Novel SIRT1 inhibitor 15-deoxy-Delta(12,14)-prostaglandin J(2) and its derivatives exhibit anticancer activity through apoptotic or autophagic cell death pathways in SKOV3 cells

Abstract

Clinically relevant sirtuin (SIRT) inhibitors may possess antitumor activities. A previous study indicated that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) exhibited potent anticancer activity by SIRT1 inhibition. Therefore, the aim of the present study was to investigate whether its derivatives (J11-C1 and J19) exhibited anticancer activity against ovarian cancer SKOV3 cells. Cell viability was determined using an MTT assay. Cell cycle arrest, apoptosis and autophagy were determined using flow cytometry or western blot analysis. J11-Cl and J19 were less cytotoxic to SKOV3 cells compared with 15d-PGJ(2). Molecular docking studies supported the interactions of 15d-PGJ(2), J11-C1 and J19 with various amino acids in SIRT1 proteins. Similar to 15d-PGJ(2), J11-C1 and J19 inhibited SIRT1 enzymatic activity and decreased SIRT1 expression levels in a concentration-dependent manner. J11-C1 induced apoptotic cell death more effectively compared with J19, which was associated with markedly decreased expression of the anti-apoptotic molecule B-cell lymphoma 2 (Bcl-2). Furthermore, the levels of light chain 3-II (LC3-II) and beclin-1 were clearly induced in SKOV3 cells treated with J11-C1. Thus, 15d-PGJ(2) and its derivatives exhibited anticancer activity possibly by inducing apoptotic or autophagic cell death pathways. Collectively, the results of the present study suggest that 15d-PGJ(2) and its derivatives exerted antitumor activity by selectively modulating the expression of genes associated with cell cycle arrest, apoptosis and autophagy. Notably, J11-C1 is a novel candidate SIRT1 inhibitor with anticancer activity.