Anticancer properties of 4-thiazolidinone derivatives depend on peroxisome proliferator-activated receptor gamma (PPARγ)

• Published in: European journal of medicinal chemistry 2017-12, Vol.141, p.162-168
• Main Authors: Szychowski, Konrad A., Leja, Marcin L., Kaminskyy, Danylo V., Kryshchyshyn, Anna P., Binduga, Urszula E., Pinyazhko, Oleh R., Lesyk, Roman B., Tobiasz, Jakub, Gmiński, Jan
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cytotoxicity; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; PPAR gamma - antagonists & inhibitors; PPAR gamma - genetics; PPARs; RNA, Messenger - drug effects; RNA, Messenger - genetics; SCC-15; Structure-Activity Relationship; Thiazolidines - chemical synthesis; Thiazolidines - chemistry; Thiazolidines - pharmacology; Thiazolidinone; Thiazolothiopyranes
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.09.071

Peroxisome proliferator-activated receptors (PPARs) play an important role in numerous chronic diseases such as diabetes, obesity, atherosclerosis and cancer, and PPAR modulators are among the approved drugs and drug-candidates for their treatment. The aim of this study was to elucidate the involvement of PPARs in the mechanism of cytotoxic and pro-apoptotic action of novel anticancer 4-thiazolidinone derivatives (Les-2194, Les-3377, Les-3640) and approved 4-thiazolidinones (Rosiglitazone, Pioglitazone) towards the human squamous carcinoma (SCC-15) cell line. Experiments with 4-thiazaolidinone derivatives and PPAR-specific siRNA were conducted and PPARα, PPARβ and PPARγ mRNA expression was studied. Moreover, after PPARα, PPARβ and PPARγ siRNA gene silencing, cell viability, cell metabolism and caspase-3 activity were measured. The results showed a decrease of mRNA expression of the studied PPARs in SCC-15 cells treated with 10 and 50 μM Les-2194, Les-3377 and Les-3640. PPARγ knockdown protected the cells from the cytotoxic effect of the tested compounds (50 μM). It was established that novel anticancer 4-thiazolidinone derivatives act mainly through the PPARγ pathway in SCC-15 cells. Our results suggest that all studied compounds act as PPARs agonists. Interestingly, silencing of PPARγ gene increases the expression of PPARα, PPARβ mRNA in SCC-15 cells. The anticancer potential of new studied compounds was more expressed as compared to Rosiglitazone and Pioglitazone. [Display omitted] •Les-2194, Les-3377 and Les-3640 act mainly through the PPARγ pathway in SCC-15 cells.•Les-2194, Les-3377 and Les-3640 decrease PPARα, PPARβ and PPARγ mRNA expression in SCC-15 cells.•The anticancer effect of Les-2194, Les-3377 and Les-3640 is stronger than of Rosiglitazone and Pioglitazone in SCC-15 cells.•50 μM of Rosiglitazone and Pioglitazone increases SCC-15 cell metabolism.•Silencing of PPARγ gene increases the expression of PPARα, PPARβ mRNA in SCC-15 cells.