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Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis.

Zhang H, Ren Y, Tang X, Wang K, Liu Y, Zhang L, Li X, Liu P, Zhao C, He J - Sci Rep (2015)

Bottom Line: Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature.However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation.Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, P.R. China.

ABSTRACT
Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage.

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Modulation effect of SH on intratumoral angiogenic factors.(A) Representive pictures of angiogenesis antibody array (1: bFGF, 2: CSF3, 3: CSF2, 4: PF-4) from control and SH-treated group, quantified in B (signal intensity of each spot). N = 4. (C–F) Changes of secreted bFGF, PF-4, G-CSF and GM-CSF in tumor extracellular fluid were measured by ELISA assay. N = 5. (G–H) bFGF levels in cell lysate were measured by ELISA assay. N = 3. Statistical significance: P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***).
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f5: Modulation effect of SH on intratumoral angiogenic factors.(A) Representive pictures of angiogenesis antibody array (1: bFGF, 2: CSF3, 3: CSF2, 4: PF-4) from control and SH-treated group, quantified in B (signal intensity of each spot). N = 4. (C–F) Changes of secreted bFGF, PF-4, G-CSF and GM-CSF in tumor extracellular fluid were measured by ELISA assay. N = 5. (G–H) bFGF levels in cell lysate were measured by ELISA assay. N = 3. Statistical significance: P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***).

Mentions: To uncover the mechanism through which SH induces vessel normalization, expression of a set of proteins known to regulate angiogenesis, inflammation and apoptosis was analyzed using an antibody array on whole-protein extracts of tumors. Of all 24 candidates analyzed, levels of granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), granulocyte colony-stimulating factor (G-CSF, CSF3) and platelet factor-4 (PF-4) were increased 1.9-fold, 3.9-fold and 6.4-fold respectively by SH treatment, while expression of one of the most important pro-angiogenic factors, basic fibroblast growth factor (bFGF), was decreased by 40% (Fig. 5A, B). We next examined the level of bFGF, PF-4, G-CSF and GM-CSF in tumor extracellular fluid in different dose groups to verify the results. bFGF was downregulated in several doses (Fig. 5C) while PF-4 was upregulated (Fig. 5D). Interestingly the level of secreted GM-CSF and G-CSF was unaffected in 100 mg/kg group, but was significantly influenced in 200 mg/kg group (Fig. 5E, F). Change of G-CSF in serum was not significant (Fig. S4A, B) and GM-CSF was undetectable in serum. To further determine the SH-dependent source of bFGF in tumors, we analyzed its expressions in tumor cells and HUVECs when treated with SH. bFGF levels were decreased in both 4T1 and 168FARN cells (Fig. 5G, H) while bFGF in HUVEC is very low and almost unaffected by SH treatment (Fig. S4C). Altogether, these data indicated that SH could modulate intratumoral angiogenic factor levels.


Vascular normalization induced by sinomenine hydrochloride results in suppressed mammary tumor growth and metastasis.

Zhang H, Ren Y, Tang X, Wang K, Liu Y, Zhang L, Li X, Liu P, Zhao C, He J - Sci Rep (2015)

Modulation effect of SH on intratumoral angiogenic factors.(A) Representive pictures of angiogenesis antibody array (1: bFGF, 2: CSF3, 3: CSF2, 4: PF-4) from control and SH-treated group, quantified in B (signal intensity of each spot). N = 4. (C–F) Changes of secreted bFGF, PF-4, G-CSF and GM-CSF in tumor extracellular fluid were measured by ELISA assay. N = 5. (G–H) bFGF levels in cell lysate were measured by ELISA assay. N = 3. Statistical significance: P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4352869&req=5

f5: Modulation effect of SH on intratumoral angiogenic factors.(A) Representive pictures of angiogenesis antibody array (1: bFGF, 2: CSF3, 3: CSF2, 4: PF-4) from control and SH-treated group, quantified in B (signal intensity of each spot). N = 4. (C–F) Changes of secreted bFGF, PF-4, G-CSF and GM-CSF in tumor extracellular fluid were measured by ELISA assay. N = 5. (G–H) bFGF levels in cell lysate were measured by ELISA assay. N = 3. Statistical significance: P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***).
Mentions: To uncover the mechanism through which SH induces vessel normalization, expression of a set of proteins known to regulate angiogenesis, inflammation and apoptosis was analyzed using an antibody array on whole-protein extracts of tumors. Of all 24 candidates analyzed, levels of granulocyte-macrophage colony-stimulating factor (GM-CSF, CSF2), granulocyte colony-stimulating factor (G-CSF, CSF3) and platelet factor-4 (PF-4) were increased 1.9-fold, 3.9-fold and 6.4-fold respectively by SH treatment, while expression of one of the most important pro-angiogenic factors, basic fibroblast growth factor (bFGF), was decreased by 40% (Fig. 5A, B). We next examined the level of bFGF, PF-4, G-CSF and GM-CSF in tumor extracellular fluid in different dose groups to verify the results. bFGF was downregulated in several doses (Fig. 5C) while PF-4 was upregulated (Fig. 5D). Interestingly the level of secreted GM-CSF and G-CSF was unaffected in 100 mg/kg group, but was significantly influenced in 200 mg/kg group (Fig. 5E, F). Change of G-CSF in serum was not significant (Fig. S4A, B) and GM-CSF was undetectable in serum. To further determine the SH-dependent source of bFGF in tumors, we analyzed its expressions in tumor cells and HUVECs when treated with SH. bFGF levels were decreased in both 4T1 and 168FARN cells (Fig. 5G, H) while bFGF in HUVEC is very low and almost unaffected by SH treatment (Fig. S4C). Altogether, these data indicated that SH could modulate intratumoral angiogenic factor levels.

Bottom Line: Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature.However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation.Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, P.R. China.

ABSTRACT
Solid tumor vasculature is characterized by structural and functional abnormality and results in a hostile tumor microenvironment that mediates several deleterious aspects of tumor behavior. Sinomenine is an alkaloid extracted from the Chinese medicinal plant, Sinomenium acutum, which has been utilized to treat rheumatism in China for over 2000 years. Though sinomenine has been demonstrated to mediate a wide range of pharmacological actions, few studies have focused on its effect on tumor vasculature. We showed here that intraperitoneally administration of 100 mg/kg sinomenine hydrochloride (SH, the hydrochloride chemical form of sinomenine) in two orthotopic mouse breast cancer models for 14 days, delayed mammary tumor growth and decreased metastasis by inducing vascular maturity and enhancing tumor perfusion, while improving chemotherapy and tumor immunity. The effects of SH on tumor vessels were caused in part by its capability to restore the balance between pro-angiogenic factor (bFGF) and anti-angiogenic factor (PF4). However 200 mg/kg SH didn't exhibit the similar inhibitory effect on tumor progression due to the immunosuppressive microenvironment caused by excessive vessel pruning, G-CSF upregulation, and GM-CSF downregulation. Altogether, our findings suggest that SH induced vasculature normalization contributes to its anti-tumor and anti-metastasis effect on breast cancer at certain dosage.

Show MeSH
Related in: MedlinePlus