Effect of caloric restriction on the efficacy of radiation in both hormone-sensitive and hormone-resistant prostate cancers.

Abstract

16 Background: Locally advanced prostate cancers (LAPC) are aggressive, have poor prognosis, and are associated with high recurrence rates and conversion to castrate resistance. The molecular underpinnings of LAPC are being investigated to identify novel therapeutics. Animal models have shown that caloric restriction (CR) can potentially prevent the initiation of prostate cancer. We propose that CR may be used as a novel therapeutic intervention to enhance outcomes of radiation treatment by altering the molecular profile of prostate tumors. Methods: To assess the effect of CR with radiation in vivo, 6 week old male nude mice were injected with LNCaP (hormone sensitive, N = 60) or PC3 (hormone refractory, N = 60) tumor cells. Once tumors were palpable, mice were randomized to be treated with one of 4 conditions: ad libitum (AL) diet, 8Gy of radiation (RT), 30% reduction in caloric intake (CR), or CR+RT. Results: After PC3 tumor injection, compared with AL, the mice had a 22% reduction in tumor size with radiation, 77% with CR (p < 0.01) and an 80% reduction with CR+RT (p < 0.01). After LNCaP tumor injection, compared with ad libitum, the mice had a 49% reduction in tumor size with CR and a 55% reduction with CR+RT (p < 0.01). Tissue evaluation of mice treated with CR or CR+RT from both the LNCaP and PC3 models revealed decreased proliferation via Ki-67 and increased apoptosis with cleaved caspase-3 levels. Furthermore we establish significant changes of the pro-inflammatory IGF-1R pathway hypothesized to play in intricate roll in prostate cancer; down regulation of serum IGF-1R, IRS-1, PI3K, pAKT, and IGF-1:IGF-BP3. Conclusions: For the first time, we have shown that the efficacy of radiation can be increased by decreasing calories by 30% in both hormone-sensitive and hormone-refractory prostate cancer models. Future clinical trials should consider the innovative use of CR to augment standard cancer therapy as it has the potential to change the biology of tumors and enhance the opportunity for clinical benefit.