Razvoj antitumorske strategije primenom inhibicije tioredoksin-reduktaze 1 u ćelijskim modelima glioblastoma i neuroblastoma
Development of antitumor strategy by inhibition of thioredoxin reductase 1 in cell models of glioblastoma and neuroblastoma
Abstract:
Thioredoxin system, cell redox regulator, has important role in tumor development, progression, metastasis and chemoresistance. Thioredoxin reductase 1 (TrxR1) high expression is in correlation with glioblastoma and neuroblastoma malignancy. Goal of this dissertation was investigating potential of Ugy-type Michael acceptors (UMAs) – TrxR1 inhibitors, for glioblastoma and neuroblastoma treatment, as well as in overcoming multidrug resistance. Accordingly, potential of TrxR1 inhibition by UMA was tested in vitro, followed by testing of UMA inhibitors on cell growth of neuroblastoma, glioblastoma and normal cells. UMA inhibitors demonstrated a stronger inhibitory effect on proliferating cells (neuroblastoma, glioblastoma, keratinocytes) in comparison to non-proliferating blood mononuclear cells. Antitumor effect mechanism of two most potent compounds, DVD-444 and DVD-445, was tested in sensitive and resistant glioma cells. UMA inhibitors caused oxidative stress, mitochondrial depolarisation and elevated expression of antioxidant enzymes in glioma cells, showed cytotoxic, antiproliferative and anti-invasive effect, and sensitized glioma cells to temozolomide. UMA inhibitors suppressed P-glycoprotein (P-gp) activity and sensitized resistant glioma cells to paclitaxel. Antitumor effects of DVD-445 analogue compounds were investigated. DVD-445 analogues induced oxidative stress, cell death and inhibited P-gp activity in glioma cells, at greater extent than DVD-445. Results presented here suggest that TrxR1 inhibition is a promising strategy in treating glioblastoma and neuroblastoma and that UMA inhibitors are aspiring candidates for novel chemotherapy development.
Keywords:
Thioredoxin (Trx) system; Thioredoxin reductase 1 (TrxR1); Thioredoxin reductase 1 inhibitors; Glioma; Neuroblastoma; Ugi-type Michael acceptors (UMAs); Oxidative stress; Multidrug resistanceSource:
Faculty of Biology, University of Belgrade, 2021, 1-105Funding / projects:
- Identification of predictive molecular markers for cancer progression, response to therapy and disease outcome (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41031)
- ERA.Net RUS+ projekta „THIOREDIN – Development of thioredoxin reductase inhibitors towards new anti-cancer agents“ (RUS_ST2017-309)