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

Molecules

Christophe Wiart¹  Teng-Jin Khoo¹  MohammedKhaled Bin Break²  Ahmed Alafnan³  HilaryM. Collins⁴  MdShahadat Hossan⁴  TraceyD. Bradshaw⁴ 

[1] Centre for Natural and Medicinal Product Research, School of Pharmacy, University of Nottingham Malaysia, Semenyih 43500, Malaysia;Department of Pharmaceutical Chemistry, College of Pharmacy, University of Hail, Hail 81411, Saudi Arabia;Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, Hail 81411, Saudi Arabia;School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, UK;

关键词: cardamonin;    complex;    cytotoxicity;    Akt;   

DOI  :  10.3390/molecules26082166

来源: DOAJ

【 摘 要 】

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 (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 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 19 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 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 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 19 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, 19 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 19 as a therapeutic agent for TNBC and pancreatic cancer.

【 授权许可】

Unknown