Antiangiogenic and Proapoptotic Effects of Dietary Restriction on Experimental Mouse and Human Brain Tumors

Abstract

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.

Cancer as a Metabolic Disease

“…However, numerous studies show that dietary energy restriction is a general metabolic therapy that naturally lowers circulating glucose levels and significantly reduces growth and progression of numerous tumor types to include cancers of the mammary, brain, colon, pancreas, lung, and prostate [10,[247][248][249][250][251][252][253][254][255][256]. The influence of energy restriction on tumor growth, however, can depend on host background and tumor growth site, as energy restriction is effective in reducing the U87 human glioma when grown orthotopically in the brain of immunodeficient SCID mice [175], but not when grown outside the brain in non-obese diabetic SCID mice [257]. Nevertheless, the bulk of evidence indicates that dietary energy restriction can retard the growth rate of many tumors regardless of the specific genetic defects expressed within the tumor.…”

“…Dietary energy restriction specifically targets the IGF-1/PI3K/Akt/HIF-1α signaling pathway, which underlies several cancer hallmarks to include cell proliferation, evasion of apoptosis, and angiogenesis [168,175,176,250,251,254,[258][259][260][261][262][263][264][265]. Calorie restriction also causes a simultaneous down-regulation of multiple Figure 2 Linking the hallmarks of cancer to impaired energy metabolism.…”

Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients

“…Among the problems associated with the translation of DR into clinical applications is that chronic DR delays but does not stop the progression of the disease (Mukherjee et al, 2004;Bonorden et al, 2009;Shelton et al, 2010), and that this delay will occur for only a subset of malignancies (Kalaany and Sabatini, 2009). Although weight loss and cachexia in the early stages of cancer progression are not as common as thought (Tisdale, 2002;Fearon et al, 2003;Fox et al, 2009), the B15% loss of body mass index caused by a moderate (20%) calorie restriction (Racette et al, 2006) would prevent its use in the great majority of cancer treatment scenarios.…”

Efficient inhibition of ovarian cancer by short hairpin RNA targeting claudin-3

“…To determine the angiogenic microvessel density (MVD), frozen sections (8-10 µm) of each group were made and stained with antibody of cD31 (1:200, BD Biosciences). then MVD was determined by examining vascular hot spots at low power (x100) as described previously (24). Vessels with a clearly defined brown-staining lumen or well defined linear vessel shape, were taken into account for blood microvessels.…”