Novel SIRT1 inhibitor 15-deoxy-Δ12,14-prostaglandin J2 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-Δ12,14-prostaglandin J2 (15d-PGJ2) 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-PGJ2. Molecular docking studies supported the interactions of 15d-PGJ2, J11-Cl and J19 with various amino acids in SIRT1 proteins. Similar to 15d-PGJ2, 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-Cl. Thus, 15d-PGJ2 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-PGJ2 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.

A new SIRT1 inhibitor, MHY2245, induces autophagy and inhibits energy metabolism via PKM2/mTOR pathway in human ovarian cancer cells

“…This is in accordance with findings of Lara and coworkers [47], who showed that SIRT1inhibitors can induce massive apoptosis in p53-dependentcancers, but not in p53-independent cells. Our previous study showed the strongest induction of apoptosis in MCF-7 cells after treatment with salermide, a SIRT1 inhibitor, but SKOV3 cells showed only about a 10% increase in apoptosis [45,[48][49][50]. It appears that this observation in MCF-7 cells was due to the presence of the wild-type p53, since p53-deficient SKOV3 cells show only a small increase in apoptosis due to salermide [51].…”

“…Furthermore, overexpression of SIRT1 increased the chemotherapy resistance in IGROV1 cells and knock-down of SIRT1 led to cell growth arrest and enhanced the sensitivity of drug-resistant cells to DOX [44]. Therefore, inhibition of SIRT1 resulted in anticancer effects in SKOV3 cells through apoptotic or autophagic cell death pathways [45]. SIRT1 enhanced cell proliferation, chemo-resistance and aggressiveness by up-regulating multiple antioxidant pathways to inhibit oxidative stress [46].…”

Analysis of alkaloids (indole alkaloids, isoquinoline alkaloids, tropane alkaloids)

“…Plant secondary metabolites are a diverse range of biologically active molecules having multiple pharmacological actions like antimicrobial, stimulant, analgesic, anthelmintic, anticoagulant, antiacne, and antioxidant, among others (Debnath et al, 2012;Bhakta, 2012, 2013;Dey et al, 2012bDey et al, , 2014Karuna et al, 2018aKaruna et al, , 2018bKundu et al, 2019). Different synthetic compounds show potential biological activity in vitro as well as in vivo ( Jeon et al, 2017;Jeong et al, 2017a, b;Kim et al, 2018;Lee et al, 2018Lee et al, , 2019Richa et al, 2019;Tae et al, 2018), and various formulations of existing drugs are also developed to increase the safety profile (Gorain et al, 2014;Karmakar et al, 2015;Maity et al, 2016). In spite of this technological development, humans from almost every culture are efficiently employing the plant-derived compounds for the anticipation and management of multiple health disorders for many centuries (Dey et al, 2012a, c).…”

Epigenetic Control of Autophagy in Cancer Cells: A Key Process for Cancer-Related Phenotypes

“…Inhibition of SIRT1 in endometric cancer cells (Ishikawa) or LumA (MCF-7) cells using MHY2256 also increased apoptosis and accumulated LC3B-II and eventually BECLIN-1, ATG5, ATG7, and autophagy vesicles [79,80]. Treatment of ovarian cancer cells (SKVO3) with different derivatives of a SIRT1 family inhibitors (J11-C1, 15dPGJ2, J19, or MHY2256) affected cell survival and also increased autophagy marker expression (LC3B-II, and/or BECLIN-1, and ATG13), whereas inhibition of autophagy using 3-MA strongly reduced cell death [78,80].…”