Apoptotic Effects of Etodolac in Breast Cancer Cell Cultures

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used as anti‐inflammatory and analgesic agents. This family of drugs suppresses prostaglandin synthesis through inhibition of cyclooxygenase (COX) enzymes. Recent studies displayed that anti‐carcinogenic actions of these drugs are mediated by COX‐2 enzyme. Currently, there is intense research on COX‐2 inhibitors as therapeutic targets. Etodolac is not perfectly selective but shows ‘preferential selectivity’ for COX‐2. Here, in this study, we wanted to take gene expression snapshots of several apoptotic proteins under different conditions of drug exposure. The aim, therefore, focused to determine differential effects of etodolac on the regulation of apoptotic genes in hormone‐responsive MCF‐7 and triple‐negative MDA‐MB‐231 cancer cell lines. Our data suggest that MDA‐MB‐231 is more responsive to etodolac exposure. Cell proliferation and apoptosis consistently regulated upon drug addiction. Furthermore, COX‐2/HER2 was explicitly an up‐regulated, phosphorylated form of Bad accumulated and anti‐apoptotic proteins SAG and survivin increased in both transcriptional and translational levels. Changes in mitochondrial Bcl‐2 family proteins were moderate and pro‐ and anti‐apoptotic proteins showed similar levels of regulation in both cell lines. We believe that these findings would be supportive for future studies targeting etodolac‐based therapies, as it reveals apoptotic factors differentially regulated in hormone‐responsive and invasive cell lines

Kanser hücre hatlarında etodolak ve türevlerinin siklooksijenaz (COX-2) sentezi üzerine etkilerinin araştırılması

Kanser Hücre Hatlarında Etodolak ve Türevlerinin Siklooksijenaz (COX-2)Sentezi Üzerine Etkilerinin AraştırılmasıÖğrencinin Adı: Sevgi KOÇYİĞİT SEVİNÇDanışmanı: Prof. Dr. Oya ORUNAnabilim Dalı: Biyofizik Anabilim DalıAmaç: Çalışmamızda, Marmara Üniversitesi Ecz. Fakültesi Farmasötik Kimya AbDlaboratuvarında sentezlenen etodolak hidrazon, tiyazolidinon ve triazol türevlerinin (SGK 206, SGK 217 ve SGK 242) anti-kanser etkilerinin belirlenmesi amaçlandı.Gereç ve Yöntem: Etodolak ve türevlerinin hücreler üzerindeki anti-kanserojen etkisi, hücre canlılığı ve apoptoz deneyleri ile belirlenmiştir. PGE2 seviyeleri ise enzimatik kitlerle tespit edilmiştir.Bulgular ve Sonuç: Etodolak'ın anti-proliferatif etkilerinin, MCF-7 ve MDA-MB231 meme kanseri hücreleri ile L-929 kontrol fibroblast hücrelerinde 0-100 μM arasında çok düşük olduğu ancak 0,5 mM'den sonra etki gösterdiği tespit edilmiştir. SGK 206 ve SGK 217 ise çok daha düşük derişimlerde etkili olup, L-929 hücrelerinde herhangi bir toksik etki göstermezken, her iki meme kanseri hücresinde sitotoksik etki göstermiştir. SGK 242 ise tüm hücrelerde toksik etki göstermiştir. Çoğalmaya benzer şekilde, SGK 206 ve SGK 217 meme kanseri hücrelerinde düşük derişimlerde önemli bir apoptotik etki göstermiştir. 50 µM derişimde uygulanan SGK 206 ve SGK 217, kanser hücrelerinde COX-2 protein ekspresyonunu önemli ölçüde inhibe etmiştir. Ayrıca SGK 206’nın, kanser hücrelerinde PGE2 salınımını etodolak ilacından daha fazla inhibe ettiği belirlenmiştir. Bu bulgulara dayanarak hidrazon türevi SGK 206 ile tiyazolidinon türevi SGK 217’nin etodolak temelli tedavileri hedefleyen gelecekteki çalışmalar için destekleyici olacağına inanıyoruz.Investigation of the Effects of Etodolac and Its Derivatives on Cyclooxygenase (COX-2) Synthesis in Cancer Cell LinesStudent Name: Sevgi KOÇYİĞİT SEVİNÇName of Supervisor: Prof. Dr. Oya ORUNDepartment: Department Of BiophysicsObjective: In our study, it was aimed to determine the anti-cancer effects of etodolac hydrazone, thiazolidinone and triazole derivatives (SGK 206, SGK 217 and SGK 242) which were synthesized in Marmara University Faculty of Pharmacy, Department of Pharmaceutical Chemistry.Material and methods: Anti-carcinogenic effect of etodolac and its derivatives was determined with cell viability and apoptosis experiments. PGE2 levels were determined with enzymatic kits.Results and Conclusion: Anti-proliferative effects of etodolac were very low between 0-100 μM on MCF-7 and MDA-MB-231 breast cancer cells and L-929 control fibroblast cells but it was effective after 0,5 mM. SGK 206 and SGK 217didn’t show any toxic effect on fibroblast cells while they had cytotoxic effect on breast cancer cells at much lower concentrations. SGK 242 showed toxic effect in all cells. Similar to proliferation, SGK 206 and SGK 217 had a significant apoptotic effect in breast cancer cells at low concentrations. SGK 206 and SGK 217 significantly inhibited COX-2 protein expression of cancer cells at 50 µM. In addition, SGK 206 inhibited PGE2 release more than etodolac in cancer cells. Based on these findings, we believe that the hydrazone derivative (SGK 206) and the thiazolidinone derivative (SGK 217) would be supportive for future studies targeting etodolac-based therapies