone or in combination with peptide 21. Decreased expressions of VEGF and bFGF and decreased microvessel density (MVD) in orthotopic tumor tissues were seen in mice treated with peptide 21 alone or in combination with peptide 19.

Conclusion: Two tumstatin peptide fragments facilitate two unique antitumor activities. Thus, they are drug candidates in the treatment of gastric carcinoma.

Show MeSH
Related in: MedlinePlus