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. 2013 Jul 3;14(7):13782-95.
doi: 10.3390/ijms140713782.

Effects of calorie restriction and IGF-1 receptor blockade on the progression of 22Rv1 prostate cancer xenografts

Colette Galet  1 , Ashley Gray, Jonathan W Said, Brandon Castor, Junxiang Wan, Pedro J Beltran, Franck J Calzone, David Elashoff, Pinchas Cohen, William J Aronson
Affiliations

Effects of calorie restriction and IGF-1 receptor blockade on the progression of 22Rv1 prostate cancer xenografts

Colette Galet et al. Int J Mol Sci. .

Abstract

Calorie restriction (CR) inhibits prostate cancer progression, partially through modulation of the IGF axis. IGF-1 receptor (IGF-1R) blockade reduces prostate cancer xenograft growth. We hypothesized that combining calorie restriction with IGF-1R blockade would have an additive effect on prostate cancer growth. Severe combined immunodeficient mice were subcutaneously injected with 22Rv1 cells and randomized to: (1) Ad libitum feeding/intraperitoneal saline (Ad-lib); (2) Ad-lib/20 mg/kg twice weekly, intraperitoneal ganitumab [anti-IGF-1R antibody (Ad-lib/Ab)]; (3) 40% calorie restriction/intraperitoneal saline (CR); (4) CR/ intraperitoneal ganitumab, (CR/Ab). CR and ganitumab treatment were initiated one week after tumor injection. Euthanasia occurred 19 days post treatment. Results showed that CR alone decreased final tumor weight, plasma insulin and IGF-1 levels, and increased apoptosis. Ganitumab therapy alone reduced tumor growth but had no effect on final tumor weight. The combination therapy (CR/Ab) further decreased final tumor weight and proliferation, increased apoptosis in comparison to the Ad-lib group, and lowered plasma insulin levels relative to the Ad-lib and Ad-lib/Ab groups. Tumor AKT activation directly correlated with plasma IGF-1 levels. In conclusion, whereas ganitumab therapy modestly affected 22Rv1 tumor growth, combining IGF-1R blockade with calorie restriction resulted in a significant decrease in final tumor weight and improved metabolic profile.

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Figures

Figure 1
Figure 1
SCID mouse weights. Mice were weighed twice weekly from the day of 22Rv1 cells injection (day 1). Values are expressed as mean ± standard errors (SE). The gray bar on the x axis indicates the length of the diet intervention. The arrows indicate the time of saline or ganitumab injections. * indicates significant differences in body weight between mice from Ad-lib groups and the CR groups, p < 0.05.
Figure 2
Figure 2
Tumor volumes and weights. (A) Tumor volumes: once the tumors became palpable, tumor volume was measured twice weekly. Values are expressed as mean ± SEM; and (B) Tumor weights. Values are expressed as mean standard errors (SE). Means with different letters are significantly different from each other (one way analysis of variance). In all cases, statistical significance was considered at p < 0.05.
Figure 3
Figure 3
Effect of the intervention on IGF-1 and Insulin receptors expression in 22Rv1 xenografts. (A) IGF-1 receptor expression; (B) Insulin receptor expression. In (A) and (B), 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 6 animals per group. Densitometric analysis is presented in the bar graphs for both IGF-1R and the insulin receptor. Means with different letters are significantly different from each other (p < 0.05, one way analysis of variance).
Figure 4
Figure 4
Effect of the intervention on the IGF axis. Fasting plasma concentration of (A) IGF-1; (B) Insulin I; (C) GFBP-3; and (D) IGFBP-1 from SCID mice on the different therapy regimen. Plasma IGF-1, IGFBP-1, IGFBP-3 and insulin levels were assessed using ELISA in 6 to 8 animals per group. Values are means ± standard errors (SE). Means with different letters are significantly different from each other (p < 0.05, one way analysis of variance).
Figure 5
Figure 5
Effect of the different therapies on Akt pathway activation, apoptosis and proliferation. (A) Activation of the Akt pathway was assessed by western blotting on xenograft tissue lysate from 6 animals for each group. The Western blots are representative of one experiment (n = 3 animals per group); (B) Apoptosis was measured by western blotting for cleaved Caspase-3 and toal caspase 3 on xenograft tissue lysate from 6 animals for each group. The Western blots are representative of one experiment (n = 3 animals per group). Apoptosis index is measured as a ratio of cleaved-Caspase 3/total Caspase 3. Values are means ± standard errors (SE). Means with different letters are significantly different from each other (p < 0.05, one way analysis of variance); (C) Proliferation was assessed by Ki67 immmunostaining. 200 cells were manually counted by a blinded pathologist, the Ki67 positive cells were expressed as a percentage of total cells. *: indicate a significant difference p < 0.05, Student’s t-test); and (D) Angiogenesis was assessed by PECAM/CD31 immunostaining. The number of vessels was counted in five 20× fields for each stained slide.
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