Hypotoxic copper complexes with potent anti-metastatic and anti-angiogenic activities against cancer cells

Abstract

Tumor metastasis and angiogenesis are the major obstacles in anticancer therapy. A series of phenanthroline copper(II) complexes with different alkyl chains (CPTn, n = 1, 4, 6, 8) are synthesized and characterized. Cellular uptake and cytotoxicity assays reveal that the complex with longer chain length exhibits higher cellular Cu accumulation and stronger inhibition against the cancer cells. Both lipophilicity and structure influence the cellular uptake and cytotoxicity of CPTn. CPT8 is the most potent complex in this series. In addition to its promising anticancer activity, CPT8 displays remarkable anti-metastatic properties by inhibiting the migratory and invasive ability of ovarian cancer cells. Furthermore, it shows excellent anti-angiogenic activity in tube formation and spheroid sprouting of human umbilical vein endothelial cells. The vasculogenic mimicry assay confirms that CPT8 can inhibit the vascular channel formation of aggressive mouse melanoma cells. The production of reactive oxygen species (ROS), the expression of matrix metalloprotease (MMP-2), and the character of tumor cells are implicated in the cytotoxicity of CPTn. CPT8 is a typical example that demonstrates the versatility of copper(II) complexes for cancer therapy through multiple pathways.