Monensinin Glioblastoma Multiformede Kaspaz-10 Aracılı Apoptoz Üzerine Etkileri

Yıl 2021, Cilt: 47 Sayı: 3, 393 - 397, 01.12.2021

Sema Serter Koçoğlu , Mücahit Seçme

https://doi.org/10.32708/uutfd.999511

Öz

Glioblastoma multiforme (GBM), en kötü huylu primer merkezi sinir sistemi tümörüdür. Şu anda, GBM için iyileştirici tedavi seçenekleri yoktur ve 5 yıllık hayatta kalma oranı %5’den daha azdır. Monensin, ‘’Streptomyces cinnamonensis’’ den elde edilen antibakteriyal ve antiparazitik etkileri bilinen iyonofor bir antibiyotiktir. Literatürde monensinin GBM hücrelerinin apoptoz mekanizması üzerine etki gösterdiği bir çalışmaya rastlanmadığından yapılan bu çalışmanın amacı monensinin U373 GBM hücrelerinde apoptoz aracılı hücre proliferasyonu üzerine etkilerini araştırmaktır. Monensinin U373 hücre canlılığı üzerine etkileri XTT ile apoptoz üzerine etkileri ise RT-PCR ve Annexin V ile araştırılmıştır. Monensinin U373 GBM hücrelerinde IC50 değeri 48’inci saatte 4 μM olarak bulunmuştur. Monensin U373 GBM hücrelerinde apoptoz oranında 6 katlık bir artışa neden olmuştur. Bununla birlikte monensin kaspaz-10 gen ekspresyonunu arttırarak apoptozu anlamlı olarak aktive etmiştir. Sunulan çalışma monensinin GBM hücrelerinin kaspaz-10 aracılı apoptoz mekanizması üzerine etkilerini gösteren ilk çalışmadır. Bizim sonuçlarımız monensinin GBM kanserinde güçlü apoptotik etkileri olan terapötik bir antikanser ilaç bileşiği olabileceğini önermektedir.

Anahtar Kelimeler

monensin, U373, apoptozis

Effects of Monensin on Caspase-10 Mediated Apoptosis in Glioblastoma Multiforme

Öz

Glioblastoma multiforme (GBM) is the most malignant primary central nervous system tumor. Currently, there are no curative treatment options for GBM and the 5-year survival rate is less than 5%. Therefore, further studies are needed to identify effective markers and therapeutic targets for GBM treatment. Monensin is an ionophore antibiotic obtained from Streptomyces cinnamonensis with known antibacterial and antiparasitic effects. In the literature, no study has been found that shows an effect of monensin on the apoptosis mechanism of GBM cells. The aim of the present study was to investigate the effects of monensin on apoptosis-mediated cell proliferation in U373 GBM cells. The effects of monensin on U373 cell viability were investigated by XTT and its effects on apoptosis were investigated by RT-PCR and Annexin V. The IC50 value of monensin in U373 GBM cells was 4 μM at 48 hours. Monensin caused a 6-fold increase in the rate of apoptosis in U373 GBM cells. Monensin also significantly triggered apoptosis by increasing caspase-10 gene expression. The present study is the first to demonstrate the effects of monensin on the caspase-10-mediated apoptosis mechanism of GBM cells. Our results suggest that monensin may be a therapeutic anticancer drug compound with potent apoptotic effects in GBM cancer.

Anahtar Kelimeler

monensin, U373, apoptosis

Kaynakça

• 1. Lapointe S, Perry A, Butowski NA. Primary brain tumours in adults. Lancet. 2018;392(10145):432-446.
• 2. Harmouch E, Seitlinger J, Chaddad H, vd. Flavagline synthetic derivative induces senescence in glioblastoma cancer cells without being toxic to healthy astrocytes. Sci Rep. 2020;10(1):13750.
• 3. Liu J-Y, Fu W-Q, Zheng X-J, vd. Avasimibe exerts anticancer effects on human glioblastoma cells via inducing cell apoptosis and cell cycle arrest. Acta Pharmacol Sin. 2020;42:97-107.
• 4. Sabbagh Q, Andre-Gregoire G, Guevel L, Gavard J. Vesiclemia: counting on extracellular vesicles for glioblastoma patients. Oncogene. 2020;39(38):6043-6052.
• 5. Avci NG, Ebrahimzadeh-Pustchi S, Akay YM, vd. NF-κB inhibitor with Temozolomide results in significant apoptosis in glioblastoma via the NF-κB(p65) and actin cytoskeleton regulatory pathways. Sci Rep. 2020;10(1):1-14.
• 6. Antoszczak M, Klejborowska G, Kruszyk M, Maj E, Wietrzyk J, Huczyński A. Synthesis and antiproliferative activity of silybin conjugates with salinomycin and monensin. Chem Biol Drug Des. 2015;86:1378-86.
• 7. Markowska A, Kaysiewicz J, Markowska J, Huczyński A. Doxycycline, salinomycin, monensin and ivermectin repositioned as cancer drugs. Bioorganic Med Chem Lett. 2019;29(13):1549-1554.
• 8. Tumova L, Pombinho AR, Vojtechova M, vd. Monensin Inhibits Canonical Wnt Signaling in Human Colorectal Cancer Cells and Suppresses Tumor Growth in Multiple Intestinal Neoplasia Mice. Mol Cancer Ther. 2014;13:812-22.
• 9. Urbaniak A, Delgado M, Antoszczak M, Huczyński A, Chambers TC. Salinomycin derivatives exhibit activity against primary acute lymphoblastic leukemia (ALL) cells in vitro. Biomed Pharmacother. 2018;99:384-390.
• 10. Ketola K, Vainio P, Fey V, Kallioniemi O, Iljin K. Monensin Is a Potent Inducer of Oxidative Stress and Inhibitor of Androgen Signaling Leading to Apoptosis in Prostate Cancer Cells. Mol Cancer Ther. 2010;9:3175-85.
• 11. Verma SP, Das P. Monensin induces cell death by autophagy and inhibits matrix metalloproteinase 7 (MMP7) in UOK146 renal cell carcinoma cell line. Vitr Cell Dev Biol - Anim. P. 2018;54:736-742.
• 12. Wang X, Wu X, Zhang Z, vd. Monensin inhibits cell proliferation and tumor growth of chemo-resistant pancreatic cancer cells by targeting the EGFR signaling pathway. Sci Rep. 2018;8(1):1-15.
• 13. Choi HS, Jeong EH, Lee TG, Kim SY, Kim HR, Kim CH. Autophagy inhibition with monensin enhances cell cycle arrest and apoptosis induced by mTOR or epidermal growth factor receptor inhibitors in lung cancer cells. Tuberc Respir Dis (Seoul). 2013;75(1):9-17.
• 14. Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25(34):4798-4811.
• 15. Degterev A, Boyce M, Yuan J. A decade of caspases. Oncogene. 2003;22(53 REV. ISS. 7):8543-8567.
• 16. Boice A, Bouchier-Hayes L. Targeting apoptotic caspases in cancer. Biochim Biophys Acta - Mol Cell Res. 2020;1867(6):118688.
• 17. Picco R, Tomasella A, Fogalari F, Brancolini C. Transcriptomic analysis unveils correlations between regulative apoptotic caspases and genes of cholesterol homeostasis in human brain. PLoS One. 2014;9(10):e110610.
• 18. Meng L, Sefah K, O'Donoghue MB, vd. Silencing of PTK7 in colon cancer cells: caspase-10-dependent apoptosis via mitochondrial pathway. PLoS One. 2010;5(11):e14018.