Damian Ryszawy1, Maciej Pudełek2, Jessica Catapano2, Małgorzata Ciarach3, Zuzanna Setkowicz3, Ewa Konduracka4, Zbigniew Madeja2, Jarosław Czyż5. 1. Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland. Electronic address: damian.ryszawy@uj.edu.pl. 2. Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland. 3. Department of Neuroanatomy, Faculty of Biology, Gronostajowa 9, 30-387 Kraków, Poland. 4. Coronary Disease Clinic, Faculty of Medicine, Jagiellonian University, Prądnicka 80, 31-202 Kraków, Poland. 5. Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland. Electronic address: jarek.czyz@uj.edu.pl.
Abstract
AIMS: Constant development of chemotherapeutic strategies has considerably improved the efficiency of tumor treatment. However, adverse effects of chemotherapeutics enforce premature treatment cessation, which leads to the tumor recurrence and accelerated death of oncologic patients. Recently, sodium ascorbate (ASC) has been suggested as a promising drug for the adjunctive chemotherapy of glioblastoma multiforme (GBM) and prostate cancer (PC). To estimate whether ASC can interfere with tumor recurrence between the first and second-line chemotherapy, we analyzed the effect of high ASC doses on the expansion of cells in vitro and in vivo. MAIN METHODS: Brightfield microscopy-assisted approaches were used to estimate the effect of ASC (1-14 mM) on the morphology and invasiveness of human GBM, rat PC and normal mouse 3T3 cells, whereas cytostatic/pro-apoptotic activity of ASC was estimated with flow cytometry. These assays were complemented by the in vitro CellROX-assisted analyses of intracellular oxidative stress and in vivo estimation of GBM tumor invasion. KEY FINDINGS: ASC considerably decreased the proliferation and motility of GBM and PC cells. This effect was accompanied by intracellular ROS over-production and necrotic death of tumor cells, apparently resulting from their "autoschizis". In vivo studies demonstrated the retardation of GBM tumor growth and invasion in the rats undergone intravenous ASC administration, in the absence of detectable systemic adverse effects of ASC. SIGNIFICANCE: Our data support previous notions on anti-tumor activity of high ASC doses. However, autoschizis-related cell responses to ASC indicate that its application in human adjunctive tumor therapy should be considered with caution.
AIMS: Constant development of chemotherapeutic strategies has considerably improved the efficiency of tumor treatment. However, adverse effects of chemotherapeutics enforce premature treatment cessation, which leads to the tumor recurrence and accelerated death of oncologic patients. Recently, sodium ascorbate (ASC) has been suggested as a promising drug for the adjunctive chemotherapy of glioblastoma multiforme (GBM) and prostate cancer (PC). To estimate whether ASC can interfere with tumor recurrence between the first and second-line chemotherapy, we analyzed the effect of high ASC doses on the expansion of cells in vitro and in vivo. MAIN METHODS: Brightfield microscopy-assisted approaches were used to estimate the effect of ASC (1-14 mM) on the morphology and invasiveness of human GBM, rat PC and normal mouse 3T3 cells, whereas cytostatic/pro-apoptotic activity of ASC was estimated with flow cytometry. These assays were complemented by the in vitro CellROX-assisted analyses of intracellular oxidative stress and in vivo estimation of GBM tumor invasion. KEY FINDINGS:ASC considerably decreased the proliferation and motility of GBM and PC cells. This effect was accompanied by intracellular ROS over-production and necrotic death of tumor cells, apparently resulting from their "autoschizis". In vivo studies demonstrated the retardation of GBM tumor growth and invasion in the rats undergone intravenous ASC administration, in the absence of detectable systemic adverse effects of ASC. SIGNIFICANCE: Our data support previous notions on anti-tumor activity of high ASC doses. However, autoschizis-related cell responses to ASC indicate that its application in human adjunctive tumor therapy should be considered with caution.