Ulipristal-temozolomide-hydroxyurea combination for glioblastoma: in-vitro studies.

Abstract

Background: Glioblastoma multiforme (GBM) is a brain malignancy with worst survival. Low dose progesterone stimulates GBM growth, while progesterone receptor (PR)-antagonist mifepristone was shown to reduce growth and to enhance temozolomide sensitivity in GBM cells. Mifepristone is not available in all countries due to ethical reasons and may cause adrenal insufficiency and pelvic infections. Ulipristal is also a PR-antagonist used in treatment of uterine leiomyomas with higher biosafety. Ulipristal is demonstrated to suppress growth of breast cancer, yet it is not tested as yet whether it can also block growth and sensitize to temozolomide in glioblastoma as it was previously shown with mifepristone. Our first aim was to detect whether ulipristal exerts antiproliferative and chemotherapy-sensitizing effects in glioblastoma. Hydroxyurea inhibits DNA replication via blocking ribonucleotide reductase (RR) and it was demonstrated to increase temozolomide antineoplasticity in GBM. Progesterone receptor-activation in the uterus enhances RR transcription. Hence, we have hypothesized that PR-inactivation with ulipristal would further enhance hydroxyurea antineoplasticity by shutting down DNA synthesis mechanisms through further suppression of RR. Lastly, there exists no study as yet whether ulipristal, hydroxyurea and temozolomide could exert ternary antineoplastic efficacy, which was our last aim to define.

Methods: To reveal interactions between ulipristal, hydroxyurea and temozolomide, we treated human U251 GBM cell line with these agents alone and in combination and measured cell proliferation, total antioxidant capacity (TAC) and total oxidant status (TOS) in conditioned medium and cellular cytokine gene expressions.

Results: All agents significantly reduced cell proliferation significantly, yet the most significant decrease of GBM cells occurred with the triple drug combination at the 96^th hour. All agents significantly decreased TAC and increased TOS in culture media, which was mostly relevant for the triple combination at the 96^th hour. All these three agents tend to reduce the expression of immunosuppressive and/or GBM-growth stimulating cytokines TGF-β, IL-10 and IL-17 while increasing the expression of GBM-growth suppressing cytokine IL-23.

Conclusions: Reproposal of these agents in treatment of GBM would be a plausible approach if future studies prove their efficacy.