January 2011 Regular Article Biol. Pharm. Bull.

34(1) 103—107 (2011) 103

The Antinociceptive and Anti-inflammatory Action of the CHCl3-Soluble

Phase and Its Main Active Component, Damnacanthal, Isolated from the
Root of Morinda citrifolia
Kanako OKUSADA,a Kazuo NAKAMOTO,a Mikako NISHIDA,a Wakako FUJITA-HAMABE,a Kohei KAMIYA,b
Yoshiyuki MIZUSHINA,c Toshiko SATAKE,b and Shogo TOKUYAMA*,a
a
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University; b Department of
Pharmacognosy and Natural Product Chemistry, School of Pharmaceutical Sciences, Kobe Gakuin University; 1–1–3
Minatojima, Chuo-ku, Kobe, Hyogo 650–8586, Japan: and c Laboratory of Food and Nutritional Sciences, Department of
Nutritional Sciences, Kobe Gakuin University; 518 Arise, Ikawadani-cho, Nishi-ku, Kobe, Hyogo 651–2180, Japan.
Received August 28, 2010; accepted October 16, 2010; published online October 21, 2010

Morinda citrifolia (Rubiaceae, Noni) is a traditional medicine with various pharmacological activities. We
investigated if the MeOH-, CHCl3- and BuOH-soluble phase and its main active component, damnacanthal, iso-
lated from the Noni root, have antinociceptive and anti-inflammatory actions in mice. The CHCl3-soluble phase
(3 g/kg, per os (p.o.)) significantly reduced pain-related behavior observed in the formalin test. These effects were
not suppressed by pretreatment with naloxone (1 mg/kg, intraperitoneally (i.p.)), an opioid receptor antagonist.
The CHCl3-soluble phase (3 g/kg, p.o.) significantly reduced histamine-induced paw edema. The MeOH- and
BuOH-soluble phase had no effect in either test. Furthermore, damnacanthal (10—100 mg/kg, p.o.)) exerted an
antinociceptive effect on chemical nociceptive stimuli, and decreased histamine-induced paw edema. Damnacan-
thal was weakly bound to the histamine H1 receptor. These data suggest that the CHCl3-soluble phase of the Noni
root has antinociceptive and anti-inflammatory effects. Furthermore, these effects of damnacanthal isolated
from the Noni root is mediated in part by the histamine H1 receptor.
Key words Morinda citrifolia; damnacanthal; histamine H1 receptor; antinociception; anti-inflammatory

Morinda citrifolia (M. citrifolia, Rubiaceae), known as therefore necessary.

