Tanshinone IIA inhibits breast cancer stem cells growth in vitro and in vivo through attenuation of IL‐6/STAT3/NF‐kB signaling pathways

Abstract

Cancer stem cells (CSCs) are maintained by inflammatory cytokines and signaling pathways. Tanshinone IIA (Tan-IIA) possesses anti-cancer and anti-inflammatory activities. The purpose of this study is to confirm the growth inhibition effect of Tan-IIA on human breast CSCs growth in vitro and in vivo and to explore the possible mechanism of its activity. Human breast CSCs were enriched and expanded under serum-free mammosphere culture condition, and identified through mammosphere formation, toluidine blue staining, immunofluorescence staining, and flow cytometry analysis of stemness markers of CD44/CD24 and ALDH, and tumorigenecity in vivo; the growth inhibition effect of Tan-IIA on human breast CSCs in vitro were tested by cell proliferation and mammosphere formation assays; inflammatory signaling pathway related protein expression in response to Tan-IIA, IL-6, STAT3, phospho-STAT3 (Tyr705), NF-κBp65 in cytoplasm and nucleus and cyclin D1 were evaluated with Western blotting; the growth inhibition effect of Tan-IIA on human breast CSCs growth were tested in vivo. A useful model of human breast CSCs for researching and developing the agents targeting CSCs was established. After Tan-IIA treatment, cell proliferation and mammosphere formation of CSCs were decreased significantly; the expression levels of IL-6, STAT3, phospho-STAT3 (Tyr705), NF-κBp65 in nucleus and cyclin D1 proteins were decreased significantly; the tumor growth and mean tumor weight were reduced significantly. Tan-IIA has the potential to target and kill CSCs, and can inhibit human breast CSCs growth both in vitro and in vivo through attenuation of IL-6/STAT3/NF-kB signaling pathways.

Tanshinone IIA inhibits the proliferation, migration and invasion of ectopic endometrial stromal cells of adenomyosis via 14-3-3ζ downregulation

“…In this study, we found that TSIIA decreased significantly the cell viability of EESCs in a dose-dependent manner, and 20 lL of TSIIA could result in obviously decreased cell viability; this is similar to recent observations that TSIIA could inhibit multiple cancer cells proliferation [20,36,37]. Furthermore, overexpression of 14-3-3f could restore cell viability of TSIIA-treated EESCs, implying that the inhibitory effect of cell viability was mediated by 14-3-3f.…”

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

“…Tan IIA activated the c-Jun N-terminal protein kinase (JNK) pathway in chronic myeloid leukemia cells (25) as well as the IL-6/STAT3/NF-κB signaling pathways in breast cancer cells (22); therefore, these pathways will be assessed in breast cancer cells in future studies. In addition, although the effect of Tan IIA on EMT markers is suggestive of inhibition of migration, further analyses will specifically assess the effects of Tan IIA on cell migration in vitro and metastasis in vivo.…”

“…Considering the in vitro and in vivo growth inhibitory effects of Tan IIA on leukemia cells (15), prostate cancer cells (16), colon cancer cells (17), pancreatic cancer cells (18), hepatocellular carcinoma (19), gastric cancer cells (20), cervical cancer cells (21), and breast cancer cells (22), the effects of Tan IIA on hypoxia-induced DOX resistance were analyzed in two breast cancer cell lines. Tan IIA increased the sensitivity of both MCF-1 and HCC1937 cells cultured in hypoxia to DOX in part through HIF-1α.…”

Differentiation therapy: sesamin as an effective agent in targeting cancer stem-like side population cells of human gallbladder carcinoma

“…In our study, we demonstrated that sesamin reduced the SP cells fraction and viability in a dose-dependent manner. Two explanations, either elimination [27,28] or differentiation [29,30] of SP cells may account for this phenomenon. The majority of the SP cells (more than 83%) were viable at this situation (after treatment with sesamin), however, as determined by trypan blue exclusion (data not shown).…”