Abstract
Apigenin, a common dietary flavonoid abundantly present in fruits and vegetables, may have the potential for prevention and therapy for prostate cancer. Here, we report for the first time that apigenin inhibits the growth of androgen-responsive human prostate carcinoma LNCaP cells and provide molecular understanding of this effect. The cell growth inhibition achieved by apigenin treatment resulted in a significant decrease in AR protein expression along with a decrease in intracellular and secreted forms of PSA. These effects were also observed in DHT-stimulated cells. Further, apigenin treatment of LNCaP cells resulted in G1 arrest in cell cycle progression which was associated with a marked decrease in the protein expression of cyclin D1, D2 and E and their activating partner cdk2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. The induction of WAF1/p21 appears to be transcriptionally upregulated and is p53 dependent. In addition, apigenin inhibited the hyperphosphorylation of the pRb protein in these cells. Apigenin treatment also resulted in induction of apoptosis as determined by DNA fragmentation, PARP cleavage, fluorescence microscopy and flow cytometry. These effects were found to correlate with a shift in Bax/Bcl-2 ratio more towards apoptosis. Apigenin treatment also resulted in down-modulation of the constitutive expression of NF-κB/p65. Taken together, these findings suggest that apigenin has strong potential for development as an agent for prevention against prostate cancer.
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Abbreviations
- PSA:
-
Prostate-specific antigen
- AR:
-
androgen receptor
- NF-κB:
-
nuclear factor-kappa B
- pRb:
-
hypo-phosphorylated retinoblastoma
- ppRb:
-
hyper-phosphorylated retinoblastoma
- DMSO:
-
dimethyl sulphoxide
- PBS:
-
phosphate buffered saline
- TBS:
-
tris buffered saline
- DHT:
-
5α-dihydrotestosterone
- cdk:
-
cyclin-dependent kinase
- cki:
-
cyclin kinase inhibitor
References
Adams PD . 2001 Biochim. Biophys. Acta 1471: 123–133
Agarwal ML, Taylor WR, Chernov MV, Chernova OB, Stark GR . 1998 J. Biol. Chem. 273: 1–4
Ahmad N, Gupta S, Mukhtar H . 1999 Oncogene 18: 1891–1896
Ahmad N, Gupta S, Mukhtar H . 2000 Arch. Biochem. Biophys. 376: 338–346
Birt DF, Mitchell D, Gold B, Pour P, Pinch HC . 1997 Anticancer Res. 17: 85–91
Birt DF, Shull JS, Yaktine AL . 1998 Chemoprevention of cancer Shils ME, Olson JA, Shike M and Ross AC (eds) Baltimore: Williams & Wilkins pp 1263–1295
Bours V, Bentires-Al M, Hellin AC, Viatour P, Robe P, Delhalle S, Benoit V, Merville MP . 2000 Biochem. Pharmacol. 60: 1085–1089
Caltagirone S, Rossi C, Poggi A, Ranelletti FO, Natali PG, Brunetti M, Aiello FB, Piantelli M . 2000 Int. J. Cancer 87: 595–600
Chaumontet C, Bex V, Gaillard-Sanchez I, Seillan-Heberden C, Suschetet M, Martel P . 1994 Carcinogenesis 15: 2325–2330
Cohen JH, Kristal AR, Stanford JL . 2000 J. Natl. Cancer Inst. 92: 61–68
Duthie G, Crozier A . 2000 Curr. Opin. Clin. Nutr. Metab. Care. 3: 447–451
Fotsis T, Pepper MS, Montesano R, Aktas E, Breit S, Schweigerer L, Rasku S, Wahala K, Adlercreutz H . 1998 Baillieres Clin. Endocrinol. Metab. 12: 649–666
Gupta S, Afaq F, Mukhtar H . 2001 Biochem. Biophys. Res. Commun. 287: 914–920
Henttu P, Lukkarinen O, Vihko P . 1990 Int. J. Cancer 45: 654–660
Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer SJ . 1993 Cell 75: 241–251
Hollman PC, Katan MB . 1999a Food Chem. Toxicol. 37: 937–942
