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Comparative Study
. 2005 Oct 11;102(41):14813-8.
doi: 10.1073/pnas.0505870102. Epub 2005 Sep 28.

Pomegranate Fruit Juice for Chemoprevention and Chemotherapy of Prostate Cancer

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Free PMC article
Comparative Study

Pomegranate Fruit Juice for Chemoprevention and Chemotherapy of Prostate Cancer

Arshi Malik et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

Prostate cancer is the most common invasive malignancy and the second leading cause of cancer-related deaths among U.S. males, with a similar trend in many Western countries. One approach to control this malignancy is its prevention through the use of agents present in diet consumed by humans. Pomegranate from the tree Punica granatum possesses strong antioxidant and antiinflammatory properties. We recently showed that pomegranate fruit extract (PFE) possesses remarkable antitumor-promoting effects in mouse skin. In this study, employing human prostate cancer cells, we evaluated the antiproliferative and proapoptotic properties of PFE. PFE (10-100 microg/ml; 48 h) treatment of highly aggressive human prostate cancer PC3 cells resulted in a dose-dependent inhibition of cell growth/cell viability and induction of apoptosis. Immunoblot analysis revealed that PFE treatment of PC3 cells resulted in (i) induction of Bax and Bak (proapoptotic); (ii) down-regulation of Bcl-X(L) and Bcl-2 (antiapoptotic); (iii) induction of WAF1/p21 and KIP1/p27; (iv) a decrease in cyclins D1, D2, and E; and (v) a decrease in cyclin-dependent kinase (cdk) 2, cdk4, and cdk6 expression. These data establish the involvement of the cyclin kinase inhibitor-cyclin-cdk network during the antiproliferative effects of PFE. Oral administration of PFE (0.1% and 0.2%, wt/vol) to athymic nude mice implanted with androgen-sensitive CWR22Rnu1 cells resulted in a significant inhibition in tumor growth concomitant with a significant decrease in serum prostate-specific antigen levels. We suggest that pomegranate juice may have cancer-chemopreventive as well as cancer-chemotherapeutic effects against prostate cancer in humans.

Figures

Fig. 1.
Fig. 1.
Effect of PFE treatment of PC3 cells on cell growth and apoptosis. (A) Effect on cell growth. The cells were treated with PFE for 48 h, and the viability of cells was determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide assay. Data shown are mean ± SD of three separate experiments in which each treatment was repeated in 10 wells. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. control. (B) Effect on cleavage of PARP. The cells were treated with vehicle only or specified concentrations of PFE for 48 h and harvested, and cell lysates were prepared. The data are representative of three independent experiments with similar results. The values above the blots represent the change in the protein expression of the bands normalized to β-actin where vehicle-treated cells are represented as 1.0. (C) Dose-dependent effect of PFE on morphological changes as detected by fluorescence microscopy. Apoptotic cells are stained with annexin V (green fluorescence), and necrotic cells are stained with propidium iodide (red fluorescence). Details are described in Materials and Methods.
Fig. 2.
Fig. 2.
Effect of PFE treatment of PC3 cells on protein expression of WAF1/p21 and KIP1/p27 (A), cyclins D1, D2, and E (B), and cdk2, cdk4, and cdk6 (C). The cells were treated with vehicle only or specified concentrations of PFE for 48 h and harvested, and cell lysates were prepared. The data are representative of three independent experiments with similar results. The values above the blots represent the change in the protein expression of the bands normalized to β-actin where vehicle-treated cells are represented as 1.0.
Fig. 3.
Fig. 3.
Effect of PFE treatment of PC3 cells on protein expression of Bax and Bcl2 (A), Bax/Bcl2 ratio (B), and protein expression of Bak and Bcl-XL (C). The cells were treated with vehicle only or specified concentrations of PFE for 48 h and harvested, and cell lysates were prepared. The data are representative of three independent experiments with similar results. The values above the blots represent the change in the protein expression of the bands normalized to β-actin where vehicle-treated cells are represented as 1.0.
Fig. 4.
Fig. 4.
Effect of treatment of PFE to CWR22Rν1 cells on protein expression of intracellular PSA and AR. The cells were treated with vehicle only or specified concentrations of PFE for 48 h and harvested, and cell lysates were prepared. The data shown are representative of three independent experiments with similar results. The values above the blots represent the change in the protein expression of the bands normalized to β-actin where vehicle-treated cells are represented as 1.0.
Fig. 5.
Fig. 5.
Effect of oral administration of PFE on CWR22Rν1 tumor growth and PSA secretion in athymic nude mice. Approximately one million CWR22Rν1 cells were s.c. injected in each flank of the mouse to initiate tumor growth. Twenty-four hours after cell implantation, the control group of animals continued to receive sterilized drinking water whereas animals of group 2 and group 3 received 0.1% and 0.2% PFE, respectively, in the same drinking water ad libitum. Water bottles were changed every other day. Once tumors started to grow, their sizes were measured twice weekly and the tumor volume was calculated. (A) Average tumor volume of water-fed, 0.1% and 0.2% PFE-fed mice plotted over days after tumor cell inoculation. Values represent mean ± SD of eight animals. *, P < 0.01; **, P < 0.001 vs. the water-fed group of mice; ***, P < 0.01 vs. the 0.1% PFE-fed group of mice. (B) Number of mice remaining with tumor volumes ≤1,200 mm3 after they consumed 0.1% and 0.2% PFE for the indicated days. (C) Serum PSA levels were analyzed by ELISA. Values represent mean ± SE of eight animals. *, P < 0.01; **, P < 0.001 vs. the water-fed group of mice. Details are described in Materials and Methods.

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