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Sunday, 16 February 2014

Prostate cancer in Vitamin A's Points of View

 Kyle J. Norton

Prostate cancer, once considered a disease of aging male, now have a tendency to effect the younger generation become major concerns of governments and scientific community in South East Asian. It may be due to over consumption of bad fats accompanied with unhealthy diet and life, because of  the economic prosperity over 2 decades.

Vitamin A is a general term of Vitamin A Retinol, retinal, beta-carotene, alpha-carotene, gamma-carotene, and beta-cryptoxanthin best known for its functions for vision health and antioxidant scavenger and essential for growth and differentiation of a number of cells and tissues.
Recommended intakes of vitamin A, according to  the Institute of Medicine of the National Academies (formerly National Academy of Sciences) is 600 µg daily as extremely high doses (>9000 mg) can be toxicity, causing dry, scaly skin, fatigue, nausea, loss of appetite, bone and joint pains, headaches, etc.

1. Retinols
Retinols derived from vitamin A, most often are used in medical field in regulation of epithelial cell growth. Suggestion of serum retinol, linking to risk of prostate cancer have produced inconclusive results. Study of Serum retinol and risk of prostate cancer, showed that higher serum of retinol elevates risk of prostate cancer by quintiles of baseline and 3-year serum retinol concentrations and by change in serum retinol levels from baseline to 3 years(1). but the study by the Erasmus University, indicated the otherwise(2)(3)and Japan-Hawaii Cancer Study, Kuakini Medical Center, showed that none of the micronutrients is strongly associated with prostate cancer risk. including serum of retinol(4).

Retinoic acid (RA), a metabolite of retinol, was found to be effective in suppression of  carcinogenesis in tumorigenic animal models for the skin, oral, lung, breast, bladder, ovarian and prostate(5). In prostate cancer LNCaP and PC3 cells, all-trans-retinoic acid (atRA) inhibited angiogenesis prostate cancer cell growth and identify retinoic acid receptor alpha as the receptor through up-regulation of retinoic acid receptor beta up-regulation and down regulation of prostate cancer cell proliferation(6). In androgen-responsive human prostate cancer cells, retinoids, the synthetic derivatives of retinol, showed to inhibit the growth of prostate caner cells and the formation and degradation of gap junctions(are ensembles of intercellular channels that permit the exchange of small growth regulatory molecules between adjoining cells), through modulation(7). In androgen receptor-negative (AR(-)) prostate cancer cells, all-trans retinoic acid (ATRA), induced the growth arrest through alteration of HOXB13(genetic variant in HOXB13 increased risk of prostate cancer by a 10-20-fold) expression as a result of epigenetic modifications(8). In mice study of p27(Kip1)(cell cycle suppressor gene) deficiency prostate cancer, 9-cis retinoic acid (9cRA) was found effectively in suppression of prostate cell proliferation (PECP) and increased cellular biological aging(9).

2. Carotenoids(beta-carotene, alpha-carotene, gamma-carotene and beta-cryptoxanthin)
Carotenoids, plant pigments, converted to vitamin A after intake, play an important role in prevention and treatment of some diseases through it antioxidant effects.
Measured serum of Plasma carotenoids, retinol once considered as a maker for risk of prostate cancer, have produced an inconsistent result. According to the University of Oxford, there was no associations between plasma concentrations of carotenoids, retinol, or tocopherols and overall prostate cancer risk. The inverse associations of lycopene and the sum of carotenoids with the risk of advanced disease may involve a protective effect(10). Unfortunately, the study by Fred Hutchinson Cancer Research Center indicated that high serum beta-carotene concentrations were associated with increased risk for aggressive, clinically relevant prostate cancer(11) and the  Harvard Medical School showed no associated at all(12).
Epidemiological studies of carotenoids in reduced risk of prostate cancer have also been inconclusive.
β-Ionone, a cyclic sesquiterpene and an end-ring analog of β-carotene, in DU145 and PC-3 cells induced apoptosis and cell cycle arrest at the G1 phase and in DU145 cells, initiated the degradation of reductase, suppressed the net growth of DU145 cells by 73%(13). Combination of  vitamin A and vitamin D, showed an effectiveness in induction of prostate cancer cells apoptosis through enhanced the expression of Bax(involved in p53-mediated apoptosis) and reduced the expression of Cyclin D1(in regulating cell cycle progression)(14). Oral administration of β-carotene (BC) inhibited the proliferation of PC-3 cells at 20 μM BC at 12 h of incubation(15). Fucoxanthin, a marine carotenoid found in brown algae, inhibited the growth of LNCap prostate cancer cells through cell cycle arrest with SAPK/JNK(involved in proliferation, apoptosis, motility) activation(16) or induces G1 arrest with GADD45 gene(growth arrest and DNA-damage inducible) expression(17). In human androgen-independent prostate carcinoma PC-3 cells, oral administration of a low or a high dose of lycopene (4 and 16 mg/kg) and a single dose of β-carotene (16 mg/kg) twice a week for 7 wk, suppressed the growth of prostate tumor cells associated with reduction of proliferation (attenuation of proliferating cell nuclear antigen expression) and with interference of the insulin-like growth factor 1 signaling (increased plasma insulin-like growth factor-binding protein-3 levels)(18).
Unfortunately, the study by the National Cancer Institute, indicated that there is not enough evidences to for a strong support for population-wide implementation of high-dose antioxidant supplementation for the prevention of prostate cancer. However, beta-carotene supplementation in men with low dietary beta-carotene intakes were associated with reduced risk of this disease(19).

