Indole analogs and the aryl sulfonamide AqB011 potently restrain the invasiveness of glioblastoma cells, as determined in ex vivo xenograft tissue slice co-cultures (XTCCs)

Abstract

Glioblastomas (GBMs) are highly invasive and heterogeneous in nature which strongly contributes to poor survival of patients, averaging 15 months after diagnosis. With little treatment options being available in particular for addressing GBM invasiveness, there is a high need for supplementary therapies in addition to classical cytostatics like Temozolomide (TMZ). The aim of this study was to examine promising compounds, the natural indole scaffold RAD114 and three semisynthetic analogs (RAD118, RAD119, RAD120) as well as the aryl sulfonamide AqB011, for their inhibitory potential specifically on tumor cell invasion. For this, GBM xenograft tissue slice tandem co-culture (XTCC) models were employed, closely reflecting the in vivo patient situation. In particular, these ex vivo tissue slice air-liquid interface (ALI) models also allow for distinguishing between inhibitory effects on bulk tumor growth vs tumor cell invasion into the normal brain tissue. Profound anti-invasive effects of the natural indole scaffold RAD114, three semisynthetic analogs (RAD118, RAD119, RAD120), and the aryl sulfonamide AqB011 were observed in XTCC models based on G55T2 and U87-MG GBM xenografts co-cultured with mouse brain slices in ALI tandem co-culture. While effects on bulk tumor growth were rather moderate, profound inhibition or even abolishment of tumor invasion was observed, dependent on the compound, its dosage and the model. At a non-toxic concentration (10 µM), RAD118 and AqB011 showed the highest effectiveness in reducing tumor invasion. Combination effects at sub-optimal compound dosages were observed as well. Both compound classes - the tested semisynthetic indole analogs and the sulfonamide derivative – may be promising lead candidates for drugs useful to specifically address the issue of GBM invasiveness. They strongly restrained GBM cell invasion, alone and in combination. Rather than acting through cytotoxic effects, they specifically inhibit cell migration into native brain tissue.