Sinomenine hydrochloride inhibits breast cancer metastasis by attenuating inflammation-related epithelial-mesenchymal transition and cancer stemness.

Xiao Li,Jianjun He,Yu Ren,Chao Liu,Ke Wang,Pingping Li,Xiaojiang Tang

doi:10.18632/oncotarget.14593

Xiao Li, Jianjun He + Show 5 more

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https://doi.org/10.18632/oncotarget.14593

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Abstract

Sinomenine hydrochloride (SH) has been investigated for its anti-tumor growth effect. We have previously reported that SH inhibited breast cancer cell proliferation via MAPKs signaling. However, whether SH could inhibit tumor metastasis has not been fully explored. In this study, we found that SH suppressed the metastasis potential of breast cancer cells. The wound healing and transwell assays showed that SH inhibited the migration and invasion ability of both 4T1 and MDA-MB-231 breast cancer cells. The orthotopic mouse model of 4T1 and the experimental mouse model of MDA-MB-231-luc (MDA-MB-231 cell line expressing firefly luciferase) demonstrated that SH treatment inhibited breast cancer metastasis by inhibiting epithelial–mesenchymal transition (EMT) and cancer stem cell (CSC) properties without obvious hepatotoxicity and renal toxicity. We also found that SH decreased spleen volume and weight in both mouse models, especially in the 4T1 mouse model. IL-6, a strong inflammatory factor causing EMT, was remarkably reduced. Overall, this anti-metastasis effect of SH could be possibly caused by attenuating inflammatory reaction, which led to inhibition of EMT and CSC characteristics of breast cancer cells. This study, together with our previous one, provides more evidence of SH as a potential drug for breast cancer therapy.

Highlights

Sinomenine (Supplementary Figure 1A) is an abstract isolated from the traditional Chinese herb Sinomenium acutum Rehd. et Wils
4T1 cells are very aggressive murine breast cancer cells which are usually used to make models of late stage breast tumor to investigate the metastatic behavior [21]. 1 × 105 4T1 cells were injected into the left second mammary fat pad of the mice to establish an orthotopic metastatic mouse model, as the 4T1 cells were obtained from BALB/c mice, they could spontaneously metastasize to secondary foci from the primary sites
In 4T1 tumor section specimens, we found that 150 mg/kg decreased matrix metalloproteinase (MMP)-9 to 38.54% compared with 75% in the control group, increased tissue inhibitor of metalloproteases (TIMP)-1 to 76.04% compared with 31.25% in the control group, and increased TIMP-2 to 66.15% compared with 33.33% in the control group, respectively

Summary

Introduction

Sinomenine (Supplementary Figure 1A) is an abstract isolated from the traditional Chinese herb Sinomenium acutum Rehd. et Wils. Lu et al found that sinomenine increased p21, decreased the Bcl-2/Bax ratio, promoted the release of Cytochrome c and Omi/ HtrA2 from the mitochondria into the cytoplasm and induced the cleavage of caspase-3 and -9 [3].Our previous study showed that sinomenine hydrochloride (SH) (Supplementary Figure 1B), a hydrochloride chemical form of sinomenine which is water soluble, arrested cell population at G1 phase, caused cell apoptosis and induced ATM/ATR-Chk1/Chk2-mediated DNA damage in breast cancer cells through regulation of MAPKs pathways [5]. During our study of the anti-proliferation effect of SH [5], we found that SH could inhibit the invasion and metastasis ability of breast cancer cells. There is no study fully investigated the anti-invasion and anti-metastasis effects of SH on breast cancer cells and explored the potential mechanisms. We carried out experiments to explain the anti-invasion and antimetastasis effect of SH on breast cancer cells

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Conclusion