Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

Abstract

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.

A biopolymeric mesh enriched with PLGA microparticles loaded with AT101 for localized glioblastoma treatment

“…In order to determine the effect of the AT101-loaded Mesh on the viability of GBM cells, U87MG and U251MG were seeded in 24-well plates with 25 000 cells per well in DMEM (Thermo Fisher Scientific) supplemented with 10% FBS (Thermo Fisher Scientific), 1% penicillin/streptomycin (10 000 U ml −1 ; Thermo Fisher Scientific). Cytotoxic effects of AT101, AT101-loaded mesh, blank mesh and DMSO treatment were determined using the CytoTox-Fluor TM Cytotoxicity Assay (Promega) according to manufacturer's instruction and as described before [30,31]. Briefly, supernatants of differently treated and control cells were collected at days three and six of stimulation, mixed with the bis-AAF-R110 substrate, and measured in a fluorescence microplate reader (Infinite M200Pro, TECAN, Zürich, Switzerland) at 485/535 nm.…”

Nitrogen-15 dynamic nuclear polarization of nicotinamide derivatives in biocompatible solutions

“…The epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were added at a concentration of 10 ng/ml. GSCs were characterized by the formation of neurospheres, the ability to survive and proliferate under stem cell conditions, and to differentiate into more mature cells, which was proven as described previously (94)(95)(96). The purity of the GSCs was ascertained by immunostaining with cell type-specific markers and by the absence of contamination with mycoplasms.…”

Potential Anti-SARS-CoV-2 Effects of Gossypol and AT-101: Molecular Docking Study Against Angiotensin Converting Enzyme 2

“…It works by inhibiting the activity of Bcl-2 protein and other antiapoptotic proteins, which can lead to apoptosis in cancer cells [4]. Several clinical trials have been conducted to evaluate the safety and efficacy of AT-101 in the treatment of various cancers, including prostate, bladder, ovarian, lung, glioblastoma, leukemia, and multiple myeloma cells with promising results [5][6][7][8][9][10][11]. Currently, it is undergoing phase II/III clinical trials for further evaluation [12].…”