Temozolomide displays antimigratory effects in human glioblastoma cells mediated through neuregulin-1 down-regulation

Lefranc F, Spiegl-Kreinecker S, Haibe-Kains B, Bontempi G, Decaestecker C, Berger W, Kiss R

In vitro temozolomide cytotoxicity on glioblastoma cells seems to be exerted through pro-autophagic and late apoptotic processes. However, we do not believe that these effects of temozolomide in vitro at 100 μmmol/L can explain the significant therapeutic benefits of relatively low repeat temozolomide PO or IV administration to athymic mice bearing human glioblastomas. We have investigated the (I) impact of temozolomide treatment duration on the survival of glioblastoma bearing mice, (II) effects of temozolomide on human glioblastoma cell migration, and (III) genome-wide effects of temozolomide treatment in vitro and in vivo on U373 glioblastomas. Our results reveal that the U373 and T98G malignant astrocytic invasive cells as well as several glioblastoma primocultures present a methylated MGMT promoter. No clear-cut cytotoxic effects are achieved with temozolomide up to 100 μmmol/L in vitro in several glioblastoma cell lines and primocultures, although this concentration induces a significant decrease in the wound-healing process of U373 cells. The therapeutic benefit of temozolomide in mouse models of human glioblastoma is found to correlate directly to the duration of treatment. The sooner the treatment begins, the higher the survival rate is achieved. Genomic analysis of temozolomide-treated U373 cells reveals 30 genes, including clusters involved in morphogenesis and iron ion homeostasis, with greater than 2 or less than 0.5-fold modification in expression compared to untreated cells.
One of these, neuregulin-1, known to activate the erbB receptor and enhance glioma cell motility, is significantly decreased after temozolomide treatment. In conclusion, these data bring additional understanding on how temozolomide contributes therapeutic benefits to glioblastoma patients.
This is very interesting research, suggesting that temozolomide may suppress glioblastoma cell invasion. Invasion throughout the neuroaxis is the key feature of glioblastomas that makes the tumor so difficult to treat. The observation that animals started on the drug as early as possible had a longer survival supports this hypothesis along with continued treatment being beneficial. Of course, these observations can be explained by other actions of the drug as well.