Planta Med 2009; 75(14): 1509-1516
DOI: 10.1055/s-0029-1185807
Pharmacology
Original Paper
© Georg Thieme Verlag KG Stuttgart · New York

Cytotoxic Activity and Cell Cycle Analysis of Quinoline Alkaloids Isolated from Haplophyllum canaliculatum Boiss.

Pegah Varamini1 , Katayoun Javidnia2 , Mohammad Soltani2 , Ahmad Reza Mehdipour2 , Abbas Ghaderi1 , 3
  • 1Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran
  • 2Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
  • 3Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran
Further Information

Publication History

received January 12, 2009 revised April 16, 2009

accepted May 11, 2009

Publication Date:
23 June 2009 (online)

Abstract

Bioassay-guided fractionation of Haplophyllum canaliculatum Boiss. (Rutaceae) extract resulted in isolation of five quinoline alkaloids: 7-isopentenyloxy-γ-fagarine, atanine, skimmianine, flindersine and perfamine. This is the first isolation of these compounds from this endemic species. The antitumor activity of these five isolates was evaluated against RAJI, Jurkat, KG-1a, HEP-2, MCF-7, HL-60 and HL-60/MX1 tumor cell lines. The highest cytotoxic effect was observed on acute lymphoblastic leukemia cell lines. 7-Isopentenyloxy-γ-fagarine, atanine, skimmianine and flindersine exhibited very high cytotoxicity against the RAJI cell line with IC50 values of 1.5, 14.5, 15.6 and 14.9 µg/mL, respectively and 7-isopentenyloxy-γ-fagarine, atanine and skimmianine exhibited very high cytotoxicity against the Jurkat cell line with IC50 values of 3.6, 9.3 and 11.5 µg/mL, respectively. 7-Isopentenyloxy-γ-fagarine was also highly cytotoxic against the MCF-7 cell line (IC50 = 15.5 µg/mL), while atanine, skimmianine, flindersine and perfamine showed moderate to low activity against these cells. All alkaloids had moderate to low cytotoxicity against KG-1a and HEP-2. Investigation of the toxic potential of the alkaloids on HL-60 and HL-60/MX1 showed a significantly higher effect against HL-60/MX1, a multidrug-resistant cell line, compared with the control etoposide (p < 0.05). In all cytotoxicity experiments, peripheral blood mononuclear cells (PBMC) were used as a control for normal hematopoietic cells. Flow cytometry analysis of the compounds resulted in the arrest of cell cycle progression at the sub-G1 phase of the RAJI and Jurkat cell lines in a dose-dependent manner. According to computational analyses, the similar cytotoxic trend in the cell lines could be indicative of the fact that these compounds may act through parallel mechanisms.

