Ability of Prenylflavanones Present in Hops to Induce Apoptosis in a Human Burkitt Lymphoma Cell Line

Abstract

The identification of effective cancer preventive compounds from hops has become an important issue in public health-related research. We compared the antiproliferative and apoptosis-inducing effects of side chain variants of prenylflavanones, e. g., 8-prenylnaringenin (7) and 8-geranylnaringenin (10), which have been identified in hops (Humulus lupulus), and their synthetic variations 8-furanmethylnaringenin (8) and 8-cinnamylnaringenin (9). These were accessible by a Mitsunobu reaction and Claisen rearrangement. Flavanones 9 and 10 showed cytotoxic and apoptotic activities. Apoptosis was induced in a mitochondrial dependent manner. 8-Cinnamylnaringenin (9) displayed noticeably improved apoptotic effects when compared to 8-prenylnaringenin. The potential of 8-prenylnaringenin (7) is shown in an ex vivo experiment on a multi-drug resistant leukaemia blast.

Abbreviations

Eu(Fod)₃:heptafluoro-7,7-dimethyloctanedionatoeuropium(III)

LDH:lactate dehydrogenase

PBS:phosphate-buffered saline

RPMI:Roswell Park Memorial Institute

Key words

Humulus lupulus - Cannabaceae - phyto-oestrogen - Burkitt lymphoma - apoptosis - mitochondrial permeability transition

References

• 1 Gester S, Metz P, Zierau O, Vollmer G. An efficient synthesis of the potent phytooestrogens 8-prenylnaringenin and 6-(1,1-dimethylallyl)naringenin by europium(III)-catalyzed Claisen rearrangement.  Tetrahedron. 2001;  57 1015-8.
• 2 Zierau O, Hauswald S, Schwab P, Metz P, Vollmer G. Two major metabolites of 8-prenylnaringenin are oestrogenic in vitro .  J Steroid Biochem Mol Biol. 2004;  92 107-10.
• 3 Kitaoka M, Kadokawa H, Sugano M, Ichikawa K, Taki M, Takahashi S. et al . Prenylflavonoids: a new class of non-steroidal phytooestrogen (Part 1). Isolation of 8-isopentenylnaringenin and an initial study on its structure-activity relationship.  Planta Med. 1998;  64 511-5.
• 4 Zierau O, Morrissey C, Watson R W, Schwab P, Kolba S, Metz P. et al . Antiandrogenic activity of the phytooestrogens naringenin, 6-(1,1-dimethylallyl)naringenin and 8-prenylnaringenin.  Planta Med. 2003;  69 856-8.
• 5 Milligan S R, Kalita J C, Pocock V, Van de Kauter V, Stevens J F, Deinzer M L. et al . The endocrine activities of 8-prenylnaringenin and related hop (Humulus lupulus L.) flavanoids.  J Clin Endocrin Metab. 2000;  85 4912-5.
• 6 Thompson C B. Apoptosis in the pathogenesis and treatment of disease.  Science. 1995;  267 1456-62.
• 7 Miranda C L, Stevens J F, Helmrich A, Henderson M C, Rodriguez R J, Yang Y -H. et al . Antiproliferative and cytotoxic effects of prenylated flavanoids from hops (Humulus lupulus) in human cancer cell lines Food.  Chem Toxicol. 1999;  37 271-85.
• 8 Schlawe D, Majdalani A, Velcicky J, Heßler E, Wieder T, Prokop A. et al . Iron-containing nucleoside analogs with pronounced apoptosis-inducing activity.  Angew Chem Int Ed Engl. 2004;  116 1763-6.
• 9 Prokop A, Wrasidlo W, Lode L, Herold R, Lang F, Henze G. et al . Induction of apoptosis by enediyne antibiotic calicheamicin II proceeds through a caspase-mediated mitochondrial ampflification loop in an entirely Bax-dependent manner.  Oncogene. 2003;  22 9107-20.
• 10 Wieder T, Prokop A, Bagci B, Essmann F, Bernicke D, Schulze-Osthoff K. et al . Picetannol, a hydroxylated analog of the chemopreventive agent resveratrol, is a potent inducer of apoptosis in the lymphoma cell line BJAB and in primary leukemic lymphoblasts.  Leukemia. 2001;  15 1735-42.
• 11 Trost B M, Toste F D. Asymmetric O- and C-alkylation of phenols.  J Am Chem Soc. 1998;  120 815-6.
• 12 Gerhauser C, Alt A, Heiss E, Gamal-Eldeen A, Klimo K, Knauft J. et al . Cancer Chemopreventive activity of xanthohumol, a natural product derived from hop.  Mol Cancer Ther. 2002;  1 959-69.
• 13 Tahara S, Ibrahim R K. Prenylated Isoflavones - an update.  Phytochemistry. 1995;  38 1073-94.
• 14 Yap S P, Shen P, Butler M S, Gong Y, Loy C J, Yong E L. New oestrogenic prenylflavone from Epimedium brevicornum inhibits the growth of breast cancer cells.  Planta Med. 2005;  71 114-9.
• 15 König A, Schwartz G K, Mohammad R M, Al-Katib A, Gabrilove J L. The novel cyclin-depedent kinase inhibitor Flavopiridol downregulates Bcl-2 and induces growth arrest and apoptosis in chronic B-cell leukemia lines.  Blood. 1997;  90 4307-12.
• 16 Kim K S, Sack J S, Tokarski J S, Quian L, Chao S T, Leith L. et al . Thio- and oxoflavopiridols, cyclin-dependent kinase 1-selective Inhibitors: synthesis and biological effects.  J Med Chem. 2000;  43 4126-34.
• 17 Diller R A, Riepl H M, Rose O, Frias C, Henze G, Prokop A. Synthesis of demethylxanthohumol, a new potent apoptosis inducing agent from hops.  Chem Biodivers. 2005;  2 1331-8.
• 18 Schaefer O, Hümpel M, Fritzemeier K H, Bohlmann R, Schleunig W D. 8-Prenylnaringenin is a potent ERα selective phytooestrogen present in hops and beer.  J Steroid Biochem Mol Biol. 2003;  84 359-6.