Antiangiogenic and Proapoptotic Effects of Dietary Restriction on
Experimental Mouse and Human Brain Tumors
Purna Mukherjee, Laura E. Abate and Thomas
N. Seyfried
Biology Department, Boston College, Chestnut Hill,
Massachusetts
Purpose. The antiangiogenic and proapoptotic mechanisms of dietary caloric
restriction (DR) are unknown.
In this study, we evaluated the effects
of moderate (40%) DR on the orthotopic growth of mouse and human
brain tumors that differ in cell origin, angiogenicity, host
environment, and biochemical composition. Experimental
Design. A malignant mouse astrocytoma (CT-2A) and a
human glioma (U87-MG) were highly angiogenic and fast growing, whereas
a mouse ependymoblastoma was less vascularized and slower growing.
The tumors were evaluated for growth, cell proliferation, microvessel
density, and apoptosis under DR and ad libitum feeding.
Serum
vascular endothelial growth factor and insulin-like growth factor I
levels were examined as angiogenic biomarkers. Results. DR significantly decreased vascularity (factor VIII) and
increased apoptosis (terminal deoxynucleotidyl transferase-mediated nick
end labeling) in all tumors.
These effects were associated with
enhanced caspase-3 and poly(ADP-ribose) polymerase cleavage in the
CT-2A and ependymoblastoma tumors, but not in the U87-MG tumor.
DR
also caused reductions of serum insulin-like growth factor I and
glucose levels. Conclusions. DR had significant antiangiogenic and proapoptotic effects
in the three distinct brain tumor models.
DR, however, had
differential effects on cell proliferation, biomarkers of angiogenesis,
and apoptosis, suggesting multiple mechanisms of action.
Because
extensive angiogenesis and resistance to apoptosis are hallmarks of
gliomas, this study provides new insight into the molecular basis of
the DR-induced inhibition of brain tumor growth.
© 2004 American
Association for Cancer Research
Source: http://clincancerres.aacrjournals.org/cgi/content/abstract/10/16/5622
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