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. 2012 Jul;11(7):1539-46.
doi: 10.1158/1535-7163.MCT-11-1003. Epub 2012 May 4.

Effect of a low-fat diet combined with IGF-1 receptor blockade on 22Rv1 prostate cancer xenografts

Ramdev Konijeti  1 , Satomi Koyama, Ashley Gray, R James Barnard, Jonathan W Said, Brandon Castor, David Elashoff, Junxiang Wan, Pedro J Beltran, Frank J Calzone, Pinchas Cohen, Colette Galet, William J Aronson
Affiliations

Effect of a low-fat diet combined with IGF-1 receptor blockade on 22Rv1 prostate cancer xenografts

Ramdev Konijeti et al. Mol Cancer Ther. 2012 Jul.

Abstract

In preclinical models, both dietary fat reduction and insulin-like growth factor I receptor (IGF-1R) blockade individually inhibit prostate cancer xenograft growth. We hypothesized that a low-fat diet combined with IGF-1R blockade would cause additive inhibition of prostate cancer growth and offset possible untoward metabolic effects of IGF-1R blockade antibody therapy. Fifty severe combined immunodeficient mice were injected with 22Rv1 cells subcutaneously. Ten days postinjection, the animals were randomized to four groups: (i) high-fat diet + saline (HF); (ii) high-fat diet + IGF-1R blocking antibody, ganitumab (HF/Ab); (iii) low-fat diet + saline (LF); and (iv) low-fat diet + ganitumab (LF/Ab). After 19 days of treatment, the animals were euthanized, serum was collected, and tumors were weighed. Tumor Ki67, Akt and extracellular signal-regulated kinase (ERK) activation, serum insulin, IGF-I and TNF-α were measured. In vitro, ganitumab treatment inhibited growth and induced apoptosis in several prostate cancer cell lines. In vivo, tumor weights and volumes were unaffected by the different treatments. The LF/Ab therapy significantly reduced proliferation (Ki67) and ERK activation in tumors. The HF/Ab group had significantly higher serum insulin levels than the HF group. However, LF/Ab combination significantly reduced serum insulin back to normal levels as well as normalizing serum TNF-α level. Whereas the combination of low-fat diet and IGF-1R blockade did not have additive inhibitory effects on tumor weight, it led to reduced tumor cell proliferation and a reduction in serum insulin and TNF-α levels.

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Figures

Figure 1
Figure 1. IGF-1R blocking antibody (ganitumab) effect on prostate cancer cell lines growth and apoptosis in vitro
A/ Cell growth assay performed after 72h of incubation in serum free media (black bars) or in presence of 1uM of the IGF-1R blocking antibody ganitumab (white bars). B/ Apoptosis was measured after 24h of incubation in serum free media (black bars) or in presence of 1uM of the IGF-1R blocking antibody ganitumab (white bars). Each assay was repeated three times. Data are expressed as mean ± SEM. Statistical analysis was performed by using an unpaired nonparametric Mann-Whitney test.
Figure 2
Figure 2. Modulation of the IGF axis by IGF-1R blockade and low-fat diet
A/ IGF-IR and insulin receptor levels in 22Rv1 xenograft tissue. Total ERK2 was used as a loading control. The Western blots are representative of one experiment (n-3 animals per group). The western blots were done on a total of 5 animals per group. B, C and D/ Fasting serum IGF-I, IGFBP-3 and IGFBP-1 concentration of SCID mice on the different therapy regimen. Serum IGF-I, IGFBP-3 and IGFBP-1 levels were assessed using ELISA. Values are means ± standard errors (SE). Means with letters a,b, or c are significantly different from each other (p<0.05, One way Analysis of variance with Tukey post test).
Figure 3
Figure 3. Effect of the different therapies on 22Rv1 xenograft proliferation
Ki67 immmunostaining was performed on xenografts from all animals in each group. 200 cells were manually counted by a blinded pathologist, the Ki67 positive cells were expressed as a percentage of total cells. Means with different letters are significantly different from each other (p<0.05, One way analysis of variance with Tukey post test).
Figure 4
Figure 4. Effect of the different therapies on Akt and ERK activation
Activation of Akt and ERK was assessed by western blotting as described in material and methods. A/ Phospho-ERK and Phospho Akt and total Akt and ERK were measured on xenograft tissue lysate from 5 animals for each group. The Western blots are representative of one experiment (n-3 animals per group). B/ The LF/Ab therapy resulted in a decrease in ERK activation measured as a ratio of phosphoERK/ total ERK2. Values are means ± standard errors (SE). *: paired t-test; p<0.05.
Figure 5
Figure 5. Combining a LF diet with ganitumab offset the increase in Insulin induced by the ganitumab antibody (A) and resulted in a significant reduction in TNF-α (B)
Values are means ± standard errors (SE). Means with different letters are significantly different from each other (p<0.05, One way analysis of variance with Tukey post test).
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