Anticancer activity of plumbagin on stem-like characteristics, tumor angiogenesis and metastatic potential in endocrine resistant breast cancer

Abstract

Plumbagin (PLB), a naphthoquinone compound and vitamin K3 derivative, was shown its potent cytotoxicity and anti-invasion in anti-hormonal resistant cells through the inhibition of Snail-induced epithelial mesenchymal transition (EMT). Overexpression of Snail leads to decrease E-cadherin and increase of beta-catenin, resulting in the activation of Wnt pathway that increases cancer stem-like characteristics in these resistant cells. This study was aimed to investigate the inhibitory effects of PLB on cancer stem-like cells (CSLCs), angiogenesis and Wnt signaling-mediated cell proliferation and invasion. In addition, our study also focused on the anticancer activity of PLB in anti-hormonal resistant breast cancer in vivo. Both anti-hormonal resistant LCC2 and LCC9 cells increased beta-catenin and dysregulated Wnt signaling. Thus, these two cell lines were able to form mammospheres with elevated stem cell markers. This property is the characteristic of CSLCs. Our study showed that PLB significantly diminished the colony and mammosphere formation in a concentration-dependent manner. PLB also dramatically reduced angiogenic factors, stem cell markers and p-Akt expression. Our findings demonstrated the anti-proliferative and anti-invasive properties of PLB were partly mediated by Wnt signaling. Importantly, the inhibitory effects of PLB in cell lines were consistent with the result in xenograft mice. PLB at the doses of 2 mg/kg/day and 4 mg/kg/day significantly inhibited tumor growth without any adverse effects on body weight and blood coagulation. Moreover, PLB treatment not only repressed tumor angiogenesis, but also inhibited lung metastasis. Overall, these findings supported the role of PLB as an anti-cancer agent for anti-hormonal resistant breast cancer.