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Synthetic hispidin, a PKC inhibitor, is more cytotoxic toward cancer cells than normal cells in vitro

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Abstract

The trypanocidal activity of naturally occurring 6-(3,4-dihydroxystyryl)-4-hydroxy-2-pyrone (hispidin) prompted us to examine its cytotoxic activity toward normal and cancerous cells in culture. Hispidin synthesized in our laboratory to a high degree of purity (checked by 1H and 13C NMR spectroscopy) was shown to be cytotoxic (between 10-3 mol/L and 10-7 mol/L) toward normal human MRC-5 fibroblasts, human cancerous keratinocytes (SCL-1 cell line), and human cancerous pancreatic duct cells (Capan-1 cell line). Interestingly, addition of hispidin in three successive doses (between 10-5 mol/L and 10-7 mol/L) led to a 100-fold increase in activity with an enhanced activity on cancer cells compared to normal cells (50%). Synthetic hispidin was found to inhibit isoform β of protein kinase C (IC50 of 2 × 10-6 mol/L), but not E. coli and placental type XV alkaline phosphatases. The enhanced activity of hispidin toward the cancerous cell lines is discussed.

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References

  • Andreu JM, Gorbunoff MJ, Medrano FJ, Rossi M, Timasheff SN. Mechanism of colchicine binding to tubulin. Tolerance of substituents in ring-C′ of biphenyl analogs. Biochemistry. 1991;30:3777–86.

    Google Scholar 

  • Ardalan B, Glazer R. An update on the biochemistry of 5-fluorouracil. Cancer Treat Rev. 1981;8:157–67.

    Google Scholar 

  • Bishop WR, Pachter JA, Pai JK. Regulation of phospholipid hydrolysis and 2nd messenger formation by protein kinase C. Adv Enzyme Regul.} 1992;32:177–92.

    Google Scholar 

  • Blum RH, Carter SK. Adriamycin: a new anti-cancer drug with significant clinical activity. Ann Int Med. 1974;80:249–59.

    Google Scholar 

  • Bollag GE, Roth RA, Beaudoin J, Mochly-Rosen D, Koshland DE. Protein kinase C directly phosphorylates the insulin receptor in vitro and reduces its protein-tyrosine kinase activity. Proc Natl Acad Sci USA. 1986;83:5822–4.

    Google Scholar 

  • Boukamp P, Tilgen W, Dzarlieva RT et al. Phenotypic and genotypic characteristics of a cell line from a squamous cell carcinoma of human skin. J Natl Cancer Inst. 1982;68:415–22.

    Google Scholar 

  • Boukamp P, Rupniak TR, Fusenig NE. Environmental mod-ulation of the expression of differentiation and malignancy in six human squamous cell carcinoma cell lines. Cancer Res. 1985;45:5582–92.

    Google Scholar 

  • Brautigan DL. Protein phosphatases. Recent Prog Hormone Res. 1994;49:197-214.

  • Chadwich M, Rogers WI. The physiological disposition of 5-fluorouracil in mice bearing solid L1210 lymphocytic leuke-mia. Cancer Res. 1972;32:1045–56.

    Google Scholar 

  • Chang BK. Differential sensitivity of pancreatic adenocarcino-ma cell lines to chemotherapeutic agents in culture. Cancer Treat Rev. 1983;67:355–61.

    Google Scholar 

  • Cohen GL, Bauer WR, Barton JK, Lippard SJ. Binding of cis-and trans-dichlorodiammineplatinum (II) to DNA: evi-dence for unwinding and shortening of the double helix. Science. 1979;203:1014–6.

    Google Scholar 

  • Cohen P. The discovery of protein phosphatases: from chaos and confusion to an understanding of their role in cell regulation and human disease. Bioassays. 1994;16:583–8.

    Google Scholar 

  • Dechecchi MC, Tamanini A, Berton G, Cabrini G. Protein kinase C activates chloride conductance in C127 cells stably expressing the cystic fibrosis gene. J Biol Chem. 1993;268: 11321–5.

    Google Scholar 

  • Edwards RL, Wilson DV. Constituents of the higher fungi. Part II. The synthesis of hispidin. J Chem Soc. 1961;4:5003–4.

    Google Scholar 

  • Edwards RL, Lewis DG, Wilson DV. Constituents of the higher fungi. Part I. Hispidin, a new 4-hydroxy-6-styryl-2-pyrone from Polyporus hispidus. J Chem Soc. 1961;4:4995–5002.

    Google Scholar 

  • Fögh J, Fogh JM, Orfeo T. One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. J Natl Cancer Inst. 1977;59:221–6.

    Google Scholar 

  • Gali RR, Pugazhenthi S, Chandelier RL. Reciprocal effects on the protein kinase C inhibitors staurosporine and H-7 on the regulation of glycol synthetase and phosphorases in the primary culture of hepatocytes. Metab Clin Exp. 1993;42: 1475–80.

    Google Scholar 

  • Gonda Y, Nishizawa K, Ando S et al. Involvement of protein kinase-C in the regulation of assembly-disassembly of neurofilaments in vitro. Biochem Biophys Res Commun. 1990;167:1316–25.

    Google Scholar 

  • Hagiwara M, Inoue S, Tanaka T, Nunoki K, Ito M, Hikada H. Differential effects of flavonoids as inhibitors of tyrosine protein kinases and serine/threonine protein kinases. Bio-chem Pharmacol. 1988;37:2987–92.

