Ability of prenylflavanones present in hops to induce apoptosis in a human burkitt lymphoma cell line

Article abstract of DOI:10.1055/s-2007-981545

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. Georg Thieme Verlag KG Stuttgart.

Full text of DOI:10.1055/s-2007-981545

Reinhard A. Diller1
Herbert M. Riepl1
Oliver Rose2
Corazon Frias2
Günter Henze2
Aram Prokop2
Ability of Prenylflavanones Present in Hops to Induce
Apoptosis in a Human Burkitt Lymphoma Cell Line
Abstract
Key words
Humulus lupulus ´ Cannabaceae ´ phyto-oestrogen ´ Burkitt lym-
The identification of effective cancer preventive compounds phoma ´ apoptosis ´ mitochondrial permeability transition
from hops has become an important issue in public health-relat-
ed research. We compared the antiproliferative and apoptosis- Abbreviations
inducing effects of side chain variants of prenylflavanones, e.g., Eu(Fod) : heptafluoro-7,7-dimethyloctanedionatoeuropium(III)
3
8
-prenylnaringenin (7) and 8-geranylnaringenin (10), which LDH:
lactate dehydrogenase
have been identified in hops (Humulus lupulus), and their syn- PBS:
thetic variations 8-furanmethylnaringenin (8) and 8-cinnamyl- RPMI:
naringenin (9). These were accessible by a Mitsunobu reaction
phosphate-buffered saline
Roswell Park Memorial Institute
and Claisen rearrangement. Flavanones 9 and 10 showed cyto- Supporting information available online at
toxic and apoptotic activities. Apoptosis was induced in a mito- http://www.thieme-connect.de/ejournals/toc/plantamedica
chondrial dependent manner. 8-Cinnamylnaringenin (9) dis-
played noticeably improved apoptotic effects when compared to
8
-prenylnaringenin. The potential of 8-prenylnaringenin (7) is
755
shown in an ex vivo experiment on a multi-drug resistant leukae-
mia blast.
Introduction
the improvement of osteoporosis is the danger of an unwanted
induction of cell proliferation. In the case of mammary carcino-
8
-Prenylnaringenin (7), a prenylated flavanone, is a molecule mas, the growth of neoplastic cells in the initial stage is strongly
present in the female flower of hops (Humulus lupulus) and in dependent on activation by oestradiol receptors. Thus, in sensi-
some other plants [e.g., it has also been found in the heart wood tive hormone-dependent neoplastic cell lines, 8-PN (7) may ac-
of a tree (Anaxagorea luzonensis) indigenous to Thailand] [2], [3]. celerate proliferation analogous to oestradiol. Information about
This compound is known to be a very potent phyto-oestrogen [4], this issue would be important in connection with a prospective
[5] due to its affinity to the oestradiol receptor. Thus, it has been hormone replacement therapy.
suggested as a substance useful for hormone replacement ther-
apy. One major disadvantage of the application of 8-PN (7) for
Affiliation
1
Institute of Technology for Biogenic Resources, Technical University of Munich, Straubing, Germany
Department of Paediatric Oncology/Haematology, University Medical Centre CharitØ, Campus Virchow,
Berlin, Germany
2
Correspondence
Dr. Herbert Riepl ´ Institute of Technology for Biogenic Resources ´ Technical University of Munich ´
Petersgasse 18 ´ 94315 Straubing ´ Germany ´ Phone: +49-9421-187-120 ´ Fax: +49-9421-187-111 ´
E-mail: herbert.riepl@wzw.tum.de
Received July 17, 2006 ´ Revised May 8, 2007 ´ Accepted May 20, 2007
Bibliography
Planta Med 2007; 73: 755±761 ꢀ Georg Thieme Verlag KG Stuttgart ´ New York
DOI 10.1055/s-2007-981545 ´ Published online July 9, 2007
ISSN 0032-0943