Hollman PC, Katan MB . 1999b Free Radic. Res. 31: 75–80
Kim HP, Mani I, Iversen L, Ziboh VA . 1998 Prostaglandins Leukot. Essent. Fatty Acids. 58: 17–24
Kolonel LN, Hankin JH, Whittemore AS, Wu AH, Gallagher RP, Wilkens LR, John EM, Howe GR, Dreon DM, West DW, Paffenbarger Jr RS . 2000 Cancer Epidemiol. Biomarkers Prev. 9: 795–804
Kuo ML, Lee KC, Lin JK . 1992 Mutat. Res. 270: 87–95
Kuo ML, Lin JK, Huang TS, Yang NC . 1994 Cancer Lett. 87: 91–97
Lamb DJ, Weigel NL, Marcelli M . 2001 Vitam. Horm. 62: 199–230
Lee C, Sutkowski DM, Sensibar JA, Zelner D, Kim I, Amsel I, Shaw N, Prins GS, Kozlowski JM . 1995 Endocrinology 136: 796–803
Lee JI, Burckart GJ . 1998 J. Clin. Pharmacol. 38: 981–993
Lepley DM, Pelling JC . 1997 Mol. Carcinog. 19: 74–82
Lepley DM, Li B, Birt DF, Pelling JC . 1996 Carcinogenesis 17: 2367–2375
Liang YC, Huang YT, Tsai SH, Lin-Shiau SY, Chen CF, Lin JK . 1999 Carcinogenesis 20: 1945–1952
Masciullo V, Khalili K, Giordano A . 2000 Int. J. Oncol. 17: 897–902
McVean M, Xiao H, Isobe K, Pelling JC . 2000 Carcinogenesis 21: 633–639
Meyers FJ, Gumerlock PH, Chi SG, Borchers H, Deitch AD, deVere White RW . 1998 Cancer 83: 2534–2539
Middleton E . 1984 Trends Pharmacol. Sci. 5: 335–338
Motokura T, Arnold A . 1993 Curr. Opin. Genet. Dev. 3: 5–10
Mueller A, Odze R, Jenkins TD, Shahsesfaei A, Nakagawa H, Inomoto T, Rustgi AK . 1997 Cancer Res. 57: 5542–5549
Navone NM, Troncoso P, Pisters LL, Goodrow TL, Palmer JL, Nichols WW, von Eschenbach AC, Conti CJ . 1993 J. Natl. Cancer Inst. 85: 1657–1669
Naz RK, Herness EA . 2001 Front. Biosci. 6: 1083–1088
Panes J, Gerritsen ME, Anderson DC, Miyasaka M, Granger DN . 1996 Microcirculation 3: 279–286
Pestell RG, Albanese C, Reutens AT, Segall JE, Lee RJ, Arnold A . 1999 Endocr. Rev. 20: 501–534
Pucci B, Kasten M, Giordano A . 2000 Neoplasia 2: 291–299
Reed JC . 1995 Curr. Opin. Oncol. 7: 541–546
Sandhu C, Slingerland J . 2000 Cancer Detect. Prev. 24: 107–118
Stamey TA, Yang N, Hay AR, McNeal JE, Freiha FS, Redwine E . 1987 N. Engl. J. Med. 317: 909–916
Takahashi T, Kobori M, Shinmoto H, Tsushida T . 1998 Biosci. Biotechnol. Biochem. 62: 2199–2204
Vidal A, Koff A . 2000 Gene 247: 1–15
Vogelstein B, Lane D, Levine AJ . 2000 Nature 408: 307–310
Wang LG, Liu XM, Kreis W, Budman DR . 1997 Cancer Res. 57: 714–719
Wang W, Heideman L, Chung CS, Pelling JC, Koehler KJ, Birt DF . 2000 Mol. Carcinog. 28: 102–110
Wei H, Tye L, Bresnick E, Birt DF . 1990 Cancer Res. 50: 499–502
Yin F, Giuliano AE, Van Herle AJ . 1999 Thyroid 9: 369–376
Yin F, Giuliano AE, Law RE, Van Herle AJ . 2001 Anticancer Res. 21: 413–420
Yin XM, Oltvai ZN, Veis-Novack D, Linette GP, Korsmeyer SJ . 1994 Cold Spring Harb. Symp. Quant. Biol. 59: 387–393
Zornig M, Hueber A, Baum W, Evan G . 2001 Biochim. Biophys. Acta 1551: F1–F37
Acknowledgements
Supported by grants from the United States Public Health Service (RO1CA 78809), American Institute for Cancer research (00A030), and Department of Defense (DAMD 17-00-1-0527).
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Gupta, S., Afaq, F. & Mukhtar, H. Involvement of nuclear factor-kappa B, Bax and Bcl-2 in induction of cell cycle arrest and apoptosis by apigenin in human prostate carcinoma cells. Oncogene 21, 3727–3738 (2002). https://doi.org/10.1038/sj.onc.1205474
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DOI: https://doi.org/10.1038/sj.onc.1205474
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