    Google Scholar 

  • Hartmann KU, Heidelberger C. Studies on fluorinated pyrimi-dines. XIII. Inhibition of thymidylate synthetase. J Biol Chem. 1961;236:3006–13.

    Google Scholar 

  • Hollande E, Levrat Di Donato JH et al. Calcium phosphate deposits in domes of human pancreatic adenocarcinoma (Capan-1) cell cultures. Bio Cell. 1990;69:191–203.

    Google Scholar 

  • Ingebritsen TS, Cohen P. The protein phosphatases involved in cellular regulation. I. Classification and substrate specifi-cities. Eur J Biochem. 1983;132:255–61.

    Google Scholar 

  • Jacobs JP, Jones CM, Baille JP. Characteristics of a human diploid cell designated MRC-5. Nature. 1970;227:168–70.

    Google Scholar 

  • Jiang JB, Hesson DP, Dusak BA, Dexter DL, Kang GH, Hamel E. Synthesis and biological evaluation of 2-styrylquinazolin-4 (3H)-ones, a new class of antimitotic anticancer agents which inhibit tubulin polymerization. J Med Chem. 1990;33:1721–8.

    Google Scholar 

  • Kyriazis AP, Kyriazis AA, Scarpelli DG, Fögh J, Rao MS, Lepera R. Human pancreatic adenocarcinoma cell line Capan-1 in tissue culture and the nude mouse. Morpholo-gic, biologic and biochemical characteristics. Am J Pathol. 1982;106:250–60.

    Google Scholar 

  • Levitzki A. Signal-transduction therapy. A novel approach to disease management. Eur J Biochem. 1994;226:1–13.

    Google Scholar 

  • Ludt J, Tonnessen TI, Sandvig K, Olsnes S. Evidence for involvement of protein kinase C in regulation of intracellu-lar pH by Cl-/HCO3 - antiport. J Membrane Biol. 1991;119: 179–86.

    Google Scholar 

  • Mahieu I, Becq F, Wolfensberger T, Gola M, Carter N, Hollande E. The expression of carbonic anhydrases II and IV in the human pancreatic cancer cell line (Capan-1) is associated with bicarbonate ion channels. Biol Cell. 1994; 81:131–41.

    Google Scholar 

  • Malet-Martino M-C, Faure F, Vialaneix J-P, Palévody C, Hollande E, Martino R. Non-invasive fluorine 19-NMR study of fluoropyrimidine metabolism in cell cultures of human pancreatic and colon adenocarcinoma. Cancer Che-mother Pharmacol. 1986;18:5-10

    Google Scholar 

  • Mullivor RA, Plutkin LI, Harris H. Differential inhibition of the products of the human alkaline phosphatase loci. Ann Hum Genet. 1978;42:1–13.

    Google Scholar 

  • Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988; 334:661–5.

    Google Scholar 

  • Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. FASEB J. 1995;9:484–96.

    Google Scholar 

  • Pawson T. Introduction: protein kinases. FASEB J. 1994;8: 1112–3.

    Google Scholar 

  • Ricouart A, Gesquiere JC, Tartar A, Sergheraert C. Design of potent protein kinase inhibitors using the bisubstrate ap-proach. J Med Chem. 1991;34:73–8.

    Google Scholar 

  • Roberts JJ, Pascoe JM. Cross-linking of complementary strands of DNA in mammalian cells by antitumour plati-num compounds. Nature. 1972;235:282–4.

    Google Scholar 

  • Rosenberg B, Van Camp L, Trosko JE, Mansour VH. Platinum compounds: a new class of potent antitumor agents. Nature. 1969;222:385–6.

    Google Scholar 

  • Sander J, Myatt L. Regulation of prostaglandin-E2 synthesis in human amnion by protein kinase-C. Prostaglandins. 1990; 39:355–63.

    Google Scholar 

  • Skoufias DA, Wilson L. Mechanism of inhibition of microtu-bule polymerization by colchicine: inhibitory potencies of unliganded colchicine and tubulin-colchicine complexes. Biochemistry. 1992;31:738–46.

    Google Scholar 

  • Tamaki T, Nomoto H, Takahashi I, Yato Y, Morimoto M, Tomita F. Staurosporine, a potent inhibitor of phospho-lipid/Ca2+ dependent protein kinase. Biochem Biophys Res Commun. 1986;135:397–403.

    Google Scholar 

  • Tarasiuk J, Kolodziejczyk P, Borowski E. Enzymatic studies of the effect of Cu (II) on oxygen radical production stimu-lated by daunorubicin and ametantrone. Biochem Pharma-col. 1990;39:1405–10.

    Google Scholar 

  • Walsh DA, Van Patten SM. Multiple pathway signal trans-duction by the cAMP-dependent protein kinase. FASEB J. 1994;8:1227–36.

    Google Scholar 

  • Walton KM, Dixon JE. Protein tyrosine phosphatase. Annu Rev Biochem. 1993;62:101–20.

    Google Scholar 

  • Wurzer JC, Tallarida RJ, Sirover MA. New mechanism of action of the cancer chemotherapeutic agent 5-fluorouracil in human cells. J Pharmacol Exp Ther. 1994;269:39–43.

    Google Scholar 

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Gonindard, C., Bergonzi, C., Denier, C. et al. Synthetic hispidin, a PKC inhibitor, is more cytotoxic toward cancer cells than normal cells in vitro. Cell Biol Toxicol 13, 141–153 (1997). https://doi.org/10.1023/A:1007321227010

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