Novel semi-synthetic Cu (II)-cardamonin complex exerts potent anticancer activity against triple negative breast and pancreatic cancer cells via inhibition of the Akt signaling pathway

Abstract

Triple negative breast cancer (TNBC) and pancreatic cancer are two of the most aggressive types of cancer that lack effective treatments. We have previously reported the semi-synthesis of a novel Cu (II)-cardamonin complex (19) that demonstrated potent anti-tumour activity. In this study, we further investigated the bioactivity and mode of action of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective anticancer agent for TNBC and pancreatic cancer, respectively. Results revealed that 19 abolished formation of MDA-MB-468 and PANC-1 colonies, exerted growth inhibitory activity and inhibited the migration of cancer cells. Further mechanistic studies showed that it induced DNA damage resulting in G2/M-phase arrest and microtubule network disruption. Moreover, there was an increase in ROS production which may have contributed to the observed induction of apoptosis, corroborated by activation of caspase-3/7, cleavage of PARP and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1 in both cell lines, which indicates that the compound exerted its activity, at least in part, via inhibition of the Akt signaling pathway. Furthermore, it decreased the expression of c-Myc in PANC-1 cells only which suggests that it may exert its bioactivity via multiple mechanisms of action pertinent to tumourigenesis. These results demonstrate the potential of 19 as a promising therapeutic agent for TNBC and pancreatic cancer.