We would like to report surprising antiproliferative and apopto- The antiproliferative effects of these flavanones were tested in
sis-inducing effects of 8-prenylnaringenin. Some analogous com- BJAB cells, a human Burkitt lymphoma cell line with a density of
pounds were then synthesised to find out which part of the oestradiol receptors of about 150 to 2000 per cell. We showed
structure is most important with respect to its apoptotic proper- that these flavanones have noticeable antiproliferative and cyto-
ties. Among the alterations of the side chain at the 8-position, 8- toxic activities. Furthermore, we were able to demonstrate that
furan-2-ylmethyl-5,7-dihydroxy-2-(4-hydroxyphenyl)-chroman-
the ability for inducing apoptosis was derived from a pathway
4-one (ªfuranmethylnaringeninº) (8) and 5,7-dihydroxy-2-(4-hy- dependent on mitochondria. After treatment with these agents,
droxyphenyl)-8-(3-phenylallyl)-chroman-4-one (ªcinnamylnarin- we observed a decrease in the mitochondrial membrane poten-
geninº) (9) were prepared for the first time using and adapting a tial which was dose-dependent and which showed a release of
published method [1], by which 8-(3,7-dimethylocta-2,6-dienyl)- cytochrome c [6] leading to the processing of the apoptosome, a
5,7-dihydroxy-2-(4-hydroxyphenyl)-chroman-4-one, (ª8-geranyl- complex with APAF-1 and pro-caspase 9.
naringeninº) (10) can be prepared also with advantage (Fig.1). 8-
Geranylnaringenin (10), which is derived from hops only as a trace The potential of 8-prenylnaringenin under ªrealº circumstances
constituent [5], is accessible now in large amounts. It is already is shown in two cases of an ex-vivo experiment with multi-drug
known as a very weak phyto-oestrogen.
resistant clones of lymphoid blasts.
Materials and Methods
Preparation of 8-substituted naringenins
8-Prenylnaringenin (7) was synthesised according to Gester and
Metz [1] from 4¢,7-diacetylnaringenin (2), subsequently used in a
Mitsunobu-reaction and then subjected to rearrangement using
Eu(Fod) (Fig. 2) in a Claisen-type rearrangement to yield 8-pre-
3
nylnaringenin diacetate. As an improvement, washing of the re-
crystallised Mitsunobu product 3 with 1% acetic acid was intro-
duced in order to completely remove the hydrazine by-product.
Spectroscopic data of 7 were identical to those of authentic sam-
ples from hops and to results that have been already published
[
1].
Similarly, the new compounds 8-furanmethylnaringenin (8), 8-
cinnamylnaringenin (9) and 8-geranylnaringenin (10) were pre-
pared. The compounds were obtained as a racemic mixture of R
and S enantiomers from this reaction sequence and no attempt
was made to resolve them to enantiopurity. Detailed experimen-
tal procedures and spectroscopic data can be found in the Sup-
porting Information. Although all Claisen rearrangements tested
gave acceptable to good yields, it was not possible to react either
5-allylnaringenin or 5-benzylnaringenin sufficiently.
7
56
Fig. 1 Chemical structures of 8-prenylnaringenin (7), 8-furanmethyl-
naringenin (8), 8-cinnamylnaringenin (9) and 8-geranylnaringenin (10).
Fig. 2 Synthesis of alkylflavanones.
Diller RA et al. Ability of Prenylflavanones¼ Planta Med 2007; 73: 755±761

