15-deoxy-delta(12-14)-prostaglandin-j2 and Ovarian-Neoplasms

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.

Topics: Antineoplastic Agents; Autophagy; Beclin-1; Cell Cycle; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Female; Gene Expression Regulation, Neoplastic; Humans; Microtubule-Associated Proteins; Models, Molecular; Molecular Docking Simulation; Ovarian Neoplasms; Prostaglandin D2; Signal Transduction; Sirtuin 1

15-Deoxy-delta-12,14-prostaglandin-J(2) (15d-PGJ(2)), an arachidonic metabolite and a natural PPARγ agonist, is known to induce apoptosis in tumor cells. In this study, we investigated new therapeutic potentials of 15d-PGJ(2) by determining its anticancer effects in wild-type and doxorubicin-resistant ovarian carcinoma cells. Despite high expression of resistance-inducing genes like MDR1, Bcl2 and Bcl-xl, 15d-PGJ(2) strongly induced apoptosis in doxorubicin-resistant (A2780/AD) cells similar to the wild-type (A2780). This was found to be related to caspase-3/7- and NF-κB pathways but not to its PPARγ agonistic activity. 15d-PGJ(2) also was able to reduce the doxorubicin resistance of A2780/AD cells at low doses as confirmed by the inhibition of gene expression of MDR1 (p-glycoprotein) and SIRT1 (a drug senescence gene). We also investigated effects of 15d-PGJ(2) on cell migration and transformation using a wound-healing assay and morphological analyses, respectively. We found that 15d-PGJ(2) inhibited migration most likely due to NF-κB inhibition and induced transformation of the round-shape A2780/AD cells into elongated epithelial cells due to HDAC1 inhibition. Using a 15d-PGJ(2) analog, we found the mechanism of action of these new activities of 15d-PGJ(2) on SIRT1 and HDAC1 gene expressions and enzyme activities. In conclusion, the present study demonstrates that 15d-PGJ(2) has a high therapeutic potential to kill drug-resistant tumor cells and, the newly described inhibitory effects of this cyclo-oxygenase product on SIRT1 and HDAC will provide new opportunities for cancer therapeutics.

Topics: Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B, Member 1; bcl-X Protein; Cell Line, Tumor; Doxorubicin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; NF-kappa B; Ovarian Neoplasms; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Signal Transduction; Sirtuin 1; Structure-Activity Relationship; Wound Healing