Hexamethoxylated Monocarbonyl Analogues of Curcumin Cause G2/M Cell Cycle Arrest in NCI-H460 Cells via Michael Acceptor-Dependent Redox Intervention

Abstract

Curcumin, derived from the dietary spice turmeric, holds promise for cancer prevention. This prompts much interest in investigating the action mechanisms of curcumin and its analogues. Two symmetrical hexamethoxy-diarylpentadienones (1 and 2) as cucumin analogues were reported to possess significantly enhanced cytotoxicity compared with the parent molecule. However, the detailed mechanisms remain unclear. In this study, compounds 1 and 2 were identified as the G2/M cell cycle arrest agents to mediate the cytotoxicity toward NCI-H460 cells via Michael acceptor-dependent redox intervention. Compared with curcumin, they could more easily induce a burst of reactive oxygen species (ROS) and collapse of the redox buffering system. One possible reason is that they could more effectively target intracellular TrxR to convert this antioxidant enzyme into a ROS promoter. Additionally, they caused up-regulation of p53 and p21 and down-regulation of redox-sensitive Cdc25C along with cyclin B1/Cdk1 in a Michael acceptor- and ROS-dependent fashion. Interestingly, in comparison with compound 2, compound 1 displayed a relatively weak ability to generate ROS but increased cell cycle arrest activity and cytotoxicity probably due to its Michael acceptor-dependent microtubule-destabilizing effect and greater GST-inhibitory activity, as well as its enhanced cellular uptake. This work provides useful information for understanding Michael acceptor-dependent and redox-mediated cytotoxic mechanisms of curcumin and its active analogues.

EF24 induces ROS-mediated apoptosis via targeting thioredoxin reductase 1 in gastric cancer cells

“…Accumulating evidence showed that ROS might be produced when the mammalian TrxR1 was chemically inhibited [ 30 , 35 ]. Analysis of the chemical structure of EF24 reveals that this molecule belongs to a class of highly reactive organic compounds whose chemical structures (michael acceptor) allow them to interact with biological molecules by forming covalent bonds [ 36 , 37 ]. Thus we speculated that EF24 might be a novel inhibitor of TrxR.…”

A Subpopulation of the K562 Cells Are Killed by Curcumin Treatment after G2/M Arrest and Mitotic Catastrophe

“…Several research groups have suggested that curcumin induces cell death in cancer and leukemia chemotherapy-resistant cells; however, the mechanisms by which curcumin induces cell death appear to be different and dose-dependent in various cell types [27]. Curcumin is considered as a potent inducer of apoptosis in cancer cells, mainly by arresting cells in G1 or G2 phase [28–30], but the underlying mechanisms are still unclear. Therefore, a more detailed analysis of the effect of curcumin in cancer and leukemia cells is required for a better understanding of its anti-oncogenic potential.…”

Targeting the Thioredoxin System as a Strategy for Cancer Therapy

“…Curcumin increased intracellular oxidative stress levels by inhibiting TrxR, thereby inducing ROS production, DNA damage, and loss of TrxR activity, ultimately leading to apoptosis. A series of structurally symmetric and asymmetric curcumin analogues 1 – 4 have been reported. − Almost all asymmetric curcumin analogs with aromatic or heterocyclic rings were more active than those with traditional symmetric structures. The β-unsaturated ketone structure was a key functional group, and the introduction of a nitrogen-containing five-membered ring increased its efficiency.…”