Antitumorski efekat mifepristona na stromalnu ćelijsku liniju humanog endometrijuma
Sažetak
Uvod/Cilj. Glavni uzrok razvoja hiperplazije endometrijuma je neoponirani efekat estrogena na endometrijalne ćelije. Cilj naše studije bio je da se prvi put istraže i uporede citotoksični i apoptotični efekti mifepristona na stromalnoj liniji humanog endometrijuma. Procenat citotoksičnih i apoptotičnih ćelija je određivan nakon tretmana različitim dozama mifepristona u periodu od 24 časa. Metode. Procenat citotoksičnih ćelija bio je procenjen korišćenjem testa za ispitivanje vijabilnosti ćelija, dok je procenat apoptotičnih ćelija bio određen korišćenjem protočne citometrije. Utvrđivanje apoptotičnog efekta je potvrđeno određivanjem ekspresije i lokalizacije aktivnog Bax proteina i Bcl-2 proteina. Rezultati. Naši rezultati su pokazali da mifepriston ispoljava citotoksični i apoptotični efekat na humanu endometrijalnu ćelijsku liniju (ThESC) putem promene nivoa ekspresije aktivnog Bax i Bcl-2 proteina. Zaključak. U ovoj studiji smo prvi put ispitali citotoksični i pro-apoptotični efekat mifepristona na humanu stromalnu ćelijsku liniju endometrijuma in vitro. Od suštinskog značaja je nalaz da je mifepriston ispoljio i citotoksični i pro-apoptotični efekat na ThESC ćelijsku liniju. Naši rezulatati ukazuju na moguć nivo lokalizacije i ekspresije ključnih proteina apoptoze u ThESC ćelijama nakon tretmana sa najnižim citotoksičnim dozama mifepristona.
Reference
Sivridis E, Giatromanolaki A. Demystifying endometrial hyper-plasia. Diagn Histopathol 2013; 19(7): 223–30.
Montgomery BE, Daum GS, Dunton CJ. Endometrial hyperplas-ia: a review. Obstet Gynecol Surv 2004; 59(5): 368–78.
Sanderson PA, Critchley HO, Williams AR, Arends MJ, Saunders PT. New concepts for an old problem: the diagnosis of endo-metrial hyperplasia. Hum Reprod Update 2017; 23(2): 232‒54.
Moore E, Shafi M. Endometrial hyperplasia. Obstet Gynaecol Reprod Med 2013; 23(3): 88–93.
Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, et al. Management of endometrial precancers. Obstet Gynecol 2012; 120(5): 1160–75.
Cadepond F, Ulmann A, Baulieu EE. RU486 (mifepristone): mechanisms of action and clinical uses. Annu Rev Med 1997; 48: 129‒56.
Narvekar N, Cameron S, Critchley HO, Lin S, Cheng L, Baird DT. Low-dose mifepristone inhibits endometrial proliferation and up-regulates androgen receptor. J Clin Endocrinol Metab 2004; 89(5): 2491–7.
Sun Y, Fang M, Davies H, Hu Z. Mifepristone: a potential clin-ical agent based on its anti-progesterone and anti-glucocorticoid properties. Gynecol Endocrinol 2014; 30(3): 169‒73.
Telleria CM, Goyeneche AA. Antiprogestins in Ovarian Cancer. In: Farghaly S, editor. OvarianCancer – Clinical and Therapeu-tic Perspectives. Chapter 11. Rijeka, Croatia: InTechopen; 2012.
Mahajan DK, London SN. Mifepristone (RU486): a review. Fertil Steril 1997; 68(6): 967‒76.
Murphy AA, Zhou MH, Malkapuram S, Santanam N, Parthasara-thy S, Sidell N. RU486-induced growth inhibition of human endometrial cells. Fertil Steril 2000; 74(5): 1014–9.
Li A, Felix JC, Minoo P, Amezcua CA, Jain JK. Effect of mife-pristone on proliferation and apoptosis of Ishikawa endome-trial adenocarcinoma cells. Fertil Steril 2005; 84(1): 202–11.
Goyeneche AA, Caron RW, Telleria CM. Mifepristone Inhibits Ovarian Cancer Cell Growth In vitro and In vivo. Clin Can-cer Res 2007; 13(11): 3370–9.
Warren CFA, Wong-Brown MW, Bowden NA. BCL-2 family isoforms in apoptosis and cancer. Cell Death Dis 2019; 10(3): 177.
Deligdisch L. Hormonal pathology of the endometrium. Mod Pathol 2000; 13(3): 285‒94.
Goncharenko VM, Beniuk VA, Kalenska OV, Demchenko OM, Spivak MY, Bubnov RV. Predictive diagnosis of endometrial hyperplasia and personalized therapeutic strategy in women of fertile age. EPMA J 2013; 4(1): 24.
Linkov F, Edwards R, Balk J, Yurkovetsky Z, Stadterman B, Lokshin A, et al. Endometrial hyperplasia, endometrial cancer and prevention: Gaps in existing research of modifiable risk factors. Eur J Cancer 2008; 44(12): 1632–44.
Tieszen CR, Goyeneche AA, Brandhagen BN, Ortbahn CT, Telleria CM. Antiprogestin mifepristone inhibits the growth of cancer cells of reproductive and non-reproductive origin regardless of progesterone receptor expression. BMC Cancer 2011; 11(1): 207.
Wempe SL, Gamarra-Luques CD, Telleria CM. Synergistic le-thality of mifepristone and LY294002 in ovarian cancer cells. Cancer Growth Metastasis 2013; 6: 1‒13.
Smith JA, Gaikwad A, Burke T, Brown J, Ramondetta LM. In vitro evaluation of the growth inhibition and apoptosis effect of mifepristone (RU486) in human Ishikawa and HEC1A en-dometrial cancer cell lines. Cancer Chemother Pharmacol 2008; 62(3): 483–9.
Ørbo A, Moe BT, Grønaas H, Paulssen RH. Early effects of high concentrations of progesterone and mifepristone A gene ex-pression study of endometrial cancer cells (Ishikawa). J Steroid Biochem Mol Biol 2009; 113(1–2): 139–49.
Zhang M, Zheng J, Nussinov R, Ma B. Release of Cytochrome C from Bax Pores at the Mitochondrial Membrane. Sci Rep 2017; 7(1): 2635.
Stehle D, Grimm M, Einsele-Scholz S, Ladwig F, Johänning J, Fischer G, et al. Contribution of BH3-domain and Transmem-brane-domain to the Activity and Interaction of the Pore-forming Bcl-2 Proteins Bok, Bak, and Bax. Sci Rep 2018; 8: 12434.
Alves S, Neiri L, Chaves SR, Vieira S, Trindade D, Manon S, et al. N-terminal acetylation modulates Bax targeting to mito-chondria. Int J Biochem Cell Biol 2018; 95: 35–42.