Abstract
Angiogenesis and metastasis are major factors affecting the growth and invasion of triple negative breast cancer (TNBC). A phenanthroline copper(II) complex CPT8 modified with an alkyl chain-linked triphenylphosphonium group showed potent antiproliferative activity against a series of cancer cells including TNBC MDA-MB-231 cells. CPT8 induced mitophagy through activation of PINK1/Parkin and BNIP3 pathways in cancer cells due to damage to mitochondria. More importantly, CPT8 reduced the tube formation ability of human umbilical vein endothelial cells (HUVEC) through downregulation of nuclear factor erythroid 2-related factor 2 (Nrf2). The anti-angiogenic potential of CPT8 was confirmed by decreased vascular endothelial growth factor (VEGF) and CD34 expression in HUVEC. Moreover, CPT8 suppressed the expression of vascular endothelial cadherin and matrix metalloproteinases MMP2 and MMP9, leading to the inhibition of vasculogenic mimicry formation. CPT8 also weakened the metastatic potential of MDA-MB-231 cells. Downregulation of Ki67 and CD34 expression indicates that CPT8 suppressed tumor proliferation and vascularization in vivo, thus providing a unique metal drug candidate for the treatment of TNBC.