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Impact of imatinib administration on the mouse ovarian follicle count and levels of intra-ovarian proteins related to follicular quality

  • Kim, Se Jeong (Department of Obstetrics and Gynecology, Fertility Center of CHA Ilsan Medical Center, CHA University School of Medicine) ;
  • Kim, Tae Eun (Department of Obstetrics and Gynecology, Seoul National University Bundang Hospital) ;
  • Jee, Byung Chul (Department of Obstetrics and Gynecology, Seoul National University College of Medicine)
  • 투고 : 2022.01.13
  • 심사 : 2022.03.24
  • 발행 : 2022.06.30

초록

Objective: The impact of imatinib, a tyrosine kinase inhibitor, on ovarian follicles and several proteins related to follicular function and apoptosis was investigated in mice. Methods: Saline, cyclophosphamide (Cp; 50 or 75 mg/kg), or imatinib (7.5 or 15 mg/kg) was injected once intraperitoneally into female B6D2F1 mice (18 mice in each group). In multiple ovarian sections, the number of various types of follicles and the proportion of good-quality (G1) follicles were counted. The levels of six proteins (anti-Müllerian hormone [AMH], BCL-xL, BAX, acid sphingomyelinase [A-SMase], caspase-3, and α-smooth muscle actin [α-SMA]) within the whole ovaries were quantified using Western blots. Results: Compared to the saline group, a significant reduction of the primordial follicle count was observed in the group treated with imatinib 7.5 and 15 mg/kg, as well as in the group treated with Cp 75 mg/kg. Administration of Cp significantly decreased the proportion of G1 primordial follicles, but administration of imatinib did not. No differences in the AMH, anti-apoptotic BCLX-L, pro-apoptotic BAX, and A-SMase levels in the ovarian tissues were observed among the five groups. However, caspase-3 and α-SMA levels were significantly higher in the imatinib and Cp groups than in the saline group. Conclusion: The administration of imatinib to mice significantly reduced the primordial follicle count and increased the protein levels of caspase-3 and α-SMA. Our findings suggest that imatinib potentially exerts ovarian toxicity via apoptotic processes, similarly to Cp.

