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DOI: 10.1055/s-2006-951747
© Georg Thieme Verlag KG Stuttgart · New York
Investigation of Cytotoxic Activity on Human Cancer Cell Lines of Arborinine and Furanoacridones Isolated from Ruta graveolens
Publication History
Received: August 31, 2006
Accepted: October 8, 2006
Publication Date:
15 November 2006 (online)
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Abstract
The cytotoxic effects of a series of furanoacridones isolated from Ruta graveolens L. (Rutaceae) and of two further acridone alkaloids (arborinine and evoxanthine) were investigated by means of the MTT assay, using the human cell lines HeLa, MCF7 and A431. Arborinine proved best in inhibiting the proliferation of all three cell lines. The cytotoxic potency of the furacridone alkaloids was a function of their lipid solubility, which was determined by means of PAMPA. The capacity of the most effective furanoacridones to induce apoptosis was demonstrated by flow cytometric cell cycle analysis and by staining with ethidium bromide and acridine orange. This finding was reinforced by determining the apoptosis-regulating factors Bcl-2 and Bax, which were revealed by means of RT-PCR to change dose-dependently. The data presented here indicate that naturally occurring furanoacridones can be regarded as excellent starting structures for the potential development of new anticancer agents.
Abbreviations
AO:acridine orange
cDNA:copy deoxyribonucleic acid
DMSO:dimethyl sulfoxide
dNTP:deoxyribonucleotide triphosphate
EB:ethidium bromide
hGAPDH:human glyceraldehyde-3-phosphate dehydrogenase
MMLV-RT:moloney murine leukemia virus-reverse transcriptase
mRNA:messenger ribonucleic acid
MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
PAMPA:parallel artificial membrane permeability assays
PBS:phosphate buffered saline
RNA:ribonucleic acid
RT-PCR:reverse transcription-polymerase chain reaction
Key words
Ruta graveolens L. - Rutaceae - acridone alkaloids - cytotoxicity - apoptosis
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References
- 1 Yamamoto N, Furukawa H, Ito Y, Yoshida S, Maeno K, Nishiyama Y. Anti-herpesvirus activity of citrusinine-I, a new acridone alkaloid, and related compounds. Antiviral Res. 1989; 12 21-36
- 2 Akanitapichat P, Bastow K F. The antiviral agent 5-chloro-1,3-dihydroxyacridone interferes with assembly and maturation of Herpes simplex virus. Antiviral Res. 2002; 53 113-26
- 3 Bastow K F. New acridone inhibitors of human herpes virus replication. Curr Drug Targets Infect Disord. 2004; 4 323-30
- 4 Fujioka H, Nishiyama Y, Furukawa H, Kumada N. In vitro and in vivo activities of atalaphillinine and related acridone alkaloids against rodent malaria. Antimicrob Agents Chemother. 1989; 33 6-9
- 5 Ahua K M, Ioset J -R, Ransijn A, Mauel J, Mavi S, Hostettmann K. Antileishmanial and antifungal acridone derivatives from the roots of Thamnosma rhodesica . Phytochemistry. 2004; 65 963-8
- 6 Viola A, Mannoni P, Chanon M, Julliard M, Mehta G, Maiya B G. et al . Phototoxicity of some novel porphyrin hybrids against the human leukemic cell line TF-1. J Photochem Photobiol. 1997; 40 263-72
- 7 Bastow K F, Itoigawa M, Furukawa H, Kashiwada Y, Bori I D, Ballas L M. et al . Antiproliferative actions of 7-substituted 1,3-dihydroxyacridones; possible involvement of DNA topoisomerase II and protein kinase C as biochemical targets. Bioorg Med Chem. 1994; 2 1403-11
- 8 Read M A, Wood A A, Harrison J R, Gowan S M, Kelland L R, Dosanjh H S. et al . Molecular modeling studies on G-quadruplex complexes of telomerase inhibitors: structure-activity relationships. J Med Chem. 1999; 42 4538-46
