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.