Abstract:
Background:
Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer having
low incidence rates, but high mortality rates. Treatment options for GBM are limited due to
heterogeneity of GBMs and inability of most agents to cross the blood brain barrier (BBB).
The current median survival is 14-15 months, and the development of novel treatment
strategies is essential.
Aims:
To characterise the New Zealand Brain (NZB) cell lines, based on their morphology, genetic
variations, protein and cytokine expression. Also, to test the efficacy of various treatments
against the NZB cell lines and to explore the mechanism of action of potent drugs.
Methods:
Whole exome sequencing was used to detect the genetic abnormalities in NZB cell lines.
Western blot and multiplex cytokine assay were used to detect the expression of proteins and
cytokines, respectively. The anticancer effects of drugs were determined using cell viability
(EC50) assay. The potential effects of simvastatin were explored in vitro by wound healing,
clonogenic, mitoplate assay and cell cycle analysis. In vivo effects were explored in murine
models.
Results:
The genetic abnormalities in various genes were explored. The NZB cell lines were classified
based on the observed copy number variations (CNVs) across the whole genome. Expression
of various proteins, growth factors and cytokines were determined in NZB cell lines and
correlations to the genetic abnormality of corresponding genes were examined. High
anticancer effects of simvastatin and synergistic activity between simvastatin and
temozolomide (TMZ) were observed against NZB cell lines. Simvastatin produced its
anticancer effects in NZB cell lines by inhibiting cell migration, disrupting cell cycle and
decreasing the metabolic activity of NZB cells. Furthermore, the results demonstrated that
simvastatin monotherapy inhibited tumour growth and increased the survival rates in two
murine models, when used alone. Also, a combination of simvastatin and TMZ was highly
effective against these murine models and no side effects were observed.
Conclusion:
NZB cell lines were extensively characterized and successfully used for screening of anticancer
agents. Simvastatin produced significant anticancer effects both in vitro and in vivo and
various mechanism were identified for these effects. The combination of simvastatin and TMZ
was highly efficient and well tolerated in murine models which justifies further research for
using simvastatin in treatment of GBMs.