- 9 David-Cordonnier M H, Laine W, Gaslonde T, Michel S, Tillequin F, Koch M. et al . Design of novel antitumor DNA alkylating agents: the benzacronycine series. Curr Med Chem Anticancer Agents. 2004; 4 83-92
- 10 Elomri A, Mitaku S, Michel S, Skaltsounis A L, Tillequin F, Koch M. et al . Synthesis and cytotoxic and antitumor activity of esters in the 1,2-dihydroxy-1,2-dihydroacronycine series. J Med Chem. 1996; 39 4762-6
- 11 Michel S, Seguin E, Tillequin F. Structure-activity relationships in the acronycine series. Curr Med Chem. 2002; 9 1689-700
- 12 Borner C. The Bcl-2 protein family: sensors and checkpoints for life-or-death decisions. Mol Immunol. 2003; 39 615-47
- 13 Gross A, McDonnell J M, Korsmeyer S J. Bcl-2 family members and the mitochondria in apoptosis. Genes Dev. 1999; 13 1899-911
- 14 Szendrei K, Reisch J, Novák I, Minker E. Acridonalkaloide aus den Wurzeln von Ruta graveolens L. Dtsch Akad Wissensch Berlin 1971: 513
- 15 Reisch J, Rózsa Z, Szendrei K, Novák I, Minker E. Weitere Acridon-alkaloide aus Ruta graveolens . Phytochemistry. 1972; 11 2121-2
- 16 Reisch J, Rózsa Z, Szendrei K, Novák I, Minker E. Acridon-alkaloid-glucoside aus Ruta graveolens . Phytochemistry. 1976; 15 240-1
- 17 Reisch J, Rózsa Z, Szendrei K, Novák I, Minker E. Furacridon, 1-hydroxy-3-methoxy-N-methylacridon und Isogravacridonchlorin aus den Wurzeln von Ruta graveolens . Phytochemistry. 1977; 16 151-2
- 18 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65 55-63
- 19 Wohnsland F, Faller B. High-throughput permeability pH profile and high-throughput alkane/water log P with artificial membranes. J Med Chem. 2001; 44 923-30
- 20 Ribble D, Goldstein N B, Norris D A, Shellman Y G. A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnol. 2005; 5 12
- 21 Vermes I, Haanen C, Reutelingsperger C. Flow cytometry of apoptotic cell death. J Immunol Methods. 2000; 243 167-90
- 22 Chomczynski P, Sacchi M. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987; 162 156-9
- 23 Buommino E, Nicoletti R, Gaeta G M, Orlando M, Ciavatta M L, Baroni A. et al . 3-O-Methylfunicone, a secondary metabolite produced by Penicillium pinophilum, induces growth arrest and apoptosis in HeLa cells. Cell Prolif. 2004; 37 413-26
- 24 Tso J U, Sun X H, Kao T, Reece K S, Wu R. Isolation of rat and human glycerinaldehyde-3-phosphate dehydrogenase cDNA: genomic complexity and molecular evolution of the gene. Nucleic Acids Res. 1985; 13 2485-502
- 25 Michael J P. Quinoline, quinazoline and acridone alkaloids. Nat Prod Rep. 2005; 22 627-46
- 26 Costes N, Le Deit H, Michel S, Tillequin F, Koch M, Pfeiffer B. et al . Synthesis and cytotoxic and antitumor activity of benzo[b]pyrano[3,2-h]acridin-7-one analogues of acronycine. J Med Chem. 2000; 43 2395-402.
- 27 Wu T -S, Furukawa H, Kuoh C -S. Acridone alkaloids IV. Structures of four new acridone alkaloids from Glycosmis citrifolia (Willd.) Lindl. Heterocycles. 1982; 19 1047-51
- 28 Demeunynck M, Charmantray F, Martelli A. Interest of acridine derivatives in the anticancer chemotherapy. Curr Pharm Des. 2001; 7 1703-24
- 29 Choi Y H, Kong K R, Kil Y -A, Jung K -O, Kil J -H, Rhee S -H. et al . Induction of Bax and activation of caspases during ß-sitosterol-mediated apoptosis in human colon cancer cells. Int J Oncol. 2003; 23 1657-62
- 30 Sohrab M H, Chowdhury R, Rahman K M, Hasan C M, Rashid M A. Antibacterial activity and cytotoxicity of extractives from Ravenia spectabilis . Fitoterapia. 2004; 75 510-3.
George Falkay
Department of Pharmacodynamics and Biopharmacy
University of Szeged
H-6720 Szeged
Eötvös u. 6
Hungary
Phone: +36-62-545-567
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Email: Falkay@pharma.szote.u-szeged.hu
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