Antitumor Effects of a New Retinoate of the Fungal Cytotoxin Illudin M in Brain Tumor Models

Abstract

While the fungal metabolite illudin M (1) is indiscriminately cytotoxic in cancer and non-malignant cells, its retinoate 2 showed a greater selectivity for the former, especially in a cerebral context. Illudin M killed malignant glioma cells as well as primary neurons and astrocytes at similarly low concentrations and destroyed their microtubule and glial fibrillary acidic protein (GFAP) networks. In contrast, the ester 2 was distinctly more cytotoxic in highly dedifferentiated U87 glioma cells than in neurons, which were even stimulated to enhanced growth. This was also observed in co-cultures of neurons with U87 cells where conjugate 2 eventually killed them by induction of differentiation based on the activation of nuclear receptors, which bind to retinoid-responsive elements (RARE). Hence, illudin M retinoate 2 appears to be a promising drug candidate.

Combining organotypic tissue culture with light‐sheet microscopy (OTCxLSFM) to study glioma invasion

“…One potential drawback of using OTCs is that, depending on the brain region used, the tumor growth can be different, as we showed here (Fig EV1). In previous studies (Remy et al, 2018;Linder et al, 2019aLinder et al, , 2022Gerstmeier et al, 2021), we harnessed this as a further layer of complexity nicely reflecting the known intertumoral heterogeneity of GBM and addressed this by using sufficiently high samples sizes. Similarly, by harnessing the acquisition speed of LSFM, intrinsic heterogeneity can be accounted for.…”

“…A rarely used, but powerful method consists of placing fluorescently labeled tumor cells onto murine brain slices and monitoring tumor development for several days to weeks. We have successfully applied these so-called organotypic tissue slice cultures (OTCs) in previous studies and could show that this method has potential for further development (Remy et al, 2018;Linder et al, 2019aLinder et al, , 2022Gerstmeier et al, 2021). So far, we have analyzed tumor growth using an epifluorescence microscope and measured the tumor area on top of the brain slices.…”

Combining organotypic tissue culture with multi-color fluorescence light-sheet microscopy (OTCxLSFM) – a novel tool to study glioma invasion/migration

“…A rarely used, but powerful method consists of placing fluorescently labeled tumor cells onto murine brain slices and monitor tumor development for several days to weeks. We have successfully applied these so-called organotypic tissue slice cultures (OTCs) in previous studies and could show that this method has potential for further development (Remy et al 2018;Linder et al 2019;Gerstmeier et al 2021;Linder et al 2022). So far, we have analyzed tumor growth using an epifluorescence microscope and measured the tumor area on top of the brain slices.…”