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참고문헌

  1. Croom KF, Perry CM. Imatinib mesylate: in the treatment of gastrointestinal stromal tumours. Drugs 2003;63:513-24. https://doi.org/10.2165/00003495-200363050-00005
  2. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 2005;105:2640-53. https://doi.org/10.1182/blood-2004-08-3097
  3. Oktay K, Harvey BE, Partridge AH, Quinn GP, Reinecke J, Taylor HS, et al. Fertility preservation in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2018;36:1994-2001. https://doi.org/10.1200/JCO.2018.78.1914
  4. Rausch JL, Boichuk S, Ali AA, Patil SS, Liu L, Lee DM, et al. Opposing roles of KIT and ABL1 in the therapeutic response of gastrointestinal stromal tumor (GIST) cells to imatinib mesylate. Oncotarget 2017;8:4471-83. https://doi.org/10.18632/oncotarget.13882
  5. Melaiu O, Catalano C, De Santi C, Cipollini M, Figlioli G, Pelle L, et al. Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines. Genes Cancer 2017;8:438-52. https://doi.org/10.18632/genesandcancer.129
  6. Zitvogel L, Rusakiewicz S, Routy B, Ayyoub M, Kroemer G. Immunological off-target effects of imatinib. Nat Rev Clin Oncol 2016;13:431-46. https://doi.org/10.1038/nrclinonc.2016.41
  7. Hutt KJ, McLaughlin EA, Holland MK. Kit ligand and c-Kit have diverse roles during mammalian oogenesis and folliculogenesis. Mol Hum Reprod 2006;12:61-9. https://doi.org/10.1093/molehr/gal010
  8. Nilsson EE, Detzel C, Skinner MK. Platelet-derived growth factor modulates the primordial to primary follicle transition. Reproduction 2006;131:1007-15. https://doi.org/10.1530/rep.1.00978
  9. Pascuali N, Scotti L, Abramovich D, Irusta G, Di Pietro M, Bas D, et al. Inhibition of platelet-derived growth factor (PDGF) receptor affects follicular development and ovarian proliferation, apoptosis and angiogenesis in prepubertal eCG-treated rats. Mol Cell Endocrinol 2015;412:148-58. https://doi.org/10.1016/j.mce.2015.04.021
  10. Carlsson IB, Laitinen MP, Scott JE, Louhio H, Velentzis L, Tuuri T, et al. Kit ligand and c-Kit are expressed during early human ovarian follicular development and their interaction is required for the survival of follicles in long-term culture. Reproduction 2006;131: 641-9. https://doi.org/10.1530/rep.1.00868
  11. Ault P, Kantarjian H, O'Brien S, Faderl S, Beran M, Rios MB, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol 2006;24:1204-8. https://doi.org/10.1200/JCO.2005.04.6557
  12. Christopoulos C, Dimakopoulou V, Rotas E. Primary ovarian insufficiency associated with imatinib therapy. N Engl J Med 2008; 358:1079-80. https://doi.org/10.1056/NEJMc0707841
  13. Zamah AM, Mauro MJ, Druker BJ, Oktay K, Egorin MJ, Cedars MI, et al. Will imatinib compromise reproductive capacity? Oncologist 2011;16:1422-7. https://doi.org/10.1634/theoncologist.2011-0137
  14. Ahmadi N, Samaee SM, Yokel RA, Tehrani A. Imatinib mesylate effects on zebrafish reproductive success: gonadal development, gamete quality, fertility, embryo-larvae viability and development, and related genes. Toxicol Appl Pharmacol 2019;379: 114645. https://doi.org/10.1016/j.taap.2019.114645
  15. Salem W, Ho JR, Woo I, Ingles SA, Chung K, Paulson RJ, et al. Long-term imatinib diminishes ovarian reserve and impacts embryo quality. J Assist Reprod Genet 2020;37:1459-66. https://doi.org/10.1007/s10815-020-01778-7
  16. Bildik G, Acilan C, Sahin GN, Karahuseyinoglu S, Oktem O. C-Abl is not activated in DNA damage-induced and Tap63-mediated oocyte apoptosis in human ovary. Cell Death Dis 2018;9:943. https://doi.org/10.1038/s41419-018-1026-7
  17. Schultheis B, Nijmeijer BA, Yin H, Gosden RG, Melo JV. Imatinib mesylate at therapeutic doses has no impact on folliculogenesis or spermatogenesis in a leukaemic mouse model. Leuk Res 2012; 36:271-4. https://doi.org/10.1016/j.leukres.2011.09.025
  18. Petzer AL, Wolf D, Fong D, Lion T, Dyagil I, Masliak Z, et al. High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study. Haematologica 2010;95:908-13. https://doi.org/10.3324/haematol.2009.013979
  19. Gonfloni S, Di Tella L, Caldarola S, Cannata SM, Klinger FG, Di Bartolomeo C, et al. Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nat Med 2009;15:1179-85. https://doi.org/10.1038/nm.2033
  20. Lundy T, Smith P, O'Connell A, Hudson NL, McNatty KP. Populations of granulosa cells in small follicles of the sheep ovary. J Reprod Fertil 1999;115:251-62. https://doi.org/10.1530/jrf.0.1150251
  21. Youm HW, Lee JR, Lee J, Jee BC, Suh CS, Kim SH. Optimal vitrification protocol for mouse ovarian tissue cryopreservation: effect of cryoprotective agents and in vitro culture on vitrified-warmed ovarian tissue survival. Hum Reprod 2014;29:720-30. https://doi.org/10.1093/humrep/det449
  22. Poruchynsky MS, Wang EE, Rudin CM, Blagosklonny MV, Fojo T. Bcl-xL is phosphorylated in malignant cells following microtubule disruption. Cancer Res 1998;58:3331-8.
  23. de Braganca AC, Volpini RA, Mehrotra P, Andrade L, Basile DP. Vitamin D deficiency contributes to vascular damage in sustained ischemic acute kidney injury. Physiol Rep 2016;4:e12829. https://doi.org/10.14814/phy2.12829
  24. Luan Y, Edmonds ME, Woodruff TK, Kim SY. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide. J Endocrinol 2019;240:243-56. https://doi.org/10.1530/JOE-18-0370
  25. Kalich-Philosoph L, Roness H, Carmely A, Fishel-Bartal M, Ligumsky H, Paglin S, et al. Cyclophosphamide triggers follicle activation and "burnout"; AS101 prevents follicle loss and preserves fertility. Sci Transl Med 2013;5:185ra62. https://doi.org/10.1126/scitranslmed.3005402
  26. Roness H, Gavish Z, Cohen Y, Meirow D. Ovarian follicle burnout: a universal phenomenon? Cell Cycle 2013;12:3245-6. https://doi.org/10.4161/cc.26358