Taking altogether, without going into reviews, vitamin A and its synthetic version induced apoptosis and exhibited anti proliferation of prostate cancer cell lines through cell cycle arrested and attenuated cancer progressive pathways and may be considered as potent agents in reduced risk and treatment of prostate cancer. But no doubt, certain vitamins and minerals deficiencies may play a critic role in the influence of development of prostate cancer. Over doses can lead to toxic symptoms. Please make sure you follow the guideline of the Institute of Medicine of the National Academies.


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References
(1) Serum retinol and risk of prostate cancer by Mondul AM, Watters JL, Männistö S, Weinstein SJ, Snyder K, Virtamo J, Albanes D.(PubMed) 
(2) Serum retinol and prostate cancer.

Hayes RB, Bogdanovicz JF, Schroeder FH, De Bruijn A, Raatgever JW, Van der Maas PJ, Oishi K, Yoshida O.(PubMed)
(3) Serum retinol and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial by Schenk JM, Riboli E, Chatterjee N, Leitzmann MF, Ahn J, Albanes D, Reding DJ, Wang Y, Friesen MD, Hayes RB, Peters U.(PubMed
(4) Serum micronutrients and prostate cancer in Japanese Americans in Hawaii by Nomura AM, Stemmermann GN, Lee J, Craft NE.(PubMed)

(5) Retinoids and their biological effects against cancer by Alizadeh F, Bolhassani A. Khavari A, Bathaie SZ, Naji T, Bidgoli SA (PubMed)
(6) Effect of an all-trans-retinoic acid conjugate with spermine on viability of human prostate cancer and endothelial cells in vitro and angiogenesis in vivo by Vourtsis D, Lamprou M, Sadikoglou E, Giannou A, Theodorakopoulou O, Sarrou E, Magoulas GE, Bariamis SE, Athanassopoulos CM, Drainas D, Papaioannou D, Papadimitriou E.(PubMed)
(7) Retinoids regulate the formation and degradation of gap junctions in androgen-responsive human prostate cancer cells by Kelsey L, Katoch P, Johnson KE, Batra SK, Mehta PP.(PubMed)

(8) ATRA inhibits the proliferation of DU145 prostate cancer cells through reducing the methylation level of HOXB13 gene by Liu Z, Ren G, Shangguan C, Guo L, Dong Z, Li Y, Zhang W, Zhao L, Hou P, Zhang Y, Wang X, Lu J, Huang B.(PubMed)
(9) p27(Kip1) deficiency promotes prostate carcinogenesis but does not affect the efficacy of retinoids in suppressing the neoplastic process by Taylor W, Mathias A, Ali A, Ke H, Stoynev N, Shilkaitis A, Green A, Kiyokawa H, Christov K.(PubMed)
(10) Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study by Key TJ, Appleby PN, Allen NE, Travis RC, Roddam AW, Jenab M, Egevad L, Tjønneland A, Johnsen NF, Overvad K, Linseisen J, Rohrmann S, Boeing H, Pischon T, Psaltopoulou T, Trichopoulou A, Trichopoulos D, Palli D, Vineis P, Tumino R, Berrino F, Kiemeney L, Bueno-de-Mesquita HB, Quirós JR, González CA, Martinez C, Larrañaga N, Chirlaque MD, Ardanaz E, Stattin P, Hallmans G, Khaw KT, Bingham S, Slimani N, Ferrari P, Rinaldi S, Riboli E.(PubMed)
(11) Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial by Peters U, Leitzmann MF, Chatterjee N, Wang Y, Albanes D, Gelmann EP, Friesen MD, Riboli E, Hayes RB.(PubMed)
(12) Intake of carotenoids and retinol in relation to risk of prostate cancer by Giovannucci E, Ascherio A, Rimm EB, Stampfer MJ, Colditz GA, Willett WC.(PubMed)
(13) β-ionone induces cell cycle arrest and apoptosis in human prostate tumor cells by Jones S, Fernandes NV, Yeganehjoo H, Katuru R, Qu H, Yu Z, Mo H.(PubMed)
(14) Synergistic effect and mechanism of vitamin A and vitamin D on inducing apoptosis of prostate cancer cells by Sha J, Pan J, Ping P, Xuan H, Li D, Bo J, Liu D, Huang Y.(PubMed)
(15) Diverse effects of β-carotene on secretion and expression of VEGF in human hepatocarcinoma and prostate tumor cells by Chen HY, Huang SM, Yang CM, Hu ML.(PubMed)
(16) Fucoxanthin induces GADD45A expression and G1 arrest with SAPK/JNK activation in LNCap human prostate cancer cells by Satomi Y.(PubMed)
(17) Fucoxanthin, a natural carotenoid, induces G1 arrest and GADD45 gene expression in human cancer cells by Yoshiko S, Hoyoku N.(PubMed)
(18) Growth inhibitory efficacy of lycopene and β-carotene against androgen-independent prostate tumor cells xenografted in nude mice by Yang CM, Yen YT, Huang CS, Hu ML.(PubMed)
 (19) Supplemental and dietary vitamin E, beta-carotene, and vitamin C intakes and prostate cancer risk by Kirsh VA, Hayes RB, Mayne ST, Chatterjee N, Subar AF, Dixon LB, Albanes D, Andriole GL, Urban DA, Peters U; PLCO Trial.(PubMed)