References

  • 1 Townsend C C. Taxonomic revision of the genus Haplophyllum (Rutaceae). Hooker's Icones Plantarum, Vol. XL, parts I, II & III. Kent; Bentham-Moxon Trustees 1986: 14-16
  • 2 Soltani M, Khosravi A R. A new species of Haplophyllum (Rutaceae) from SW Iran.  Willdenowia. 2005;  35 293-298
  • 3 Saglam H, Gozler T, Kivcak B, Demirci B, Baser K HC. Volatile compounds from Haplophyllum myrtifolium.  Chem Nat Commun. 2001;  37 442-444
  • 4 Ea S, Giacometti S, Ciccolini J, Akhmedjanova V, Aubert C. Cytotoxic effects of haplamine and its major metabolites on human cancer cell lines.  Planta Med. 2008;  74 1265-1268
  • 5 Akhmedzhanova V I, Rasulova Kh A, Bessonova I A, Shashkov A S, Abdullaev N D, Angenot L. Folipidine, a new type quinoline alkaloid from plants of the Haplophyllum genus.  Chem Nat Commun. 2005;  41 60-64
  • 6 Nazrullaev S S, Bessonova I A, Akhmedkhodzhaeva Kh S. Estrogenic activity as a function of chemical structure in Haplophyllum quinoline alkaloids.  Chem Nat Commun. 2001;  37 551-555
  • 7 Jones K, Roset X, Rossiter S, Whitfield P. Demethylation of 2,4-dimethoxyquinolines: the synthesis of atanine.  Org Biomol Chem. 2003;  24 4380-4383
  • 8 Jansen O, Akhmedjanova V, Angenot L, Balansard G, Chariot A, Ollivier E, Tits M, Frédérich M. Screening of 14 alkaloids isolated from Haplophyllum A. Juss. for their cytotoxic properties.  J Ethnopharmacol. 2006;  105 241-245
  • 9 Akhmedkhodzhaeva Kh S, Kurmukov A G. Pharmacology of haplamine.  Doklady Akademii Nauk UzSSR. 1975;  8 36
  • 10 Cantrell C L, Schrader K K, Mamonov L K, Sitpaeva G T, Kustova T S, Dunbar J, Wedge D E. Isolation and identification of antifungal and antialgal alkaloids from Haplophyllum sieversii.  Agric Food Chem. 2005;  53 7741-7748
  • 11 Varamini P, Doroudchi M, Mohagheghzadeh A, Soltani M, Ghaderi A. Cytotoxic evaluation of four Haplophyllum species with various tumor cell lines.  Pharm Biol. 2007;  45 299-302
  • 12 Bessonova A, Akhmedzhanova V I, Yunosov S Y. 7-Isopentenyloxy-γ-fagarine from Haplophyllum perforatum.  Chem Nat Commun. 1974;  10 701-702
  • 13 Chen I S, Tsai I W, Teng C M, Chen J J, Chang Y L, Ko F N, Lu M C, Pezzuto J M. Pyranoquinoline alkaloids from Zanthoxylum simulans.  Phytochemistry. 1997;  46 525-529
  • 14 Brader G, Bacher M, Greger H, Hofer O. Pyranoquinolones and acridones from Vepris bilocularis.  Phytochemistry. 1996;  42 881-884
  • 15 Razakova D M, Bessonova I A, Yunosove S Yu. Perfamine – a new alkaloid from the seeds of Haplophyllum perforatum. .  Chem Nat Commun. 1975;  6 812-813
  • 16 Frisch M J, Trucks G W, Schlegel H B, Scuseria G E, Robb M A, Cheeseman J R, Zakrzewski V G, Montgomery J A, Stratmann R E, Burant J C, Dapprich S, Millam J A, Daniels A D, Kudin K N, Strain M C, Farkas O, Tomasi J, Barone V, Cossi M, Menucci B, Pomelli C, Adamo C, Clifford S, Ochterski J, Petersson G A, Ayala P Y, Cui Q, Morokuma K, Malick D K, Rabuck A D, Raghavachari K, Foresman J B, Cioslowski J, Ortiz J V, Stefanov B B, Liu A, Liashenko A, Piskorz P, Komaromi I, Gomperts R, Martin R L, Fox D J, Keith T, Al-Laham M A, Peng C Y, Nanayakkara A, Gonzalez C, Challacombe M, Gill P MW, Johnson B G, Chen W, Wong M W, Andres J L, Head-Gordon M, Replogle E S, Pople J A. Gaussian 98, Revision A.7. Pittsburgh, PA; Gaussian, Inc. 1998
  • 17 Fiot J, Jansen O, Akhmedjanova V, Angenot L, Balansard G, Ollivier E. HPLC quantification of alkaloids from Haplophyllum extracts and comparison with their cytotoxic properties.  Phytochem Anal. 2006;  17 365-369
  • 18 Harker W G, Slade D L, Dalton W S, Meltzer P S, Trent J M. Multidrug resistance in mitoxantrone-selected HL‐60 leukemia cells in the absence of P-glycoprotein overexpression.  Cancer Res. 1989;  16 4542-4549
  • 19 Harker W G, Slade D L, Parr R L, Feldhoff P W, Sullivan D M, Holguin M H. Alterations in the topoisomerase II alpha gene, messenger RNA, and subcellular protein distribution as well as reduced expression of the DNA topoisomerase II beta enzyme in a mitoxantrone-resistant HL‐60 human leukemia cell line.  Cancer Res. 1995;  55 1707-1716
  • 20 Harker W G, Slade D L, Drake F H, Parr R L. Mitoxantrone resistance in HL‐60 leukemia cells: reduced nuclear topoisomerase II catalytic activity and drug-induced DNA cleavage in association with reduced expression of the topoisomerase II beta isoform.  Biochemistry. 1991;  41 9953-9961
  • 21 Hughes J D, Blagg J, Price D A, Bailey S, Decrescenzo G A, Devraj R V, Ellsworth E, Fobian Y M, Gibbs M E, Gilles R W, Greene N, Huang E, Krieger-Burke T, Loesel J, Wager T, Whiteley L, Zhang Y. Physiochemical drug properties associated with in vivo toxicological outcomes.  Bioorg Med Chem Lett. 2008;  18 4872-4875

Professor of Immunology Abbas Ghaderi

Shiraz Institute for Cancer Research
Shiraz University of Medical Sciences

PO Box 71345–3119

Shiraz

Iran

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Email: ghaderia@sums.ac.ir