Imatinib mesylate does not counteract ovarian tissue fibrosis in postnatal rat ovary

Abstract

Chemotherapy may result in ovarian atrophy, a depletion of the primordial follicle pool, diminished ovarian weight, cortical and stromal fibrosis. Imatinib mesylate is an anticancer agent that inhibits competitively several receptor tyrosine kinases (RTKs). RTKs play important roles in cell metabolism, proliferation, and apoptosis. In clinic, imatinib mesylate is also known as an anti-fibrotic medicine. In the present study, the impact of imatinib on the ovarian tissue was investigated by assessing ovarian tissue fibrosis in postnatal rat administered with or without imatinib for three days. Fibrosis in the ovarian tissue was determined by histology (Picrosirius and Masson's trichrome staining) and the protein expression of vimentin and alpha-smooth muscle actin (α-SMA). Furthermore, mRNA expression of Forkhead box transcription factor O1 and O3 (FOXO1 and FOXO3), which are markers of cell proliferation was quantified. A short-term exposure to imatinib showed to increase tissue fibrosis in ovaries. This was observed by Masson's trichrome staining. Exposure to imatinib led also to a down-regulation of vimentin protein expression and up-regulation mRNA expression of FOXO3. This may indicate a role of FOXO3 in ovarian tissue fibrosis in postnatal rat ovaries.

Overactivation or Apoptosis: Which Mechanisms Affect Chemotherapy-Induced Ovarian Reserve Depletion?

“…Stromal changes such as fibrosis and neovascularization have been suggested as indirect chemotherapy-induced mechanisms of ovarian reserve depletion. Clinical studies have found significant damage to stromal components following exposure to ovotoxic chemotherapy, including obstruction of cortical stromal blood vessels, neovascularization of small, non-mature, disorganized blood vessels in the ovarian cortex surrounding obstructed vessels, and subcapsular focal cortical fibrosis, following exposure to non-sterilizing doses of combined chemotherapy [83][84][85][86]. Increased follicular atresia and collagen deposition [87] and a significant acute reduction of ovarian blood volume and narrowing Important results in human ovaries have been presented by Shai et al They showed follicle activation in vivo in ovaries of patients recently treated (4-12 days) with alkylating agents, as alkylating agent-treated ovaries displayed significant loss of PMFs, and a significant increase in absolute numbers of growing follicles, in addition to activation markers, indicating chemotherapy-induced PMF reserve loss [74].…”