Tanshinone IIA inhibits metastasis after palliative resection of hepatocellular carcinoma and prolongs survival in part via vascular normalization

Abstract

BackgroundPromotion of endothelial normalization restores tumor oxygenation and obstructs tumor cells invasion, intravasation, and metastasis. We therefore investigated whether a vasoactive drug, tanshinone IIA, could inhibit metastasis by inducing vascular normalization after palliative resection (PR) of hepatocellular carcinoma (HCC).MethodsA liver orthotopic double-tumor xenograft model in nude mouse was established by implantation of HCCLM3 (high metastatic potential) and HepG2 tumor cells. After removal of one tumor by PR, the effects of tanshinone IIA administration on metastasis, tumor vascularization, and survival were evaluated. Tube formation was examined in mouse tumor-derived endothelial cells (TECs) treated with tanshinone IIA.ResultsPR significantly accelerated residual hepatoma metastases. Tanshinone IIA did not inhibit growth of single-xenotransplanted tumors, but it did reduce the occurrence of metastases. Moreover, it inhibited PR-enhanced metastases and, more importantly, prolonged host survival. Tanshinone IIA alleviated residual tumor hypoxia and suppressed epithelial-mesenchymal transition (EMT) in vivo; however, it did not downregulate hypoxia-inducible factor 1α (HIF-1α) or reverse EMT of tumor cells under hypoxic conditions in vitro. Tanshinone IIA directly strengthened tube formation of TECs, associated with vascular endothelial cell growth factor receptor 1/platelet derived growth factor receptor (VEGFR1/PDGFR) upregulation. Although the microvessel density (MVD) of residual tumor tissue increased after PR, the microvessel integrity (MVI) was still low. While tanshinone IIA did not inhibit MVD, it did dramatically increase MVI, leading to vascular normalization.ConclusionsOur results demonstrate that tanshinone IIA can inhibit the enhanced HCC metastasis associated with PR. Inhibition results from promoting VEGFR1/PDGFR-related vascular normalization. This application demonstrates the potential clinical benefit of preventing postsurgical recurrence.

Tanshinone IIA blocks epithelial-mesenchymal transition through HIF-1α downregulation, reversing hypoxia-induced chemotherapy resistance in breast cancer cell lines

“…These results suggest that Tan IIA may inhibit metastasis (28) possibly through inhibition of HIF-1α/TWIST-induced EMT (14). These results are partially consistent with Wang et al (12) who reported reduced EMT with Tan IIA in an in vivo model of hepatocellular carcinoma. However, similar results were not observed in hypoxic conditions in vitro (12).…”

“…This is consistent with Xu et al (26) who reported that Tan IIA reduced LPS-induced sepsis syndrome through targeting HIF-1α. However, in hepatocellular carcinoma cells, HIF-1α levels were not altered with Tan IIA in hypoxic conditions in vitro (12).…”

“…In addition, Tan IIA alleviated residual tumor hypoxia and inhibited EMT in vivo without altering HIF-1α expression (12). Thus, the present study examined the hypothesis that Tan IIA downregulates HIF-1α and blocks EMT, thereby reversing hypoxia-induced chemoresistance in breast cancer cells.…”

Tanshinone IIA ameliorates bleomycin-induced pulmonary fibrosis and inhibits transforming growth factor-beta-β–dependent epithelial to mesenchymal transition

“…Fu et al [18] have found that Tan ⅡA blocks EMT in MCF-7 and HCC1973 breast cancer cell lines Q5 . Likewise, Wang et al [19] have reported that Tan ⅡA inhibits EMT and metastasis of hepatocellular carcinoma in vivo. These two previous lines of evidence indicate an inhibitory effect of Tan ⅡA on EMT of breast and liver cancer cells.…”

Reasons for cancer metastasis: A holistic perspective

“…If promotion of blood circulation was used alone, it would not have triggered cancer cell metastasis. Indeed, it was demonstrated that improving blood circulation reduced cancer metastasis (45). However, the problem with using Chinese medicine to promote blood circulation alone, is that it would be difficult to detect a tumor size reduction or disappearance; this may be difficult for physicians and patients to accept.…”