Cell culture
metric determination of cells with decreased fluorescence, i.e.,
BJAB cells were grown in RPMI 1640 medium (Rosewell Park with mitochondria displaying a lower membrane potential.
Memorial Institute) supplemented with 10% foetal calf serum, Data were collected and analysed using a FACScan (Becton Dick-
0
.56 g/L of -glutamine, 100,000 U/L of penicillin and 0.1 g/L of inson; Heidelberg, Germany) equipped with the CELLQuest soft-
L
streptomycin. Media and culture reagents were from Life Tech- ware (Becton-Dickinson). Data are given in % cells showing a de-
nologies GmbH (Karlsruhe, Germany). BJAB cells were subcul- crease in mitochondrial membrane potential which reflects the
tured every 3±4 days by dilution of the cells to a concentration number of cells undergoing apoptosis via a mitochondrial de-
5
of 1”10 cells/mL.
pendent pathway.
Cell counts, measurement of cytotoxicity
Ex vivo studies
7
Cell counts were obtained by Casy (Schärfe System GmbH; Reu- Samples containing at least 5”10 leukaemic cells of 2children
tlingen, Germany) and using a Neubauer chamber after staining with relapsed acute myeloid leukaemia (ALL) were analysed in
with trypan blue. Both quantification methods gave nearly equal this study. Both children were male. The ages at diagnosis were
results. Cytotoxicity was assessed by release of lactate dehydro- 7 and 15 years. Leukaemic cells were obtained after bone mar-
genase (LDH) as described previously [8]. After incubation with row aspiration and Ficoll preparation. Ex vivo drug resistance a-
different concentrations of naringenins, LDH activity released nalysis of lymphoblasts from children with relapsed acute lym-
by BJAB cells was measured in the cell culture supernatants phoblastic leukaemia (ALL) is a part of the ALL REZ BFM 2002
using the cytotoxicity detection kit from Boehringer-Mannheim study for treatment of children with relapsed ALL. For this study
(
3
Mannheim, Germany). The supernatants were centrifuged at we have obtained ethics approval on 14.12.2000.
00”g for 5 min. 20 mL of cell-free supernatants were diluted
with 80 mL of phosphate-buffered saline (PBS) and 100 mL of the Supporting information
reaction mixture containing 2-(4-iodophenyl)-3-(4-nitrophe- Full analytical data of the compounds are available in the Sup-
+
nyl)-5-phenyltetrazolium chloride (INT), sodium lactate, NAD , porting information.
and diaphorase were added. Then, the time-dependent forma-
tion of the reaction product was quantified photometrically at
4
92nm. The maximum amount of LDH activity released by the
Results and Discussion
cells was determined by cell lysis using 0.1% Triton X-100 in the
culture medium and set as 100% cell death.
The antiproliferative effects of 8-prenylnaringenin (7), 8-furfur-
ylnaringenin (8), 8-cinnamylnaringenin (9) and 8-geranylnarin-
genin (10) in BJAB cells were tested. 8-Prenylnaringenin (7) in-
Measurement of DNA fragmentation
DNA fragmentation was measured essentially as described [9]. hibited proliferation at concentrations higher than 50 mM (data
After treatment with different concentrations of naringenins for not shown). The inhibition at 50 mM was 17%, and at 100 mM it
72h, cells were collected by centrifugation at 300” g for 5 min was 41%. 8-Furfurylnaringenin (8) showed no antiproliferative
757
and washed with PBS at 4 8C. Cells were fixed in PBS/2% (v/v) for- effect (data not shown). 50 mM of 8-geranylnaringenin (10) in-
maldehyde on ice for 30 min, pelleted, incubated with ethanol/ hibited the proliferation in 34% of the BJAB cells. The effect in-
PBS (2:1, v/v) for 15 min, pelleted and resuspended in PBS con- creased to 56% inhibition at 100 mM (Fig. 3). The strongest anti-
taining 40 mg/mL RNase A. RNA was digested for 30 min at 37 8C. proliferative effect was induced by 8-cinnamylnaringenin (9) at
Cells were pelleted again and finally resuspended in PBS contain- a concentration of 50 mM which reduced proliferation to about
ing 50 mg/mL of propidium iodide. Nuclear DNA fragmentation 41% (Fig. 4).
was quantified by flow cytometric determination of hypodiploid
DNA. Data were collected and analysed using a FACScan (Becton In contrast to 8-prenylnaringenin (Fig. 5), 8-cinnamylnaringenin
Dickinson; Heidelberg, Germany) equipped with the CELLQuest significantly induced apoptosis in BJAB cells at a concentration of
software. Data are given in % hypoploidy (subG1) which reflects 50 mM (Fig. 6). The apoptotic effect of 8-cinnamylnaringenin ex-
the number of apoptotic cells.
ceeded those of all other naringenins tested in this study. The in-
duction of apoptosis depended on the concentration of 8-cinna-
mylnaringenin (11% apoptotic cells at 50 mM and 38% at 100 mM).
Measurement of the mitochondrial permeability transition
After incubation with different concentrations of the naringenins
7
4
±10, BJAB cells were collected by centrifugation at 300”g and We were able to show that, in our experiments, apoptosis induc-
8C for 5 min. Mitochondrial permeability transition was then tion took place via the mitochondrial pathway (Fig. 7). All flava-
determined by staining the cells with 5,5¢,6,6¢-tetrachloro- nones were able to decrease the mitochondrial membrane po-
,1¢,3,3¢-tetraethylbenzimidazolylcarbocyanin iodide (JC-1; Mo- tential in BJAB cells after treatment for 48 h. Despite a low capa-
1
lecular Probes; Leiden, The Netherlands) as described [10]. city of 8-prenylnaringenin to induce apoptosis (Fig. 5), it also in-
5
1
”10 cells were resuspended in 500 mL of phenol red-free RPMI duced a decrease of the mitochondrial membrane potential.
1640 without supplements and JC-1 was added to give a final However, 8-geranylnaringenin caused a change in the membrane
concentration of 2.5 mg/mL. The cells were incubated for 30 min potential at much lower concentrations. At 100 mM we noticed a
at 37 8C with moderate shaking. Control cells were likewise incu- saturation effect in the decrease of mitochondrial membrane po-
bated in the absence of JC-1 dye. The cells were harvested by cen- tential. But the greatest effect was demonstrated with 8-cinna-
trifugation at 300”g and 4 8C for 5 min, washed with ice-cold of mylnaringenin. Even at a concentration of 50 mM, we observed a
PBS and resuspended in 200 mL of PBS at 4 8C. The mitochondrial transition in 77% of the BJAB cells. A kind of saturation effect
permeability transition was then quantified using the flow cyto- could explain why this percentage does not increase at 100 mM.
Diller RA et al. Ability of Prenylflavanones¼ Planta Med 2007; 73: 755±761

