Abstract
Purpose
A structure-activity study was undertaken to determine the influence of side chain length of phenyl alkanoic acids and the degree of unsaturation of phenyl alkenoic acids on the induction of histone acetylation and inhibition of cancer cell proliferation.
Materials and methods
Studies on cell proliferation were performed with DS19 mouse erythroleukemic cells, PC-3 human prostate cancer cells and Caco-2 human colon cancer cells. Actions on histone deacetylase and the induction of histone acetylation were compared for 4-phenylbutyrate and structurally related molecules.
Results
Increasing inhibition of cell proliferation by phenyl alkanoic acids together with a decrease in cells in S phase and an increase in apoptotic cells was observed with increased chain length between four and ten carbons. Introduction of double bonds into the side chain was associated with increased growth inhibition. In contrast, 4-phenylbutyrate was a more potent inhibitor of histone deacetylase and inducer of histone acetylation than the other phenyl alkanoic acids examined.
Conclusions
In comparison with the action of 4-phenylbutyrate, actions other than inhibition of histone deacetylase appear to be more important for growth inhibition by longer chain phenyl alkanoic and phenyl alkenoic acids.
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References
Boffa LC, Vidali G, Mann RS, Allfrey VG (1978) Suppression of histone deacetylation in vivo and in vitro by sodium butyrate J Biol Chem 253:3364
Carducci MA, Nelson JB, Chan-Tack KM, Ayyagari SR, Sweatt WH, Campbell PA, Nelson WG, Simons JW (1996) Phenylbutyrate induces apoptosis in human prostate cancer and is more potent than phenylacetate. Clin Res 2:379
Chang T-H, Szabo E (2002) Enhanced growth inhibition by combination differentiation therapy with ligands of peroxisome proliferator-activated receptor-γ and inhibitors of histone deacetylase in adenocarcinoma of the lung. Clin Cancer Res 8:1206
Clarke KO, Ludeman SM, Springer JB, Colvin OM, Lea MA, Harrison LE, (2002) Exposure to a deuterated analogue of phenylbutyrate retards S phase progression in HT-29 colon cancer cells. J Pharm Sci 91:1054
Fajas L, Egler V, Reiter R, Hansen J, Kristiansen K, Debril MB, Miard S, Auwerx J (2002) The retinoblastoma-histone deacetylase 3 complex inhibits PPARγ and adipocyte differentiation. Dev Cell 3:903
Feinman R, Clarke KO, Harrison LE (2002) Phenylbutyrate-induced apoptosis is associated with inactivation of NF-κB in HT-29 colon cancer cells. Cancer Chemother Pharmacol 49:27
Gilbert J, Baker SD, Bowling MK, Grochow L, Figg WD, Zabelina Y, Donehower RC, Carducci MA (2001) A phase I dose escalation and bioavailability study of oral sodium phenylbutyrate in patients with refractory solid tumor malignancies. Clin Cancer Res 7:2292
Gore SD, Carducci MA (2000) Modifying histones to tame cancer: clinical development of sodium phenylbutyrate and other histone deacetylase inhibitors. Exp Opin Invest Drugs 9:2923
Gore SD, Weng L-J, Figg WD, Zhai SZ, Donehower RC, Dover G, Grever MR, Griffin C, Grochow LB, Hawkins A, Burks, K, Zabelena Y, Miller CB (2002) Impact of prolonged infusions of the putative differentiating agent sodium phenylbutyrate on myelodysplastic syndromes and acute myeloid leukemia. Clin Cancer Res 8:963
Houseknecht KL, Cole BM, Steele PJ (2002) Peroxisome proliferator-activated receptor gamma (PPARγ) and its ligands: a review. Domestic Animal Endocrinol 22:1
Hruban Z, Morris HP, Mochizuki Y, Meranze DR, Slesers A (1971) Light microscopic observations of Morris hepatomas. Cancer Res 31:752
Jung M (2001) Inhibitors of histone deacetylase as new anticancer agents. Curr Med Chem 8:1505
Krämer OH, Göttlicher M, Heinzel T (2001) Histone deacetylase as a therapeutic target. Trends Endocrinol Metab 12:294
Lea MA, Randolph VM (1998) Induction of reporter gene expression by inhibitors of histone deacetylase. Anticancer Res 18:2717
Lea MA, Tulsyan N (1995) Discordant effects of butyrate analogues on erythroleukemia cell proliferation and histone deacetylase. Anticancer Res 15:879
Lea MA, Randolph VM, Hodge SK (1999) Induction of histone acetylation and growth regulation in erythroleukemia cells by 4-phenylbutyrate and structural analogs. Anticancer Res 19:1971
Lea MA, Rasheed M, Randolph VM, Khan F, Shareef A, desBordes C (2002) Induction of histone acetylation and inhibition of growth of mouse erythroleukemia cells by S-allylmercaptocysteine. Nutr Cancer 43:90
Lea MA, Shareef A, desBordes C (2003) Actions other than inhibition of histone deacetylase may be more important for growth inhibition by some phenyl alkanoic and phenyl alkenoic acids. Proc Am Assoc Cancer Res 44 (2nd edn), 1315
Marks PA, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK (2001) Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer 1:194
Melchior SW, Brown LG, Figg WD, Quinn JA, Santucci RA, Brunner J, Thüroff JW, Lange PH, Vessella RL (1999) Effects of phenylbutyrate on proliferation and apoptosis in human prostate cancer cells in vitro and in vivo. Int J Oncol 14:501
Morris HP, Meranze DR (1974) Induction and some characteristics of “minimal deviation” and other transplantable rat hepatomas. Recent Results Cancer Res 44:102
Pili R, Kruszewski MP, Hager BW, Lantz J, Carducci MA (2001) Combination of phenylbutyrate and 13-cis retinoic acid inhibits prostate tumor growth and angiogenesis. Cancer Res 61:1477
Pineau T, Hudgins WR, Liu L, Chen L-C, Sher T, Gonzalez FJ, Samid D (1996) Activation of a human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogs. Biochem Pharmacol 52:659
Reeves R, Candido EPM (1978) Turnover of histone acetyl groups in cultured cells is inhibited by sodium butyrate. FEBS Lett 91:117
Rosen ED, Spiegelman BM (2001) PPARγ: a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem 276:37731
Samid D, Wells M, Greene ME, Shen W, Palmer CAN, Thibault A (2000) Peroxisome proliferator-activated receptor γ as a novel target in cancer therapy: binding and activation by an aromatic fatty acid with clinical antitumor activity. Clin Cancer Res 6:933
Sealy L, Chalkley R (1978) The effect of sodium butyrate on histone modification. Cell 14:115
Warrell RP, He L-Z, Richon V, Calleja E, Pandolfi PP (1998) Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase. J Natl Cancer Inst 90:1621
Yoshida M, Furumai R, Nishiyama M, Komatsu Y, Nishino N, Horinouchi S (2001) Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemother Pharmacol 48:S20
Acknowledgements
This research was supported in part by a grant from the Alma Toorock Memorial for Cancer Research. Phenyl alkanoic acids and structurally related molecules other than 4-phenylbutyric acid were provided by CircaGen Pharmaceutical, Phoenix, Md. We are grateful to Ms. Dana Stein for performing the analysis of cell cycle parameters.
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Lea, M.A., Shareef, A., Sura, M. et al. Induction of histone acetylation and inhibition of growth by phenyl alkanoic acids and structurally related molecules. Cancer Chemother Pharmacol 54, 57–63 (2004). https://doi.org/10.1007/s00280-004-0782-5
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DOI: https://doi.org/10.1007/s00280-004-0782-5