Plaunotol Induces Apoptosis of Gastric Cancer Cells

Abstract

Although some isoprenoids, such as taxans and geranylgeraniol (GGOH), have been reported to have strong anticancer activities, the effect of plaunotol, the isoprenoid extracted from the leaves of Plau-noi, on cancer has not yet been evaluated. Here, we aimed to investigate the effect of plaunotol on gastric cancer cell lines. Three gastric cancer cell lines, namely MKN-45, MKN-74 and AZ-521 were used. Plaunotol was tested at 10, 20, 30 and 40 μmol/L. Plaunotol dose-dependently inhibited the growth of all gastric cancer cells, dependent on the induction of apoptosis. Caspases-8, -9 and -3, were found to be activated in the apoptotic cells. The expression of Bax protein was increased, but Bcl-2 and Bcl-xL protein expressions were not significantly affected. Plaunotol should be a promising new antitumor agent, and since it is already available for clinical use in Japan, its anticancer properties should be confirmed in clinical trials.

Abbreviations

COX: cyclooxygenase

DMSO: dimethyl sulfoxide

FITC: fluorescein isothiocyanate

GGOH: geranylgeraniol

MTS: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfo-phenyl)-2H-tetrazolium

PBS: phosphate-buffered saline

PG: prostaglandin

PI: propidium iodide

TUNEL: terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling

Key words

Plaunotol - cell apoptosis - isoprenoids - gastric cancer

References

• 1 Ushiyama S, Matsuda K, Asai F, Yamazaki M. Stimulation of prostaglandin production by (2E,6Z,10E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraen-1-ol (plaunotol), a new anti-ulcer drug, in vitro and in vivo .  Biochem Pharmacol. 1987;  36 369-75.
• 2 Kohda I, Nagai H, Iwai M, Watanabe M, Yokoyama K, Tsujikawa K. et al . Further studies on the anti-ulcerogenic effects of compound, 2-(E-2-decenoylamino)ethyl 2-(cyclohexylethyl) sulfide.  Chem Pharm Bull (Tokyo). 1991;  39 1832-6.
• 3 Okabe N, Okada M, Sakai T, Kuroiwa A. Effect of plaunotol on superoxide production activity in vivo .  Dig Dis Sci. 1995;  40 2321-2.
• 4 Shiratori K, Watanabe S, Takeuchi T, Shimizu K. Plaunotol inhibits postprandial gastrin release by its unique secretin-releasing action in humans.  Dig Dis Sci. 1990;  35 1140-5.
• 5 Murakami K, Okajima K, Harada N, Isobe H, Liu W, Johno M. et al . Plaunotol prevents indomethacin-induced gastric mucosal injury in rats by inhibiting neutrophil activation.  Aliment Pharmacol Ther. 1999;  13 521-30.
• 6 Karita M, Li Q, Okita K. Evaluation of new therapy for eradication of H. pylori infection in nude mouse model.  Am J Gastroenterol. 1993;  88 1366-72.
• 7 Matsumoto Y, Hamashima H, Masuda K, Shiojima K, Sasatsu M, Arai T. The antibacterial activity of plaunotol against Staphylococcus aureus isolated from the skin of patients with atopic dermatitis.  Microbios. 1998;  96 149-55.
• 8 Mo H, Elson C E. Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention.  Exp Biol Med (Maywood). 2004;  229 567-85.
• 9 Elson C E, Peffley D M, Hentosh P, Mo H. Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer.  Proc Soc Exp Biol Med. 1999;  221 294-311.
• 10 Tanaka M, Obata T, Sasaki T. Evaluation of antitumour effects of docetaxel (Taxotere) on human gastric cancers in vitro and in vivo .  Eur J Cancer. 1996;  32A 226-30.
• 11 Diaz J F, Andreu J M. Assembly of purified GDP-tubulin into microtubules induced by taxol and taxotere: reversibility, ligand stoichiometry, and competition.  Biochemistry. 1993;  32 2747-55.
• 12 Burke Y D, Stark M J, Roach S L, Sen S E, Crowell P L. Inhibition of pancreatic cancer growth by the dietary isoprenoids farnesol and geraniol.  Lipids. 1997;  32 151-6.
• 13 Miquel K, Pradines A, Favre G. Farnesol and geranylgeraniol induce actin cytoskeleton disorganization and apoptosis in A549 lung adenocarcinoma cells.  Biochem Biophys Res Commun. 1996;  225 869-76.
• 14 Ohizumi H, Masuda Y, Nakajo S, Sakai I, Ohsawa S, Nakaya K. Geranylgeraniol is a potent inducer of apoptosis in tumor cells.  J Biochem (Tokyo). 1995;  117 11-3.
• 15 Takeda Y, Nakao K, Nakata K, Kawakami A, Ida H, Ichikawa T. et al . Geranylgeraniol, an intermediate product in mevalonate pathway, induces apoptotic cell death in human hepatoma cells: death receptor-independent activation of caspase-8 with down-regulation of Bcl-xL expression.  Jpn J Cancer Res. 2001;  92 918-25.
• 16 Oiso T. Incidence of stomach cancer and its relation to dietary habits and nutrition in Japan between 1900 and 1975.  Cancer Res. 1975;  35 3254-8.
• 17 Kawai K, Tsuno N H, Kitayama J, Okaji Y, Yazawa K, Asakage M. et al . Anti-angiogenic properties of plaunotol.  Anticancer Drugs. 2005;  16 401-7.
• 18 Edwards P A, Ericsson J. Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway.  Annu Rev Biochem. 1999;  68 157-85.
• 19 Crick D C, Andres D A, Waechter C J. Novel salvage pathway utilizing farnesol and geranylgeraniol for protein isoprenylation.  Biochem Biophys Res Commun. 1997;  237 483-7.
• 20 Bifulco M. Role of the isoprenoid pathway in ras transforming activity, cytoskeleton organization, cell proliferation and apoptosis.  Life Sci. 2005;  77 1740-9.
• 21 Winter-Vann A M, Casey P J. Post-prenylation-processing enzymes as new targets in oncogenesis.  Nat Rev Cancer. 2005;  5 405-12.
• 22 Hashimoto K, Morishige K, Sawada K, Tahara M, Shimizu S, Sakata M. et al . Geranylgeranylacetone inhibits lysophosphatidic acid-induced invasion of human ovarian carcinoma cells in vitro .  Cancer. 2005;  103 1529-36.
• 23 Naka K, Yokozaki H, Domen T, Hayashi K, Kuniyasu H, Yasui W. et al . Growth inhibition of cultured human gastric cancer cells by 9-cis-retinoic acid with induction of cdk inhibitor Waf1/Cip1/Sdi1/p21 protein.  Differentiation. 1997;  61 313-20.
• 24 Fang J Y, Xiao S D. Effect of trans-retinoic acid and folic acid on apoptosis in human gastric cancer cell lines MKN-45 and MKN-28.  J Gastroenterol. 1998;  33 656-61.
• 25 Wendum D, Masliah J, Trugnan G, Flejou J F. Cyclooxygenase-2 and its role in colorectal cancer development.  Virchows Arch. 2004;  445 327-33.
• 26 Elsom LFC H D, Darragh A, Lambe R F. The pharmacokinetics of ¹⁴C-plaunotol in human subjects after oral administration.  Prog Med. 1985;  5 863-8.