Fig. 3 Viability of BJAB cells after 4 h of
treatment with 8-geranylnaringenin (10).
The viability decreased in a dose dependent
manner. The bars represent the mean of
three determinations. The experiments
were repeated twice and yielded similar re-
sults.
Fig. 4 Viability of BJAB after 4 h under in-
fluence of 8-cinnamylnaringenin (9). It de-
creased in a dose dependent manner with
IC50 = 37.0 mM. The bars represent the
mean of three determinations. The experi-
ments were repeated twice and yielded sim-
ilar results.
7
58
Fig. 5 Apoptosis induction (number of
apoptotic cells in %) after treatment with 8-
prenylnaringenin (7) in different concentra-
tions over 72 h in human Burkitt lymphoma
cells (BJAB). Apoptosis induction was de-
tected by DNA fragmentation via FACS
measurement after staining the cells with
propidium iodide. Bars represent the mean
of three determinations from separate cul-
tures. The experiments were repeated twice
and yielded similar results.
To demonstrate the apoptosis inducing potency of 8-prenylnar- Thirty-four percent of the patient's myeloblasts underwent
ingenin, primary leukaemic cells from children with acute mye- apoptosis after ex vivo treatment for 72h.
loid leukaemia (AML) were examined. The primary leukaemia
cells of a 7-year-old boy (Fig. 8) were multi-drug-resistant. Idar- Previous studies showed no antiproliferative and apoptotic ac-
ubicin was able to induce significant apoptosis ex vivo (15%). 8- tivities of naturally occurring naringenins in human cancer cell
Prenylnaringenin (100 mM, lane 1) caused remarkable apoptosis. lines [7]. The potency of the naringenins 7±10 as inhibitors of
Diller RA et al. Ability of Prenylflavanones¼ Planta Med 2007; 73: 755±761

