PARENT SESSION

Experimental and Clinical Therapeutics

(PP100) Curcumin ameliorates radiation-induced pulmonary fibrosis and decreases tumor burden in a C57/Bl6/Lewis lung carcinoma model system.

McDonough, James¹, Arguiri, Evguenia², Solomides, Charalambos², Cengel, Keith¹, Christofidou-Solomidou, Melpo², ¹ University of Pennsylvania, Philadelphia, PA, USA² Department of Medicine, Philadelphia, PA, USA

ABSTRACT- Purpose/Objective: Local failure following radiation therapy for non-small cell lung cancer remains a problem that can cause significant morbidity. The effectiveness of radiation in maintaining local control depends on the dose of radiation delivered, which is limited by the radiation tolerance of the surrounding normal tissues, and on the intrinsic radiosensitivity of the lung cancer cells. Curcumin, an antioxidant derived from the spice turmeric, has previously been shown to reduce normal tissue injury resulting from oxidative stress and also to increase the radiosensitivity of head and neck carcinoma cells in tissue culture. Thus, curcumin has the potential to affect both normal tissue damage as well as radioresistance. We have therefore tested the effect of dietary curcumin radiation induced pneumonopathy and radiation mediated lung tumor regression in a murine model system. Materials/Methods: Mice were fed a 5% curcumin diet or an isocaloric control diet for 2 weeks prior to radiation and weaned off to a normal diet within 48 hours post XRT. The primary endpoint for fibrosis was lung hydroxyproline content and histological evaluation. Mice were injected intravenously with 1 x 106 Lewis lung carcinoma cells as indicated concurrently with the start of a diet curcumin. To establish a non-irradiated baseline, half of the mice were sacrificed after 2 week. The remaining animals were irradiated at 2 weeks post injection and then sacrificed at 1 week after irradiation. Total lung weights were used to estimate total tumor burden and histological evaluation was used to confirm that the difference in lung weight was attributable to variation in tumor burden as opposed to alteration in tumor-associated edema. All numbers are presented as mean standard error of the means. Results: Pulmonary irradiation of mice that were fed a normal diet, as compared to the non-irradiated, age-matched control mice, led to a 2.1 0.1 fold increase in total lung hydroxyl-proline content (36 2 g/lung vs. 17 1 g/lung). In contrast, mice fed a 5% curcumin diet showed significantly less radiation induced fibrosis, with only a 1.4 0.1 fold increase in total lung hydroxyl-proline content (27 1 g/lung vs. 19 1 g/lung). These differences were verified by histologic evaluation and were reflected in a decrease in overall survival at 4 months following irradiation for control vs. curcumin fed animals (23% vs. 45%). To begin evaluating the effect of curcumin on tumor regression following irradiation, mice were injected intravenously with a Lewis lung carcinoma cell suspension and tumor burden was estimated by lung weight at two weeks post injection. Tumor-bearing lungs in control diet-fed mice appeared larger than lungs from curcumin-fed mice 2 weeks after curcumin supplementation and had significantly more tumor (0.17 0.01 mg vs.0.15 0.01 mg for normal diet vs. curcumin). This finding was verified in a repeat experiment (0.27 0.02 vs. 0.24 0.02) and the decrease in tumor burden was also confirmed by histology. However, the lung weights from tumor-injected, irradiated mice from both treatment groups were similar to those of non-irradiated animals that had not been injected with tumor.This suggests that curcumin may not interfere with radiation mediated tumor regression, but further study using a tumor growth delay model are needed. Conclusions: Our findings indicate that dietary curcumin ameliorates radiation-induced pulmonary fibrosis and increases mouse survival rate. Moreover, the tumor burden in mouse lungs was decreased with dietary curcumin supplementation even without radiation treatment, while curcumin did not appear to impair the radiation effect on tumor regression.

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