A novel molecular mechanism for anticancer drug-induced ovarian failure: Irinotecan HCl, an anticancer topoisomerase I inhibitor, induces specific FasL expression in granulosa cells of large ovarian follicles to enhance follicular apoptosis

  • Authors:
    • Tomoko Utsunomiya
    • Tetsuji Tanaka
    • Hirotoshi Utsunomiya
    • Naohiko Umesaki
  • View Affiliations

  • Published online on: May 1, 2008     https://doi.org/10.3892/ijo.32.5.991
  • Pages: 991-1000
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Clinical use of CPT-11 combination chemotherapy frequently induces ovarian dysfunction in premenopausal and perimenopausal cancer patients, but its mechanism remains unclear. Mouse experiments were performed to clarify the molecular mechanism of CPT-11-induced ovarian dysfunction. Clinically therapeutic doses of CPT-11 were injected intraperitoneally into 8-week-old female MCH mice, and their ovaries were examined by the TUNEL assay to detect dead cells. Immunohistochemical examinations were simultaneously performed to detect the expression of activated caspase 3, Fas antigen and Fas ligand (FasL). Furthermore, normal murine ovarian tissue fragments were incubated with recombinant soluble FasL in organ cultures and stained by the TUNEL assay to detect apoptotic cells. Intraperitoneal CPT-11 injections induced specific TUNEL-positive cells and cell death with cleaved caspase 3 expression among large ovarian follicular granulosa cells. Apoptotic follicles (follicles containing ≥10 TUNEL-positive cells per ovarian section) were only found among large follicles. The final apoptotic follicle ratios were ≈30% of the total follicles independent of the CPT-11 dose, while CPT-11 dose-dependently enhanced apoptotic processes in murine ovarian follicles. Fas antigen was expressed in most ovarian cells, with extremely high expression levels detected in luteal cells. CPT-11 injections did not significantly increase the Fas expression levels in ovarian cells. Although no FasL expression was detected in normal ovarian tissues, CPT-11 injections significantly induced specific FasL expression in granulosa cells. Incubation of organ-cultured normal murine ovarian tissue fragments with recombinant mouse soluble FasL significantly increased the numbers of TUNEL-positive granulosa and luteal cells. In conclusion, CPT-11 dose-dependently induced specific FasL expression in granulosa cells of developing ovarian follicles. The induced FasL reacted with the Fas antigen constitutively expressed on granulosa cells, such that apoptosis can only be enhanced and induced in granulosa cells in an autocrine and/or paracrine manner. This cell lineage-specific and differentiation stage-specific apoptosis in granulosa cells is thought to be the main molecular mechanism of the ovarian dysfunction induced by CPT-11 combination chemotherapy.

Related Articles

Journal Cover

May 2008
Volume 32 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Utsunomiya, T., Tanaka, T., Utsunomiya, H., & Umesaki, N. (2008). A novel molecular mechanism for anticancer drug-induced ovarian failure: Irinotecan HCl, an anticancer topoisomerase I inhibitor, induces specific FasL expression in granulosa cells of large ovarian follicles to enhance follicular apoptosis. International Journal of Oncology, 32, 991-1000. https://doi.org/10.3892/ijo.32.5.991
MLA
Utsunomiya, T., Tanaka, T., Utsunomiya, H., Umesaki, N."A novel molecular mechanism for anticancer drug-induced ovarian failure: Irinotecan HCl, an anticancer topoisomerase I inhibitor, induces specific FasL expression in granulosa cells of large ovarian follicles to enhance follicular apoptosis". International Journal of Oncology 32.5 (2008): 991-1000.
Chicago
Utsunomiya, T., Tanaka, T., Utsunomiya, H., Umesaki, N."A novel molecular mechanism for anticancer drug-induced ovarian failure: Irinotecan HCl, an anticancer topoisomerase I inhibitor, induces specific FasL expression in granulosa cells of large ovarian follicles to enhance follicular apoptosis". International Journal of Oncology 32, no. 5 (2008): 991-1000. https://doi.org/10.3892/ijo.32.5.991