Fig. 6 Apoptosis induction in BJAB cells
after treatment for 72 h depends on the
concentration of 8-cinnamylnaringenin (9).
It showed the strongest apoptosis inducing
effects of all tested naringenins. The
amount of hypodiploid cells increased from
11% at 50 mM to 38% at 100 mM. Apoptosis
induction was detected by DNA fragmenta-
tion via FACS measurements after staining
the cells with propidium iodide. Bars repre-
sent the mean of three determinations
from separate cultures. The experiments
were repeated twice and yielded similar re-
sults.
Fig. 7 Decrease of mitochondrial mem-
brane potential in BJAB cells induced after
treatment with 7, 9 and 10 in different con-
centrations for 48 h. The mitochondrial per-
meability transition was determined by
FACS measurements after staining the cells
with JC-1. The bars represent the mean of
three determinations from separate cul-
tures. The experiments were repeated twice
and yielded similar results.
759
Fig. 8 Induction of apoptosis after treat-
ment with 8-prenylnaringenin (7) and eight
cytostatic drugs under same conditions in
primary myeloblasts from a 7-year-old boy
with acute myeloblastic leukaemia (AML).
In a concentration of 100 mM, 8-prenylnarin-
genin showed the strongest apoptosis indu-
cing effect. Apoptosis induction was detect-
ed by DNA fragmentation via FACS meas-
urements after staining with propidium io-
dide. The bars represent the mean of three
determinations from separate cultures.
Diller RA et al. Ability of Prenylflavanones¼ Planta Med 2007; 73: 755±761

BJAB cell-proliferation was dependent on the chemical structure binectariferium, shows how promising the structure of substitu-
of the alkyl side chain in position 8. We observed a meaningful ted flavanones can be. It induces growth arrest and apoptosis in
apoptosis inducing effect for 8-geranylnaringenin (10) and espe- several chronic B-cell leukaemia lines [15]. It selectively inhibits
cially for 8-cinnamylnaringenin (9) than for compound (7) cycline-dependent kinase 1 (CDK 1) a serine/threonine protein
(
Fig. 5). In contrast to this result, the furanmethyl residue confer- kinase, the driving force behind cell proliferation [16], with an
red no antiproliferative activity. Therefore, one could draw the IC50 of 110 and 130 nM. The quest for a potent apoptotic agent
cautious conclusion for further research that a larger alkyl side might lead to inspecting chalcones from hops like xanthohumol
chain at position 8 increases the antiproliferative properties. that possesses a larger alkyl side chain in position 8.
The differences in the cytotoxicity of 8-geranylnaringenin and
8
-cinnamylnaringenin demonstrate possibly the effect of a fold-
ing in the side chain.
Acknowledgements
The observations with compounds 9 and 10 on the transition Wissenschaftliche Station für Brauerei in München e.V., The
point of the mitochondrial membrane potential suggests that Deutsche JosØ Carreras Leukämie-Stiftung, Kinderleben e. V., Ber-
BJAB cells underwent apoptosis initiated by intrinsic signals. lin, The Schärfe System GmbH, Reutlingen, The Volkswagen-Stif-
The extent of the transition increases with the size of the alkyl tung, Hannover, and the Kind-Philipp-Stiftung für Leukämiefor-
side chain in the 8-position. 8-Cinnamylnaringenin caused a schung, Essen, are gratefully acknowledged for their financial
stronger decrease of the mitochondrial membrane potential and technical support. Technical assistance by Birgit Bonitzki in
than both 8-geranylnaringenin and 8-prenylnaringenin. This the performance of cell assays is gratefully acknowledged.
finding can be explained by the stronger apoptotic effects of
compound 9.
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ꢀ
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Diller RA et al. Ability of Prenylflavanones¼ Planta Med 2007; 73: 755±761