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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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Effect of SH on primary tumor growth and spontaneous metastasis in vivo.(A) Primary tumor volumes were determined regularly in 4T1 tumor models. (B) Tumor burdens after 14-day treatment by different dose of SH were measured. (C) PCNA staining was carried out in control and SH-treated tumors. Bars: 100 μm; (D) proliferation index (PCNA+/total cells). (E) Tumor volumes of 168FARN tumor models were measured every 4 days. (F) Body weights throughout the treatment were determined in both models. (G) Visualized lung metastasis in 4T1 tumor models after resection (arrows: metastatic foci). Bars: 2.5 mm; HE staining of lung sections. Bars: 200 μm. (H) HE staining of liver sections showing tumor hepatic metastasis in 4T1 tumor models. Bars: 200 μm. (I, J) The number of metastatic foci was counted and metastatic index was determined as nodules per gram tumor. Statistical significance: P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***), N = 6.
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f2: Effect of SH on primary tumor growth and spontaneous metastasis in vivo.(A) Primary tumor volumes were determined regularly in 4T1 tumor models. (B) Tumor burdens after 14-day treatment by different dose of SH were measured. (C) PCNA staining was carried out in control and SH-treated tumors. Bars: 100 μm; (D) proliferation index (PCNA+/total cells). (E) Tumor volumes of 168FARN tumor models were measured every 4 days. (F) Body weights throughout the treatment were determined in both models. (G) Visualized lung metastasis in 4T1 tumor models after resection (arrows: metastatic foci). Bars: 2.5 mm; HE staining of lung sections. Bars: 200 μm. (H) HE staining of liver sections showing tumor hepatic metastasis in 4T1 tumor models. Bars: 200 μm. (I, J) The number of metastatic foci was counted and metastatic index was determined as nodules per gram tumor. Statistical significance: P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***), N = 6.

Mentions: We next examined the effects of SH on inhibition of a 4T1 murine breast cancer model using different doses of SH. The growth of primary tumors in mice treated with 100 mg/kg SH was decreased compared with that of tumors in control group (Fig. 2A). After 14 days of treatment, only the dose of 100 mg/kg caused significant reduction in tumor weight by 31% compared with control (Fig. 2B). Consistent with the reduction in tumor growth, PCNA staining was also decreased in 100 mg/kg SH-treated tumors (Fig. 2C, D). Since this tumor is an animal model for stage IV human breast cancer, we then used another murine breast cancer model to mimic the early stage tumor. 168FARN cells which are less aggressive and could only spread to the regional lymph nodes through lymphatic circulation were injected at 2 × 105 into the mammary fat pad. Result showed that lower dose of SH exhibited stronger inhibition on tumor growth (Fig. 2E). We did not find any gross signs of toxicity following SH administration in either model, demonstrated by no obvious changes in body weight throughout the study (Fig. 2F).


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)

Effect of SH on primary tumor growth and spontaneous metastasis in vivo.(A) Primary tumor volumes were determined regularly in 4T1 tumor models. (B) Tumor burdens after 14-day treatment by different dose of SH were measured. (C) PCNA staining was carried out in control and SH-treated tumors. Bars: 100 μm; (D) proliferation index (PCNA+/total cells). (E) Tumor volumes of 168FARN tumor models were measured every 4 days. (F) Body weights throughout the treatment were determined in both models. (G) Visualized lung metastasis in 4T1 tumor models after resection (arrows: metastatic foci). Bars: 2.5 mm; HE staining of lung sections. Bars: 200 μm. (H) HE staining of liver sections showing tumor hepatic metastasis in 4T1 tumor models. Bars: 200 μm. (I, J) The number of metastatic foci was counted and metastatic index was determined as nodules per gram tumor. Statistical significance: P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***), N = 6.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Effect of SH on primary tumor growth and spontaneous metastasis in vivo.(A) Primary tumor volumes were determined regularly in 4T1 tumor models. (B) Tumor burdens after 14-day treatment by different dose of SH were measured. (C) PCNA staining was carried out in control and SH-treated tumors. Bars: 100 μm; (D) proliferation index (PCNA+/total cells). (E) Tumor volumes of 168FARN tumor models were measured every 4 days. (F) Body weights throughout the treatment were determined in both models. (G) Visualized lung metastasis in 4T1 tumor models after resection (arrows: metastatic foci). Bars: 2.5 mm; HE staining of lung sections. Bars: 200 μm. (H) HE staining of liver sections showing tumor hepatic metastasis in 4T1 tumor models. Bars: 200 μm. (I, J) The number of metastatic foci was counted and metastatic index was determined as nodules per gram tumor. Statistical significance: P < 0.05 (*), P < 0.01 (**) or P < 0.001 (***), N = 6.
Mentions: We next examined the effects of SH on inhibition of a 4T1 murine breast cancer model using different doses of SH. The growth of primary tumors in mice treated with 100 mg/kg SH was decreased compared with that of tumors in control group (Fig. 2A). After 14 days of treatment, only the dose of 100 mg/kg caused significant reduction in tumor weight by 31% compared with control (Fig. 2B). Consistent with the reduction in tumor growth, PCNA staining was also decreased in 100 mg/kg SH-treated tumors (Fig. 2C, D). Since this tumor is an animal model for stage IV human breast cancer, we then used another murine breast cancer model to mimic the early stage tumor. 168FARN cells which are less aggressive and could only spread to the regional lymph nodes through lymphatic circulation were injected at 2 × 105 into the mammary fat pad. Result showed that lower dose of SH exhibited stronger inhibition on tumor growth (Fig. 2E). We did not find any gross signs of toxicity following SH administration in either model, demonstrated by no obvious changes in body weight throughout the study (Fig. 2F).

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