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

• Main Authors: Md Shahadat Hossan, Mohammed Khaled Bin Break, Tracey D. Bradshaw, Hilary M. Collins, Christophe Wiart, Teng-Jin Khoo, Ahmed Alafnan
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: Molecules
• Subjects: cardamonin; complex; cytotoxicity; Akt
• Online Access: https://www.mdpi.com/1420-3049/26/8/2166

Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)–cardamonin complex (<b>19</b>) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of <b>19</b> against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that <b>19</b> abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that <b>19</b> induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, <b>19</b> generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex <b>19</b> also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, <b>19</b> decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of <b>19</b> as a therapeutic agent for TNBC and pancreatic cancer.