“Noni,” is a tropical plant that grows widely across Polyne-
sia. In Japan, it is called “Yaeyama-aok” and grows in Oki-
nawa Prefecture. Noni has traditionally been used for the pre-
vention and treatment of various diseases,1) and is widely
known as a health food and supplement.
We have reported that the Noni fruit inhibits copper-
induced low-density lipoprotein oxidation,2) and prevents is-
chemic neuronal damage through suppression of the develop-
ment of post-ischemic glucose intolerance.3) Noni, which
contains many biologically active compounds, could there-
fore be an important source of new drugs.
There are few pharmacological studies of the dried root of
the Noni plant. We recently reported that two anthraquinone
glycosides from the BuOH-soluble phase of the Noni root
decreased blood glucose levels in streptozotocin-induced
type-1 diabetes in mice.4) Furthermore, we isolated 10 an-
thraquinones in the CHCl3-soluble phase of the Noni root,
and found that damnacanthal was the main component.5)
Other pharmacological studies of the Noni root reported that
monotropein isolated from the BuOH-soluble phase of the
M. officinalis root exhibits antinociceptive and anti-inflam-
matory effects in mice.6) It has been reported that the phar-
macological activity of the Noni root was similar to that of
the M. officinalis root.7) However, the antinociceptive and
anti-inflammatory activities of the CHCl3-soluble phase and
damnacanthal isolated from the Noni root are unknown.
A considerable number of analgesic drugs are currently
available for the treatment of pain. However, their use is lim-
ited due to their side effects, such as vomiting after opioid
treatment and serious cardiovascular effects associated with
the long-term use of non-steroidal anti-inflammatory drugs
(NSAIDs). The development of alternative analgesic drugs is
∗ To whom correspondence should be addressed. e-mail: stoku@pharm.kobegakuin.ac.jp
The present study was designed to investigate if the
CHCl3-soluble phase of the Noni root and damnacanthal has
antinociceptive and anti-inflammatory effects.
MATERIALS AND METHODS
Animals Male ddY mice (age, 5—6 weeks) were ob-
tained from SLC (Hamamatsu, Japan). Mice were housed in
cages at 23—24 °C with a 12-h light–dark cycle (light on at
8 a.m. to 8 p.m.). Food and water were available ad libitum.
The present study was conducted in accordance with the
Guiding Principles for the Care and Use of Laboratory Ani-
mals, which has been adopted by the Japanese Pharmacologi-
cal Society. Experiments were approved by Ethical Commit-
tee for Animal Experimentation at Kobe Gakuin University
(approved number: A060601-9).
Plant Materials The dried roots of the tropical plant
Noni (M. citrifolia, Rubiaceae) were collected in August
2004 at Okinawa in Japan and the plant was identified by Dr.
K. Kamiya. A voucher specimen has been deposited in De-
partment of Pharmacognosy and Natural Product Chemistry,
Kobe Gakuin University.
Extraction, Fractionation and Isolation Dried pow-
dered roots were extracted with MeOH ten under reflux. Ex-
tracts was then filtered and evaporated on a rotary evaporator
under reduced pressure. These MeOH extracts were then sus-
pended in H2O. They were partitioned with chloroform
(CHCl3) and the butanol (BuOH) layer concentrated in
vacuo. The obtained extract was freeze-dried to give the
CHCl3 extract. The CHCl3 extract (122 g) was chro-
matographed on Sephadex LH-20 using CHCl3–MeOH
(1 : 1) to give an anthraquinone-containing fraction. This
© 2011 Pharmaceutical Society of Japan
104
fraction was subjected to repeated SiO2 column chromatogra-
phy using n-hexane–CHCl3 solvent system. It was purified by
preparative TLC using a CHCl3–MeOH solvent system to af-
ford compounds.
HPLC was performed with a Diol column (Inertsil Diol
5 mm, 4.6250 mm, GL Sciences, Tokyo, Japan). The detec-
tion wavelength was 254 nm. Elution was carried out with n-
hexane : CHCl3 (a, 25 : 75), (b, 50 : 50) and (c, 75 : 25) at a
flow rate of 1 ml/min. The injection volume was 10 m l (1.0
mg/ml, chloroform-soluble phase in CHCl3). Damnacanthal
contained in the chloroform-soluble phase could be separated
by HPLC using three solvent systems (Fig. 1A). The yields
of damnacanthal from the dried root 0.434%. The purified
damnacanthal were analysed by IR, UV, 1H- and 13C-NMR
spectra, and the chemical structures of the isolated
damnacanthal are shown in Fig. 1B. Damnacanthal: Yellow
1
amorphous powder; IR n KBr max cm : 3070, 1668, 1647, 1565,
1344, 1329, 1261, 1132, 980; UV l max (MeOH) nm (log e ):
283 (4.23), 247 (4.26), 203 (4.12); 1H-NMR (400 MHz, pyri-
dine-d5) d : 7.77 (1H, s, H-4), 8.24 (1H, dd, J7.5, 1.3 Hz, H-
5), 7.64 (1H, td, J7.5, 1.2 Hz, H-6), 7.70 (1H, td, J7.5,
1.3 Hz, H-7), 8.33 (1H, dd, J7.5, 1.2 Hz, H-8), 10.57 (1H,
s, H- 11), 4.14 (3H, s, 1-OCH3); 13C-NMR (100 MHz, pyri-
dine-d5) d : 166.58 (C-1), 119.51 (C-2), 166.41 (C-3), 112.67
(C-4), 141.58 (C- 4a), 126.96 (C-5), 133.67 (C-6), 134.89
(C-7), 127.39 (C-8), 135.41 (C-8a), 180.07 (C-9), 118.21 (C-
9a), 182.22 (C-10), 132.92 (C-10a), 194.98 (C-11), 64.31 (1-
OCH3).
Sample Preparation and Drugs The MeOH (3 g/kg)-,
CHCl3 (3 g/kg)-, and BuOH (3 g/kg)-soluble phase and
damnacanthal (10—100 mg/kg) were orally administrated to
mice 30 min before each test. Samples were suspended in 1%
CMC-Na. Indomethacin (50 mg/kg), a non-steroidal anti-in-
flammatory drug (NSAIDs), was orally administrated to mice
30 min before administration of each soluble phase and
damnacanthal. Morphine (5 mg/kg), a m opioid receptor ago-
nist, was subcutaneously administrated to mice 30 min before
administration of each soluble phase and damnacanthal.
A
B
Fig. 1. HPLC Profiles (A) and Structural Formula (B) of Damnacanthal,
Isolated from the CHCl3-Soluble Phase of the Noni Root
Elution was carried out with n-hexane : chloroform25 : 75 (a), 50 : 50 (b) and
75 : 25 (c).
Vol. 34, No. 1
Naloxone (NLX; 1 mg/kg, intraperitoneally (i.p.)), a non-se-
lective opioid receptor antagonist, was administered 10 min
before administration of each soluble phase.
Formalin Test The formalin test was carried out as de-
scribed.8) Mice were injected with 10 m l of 5% formalin
[formaldehyde solution 37% (w/w) diluted in saline] into the
subplantar space of the right hind paw 30 min after the treat-
ment of the CHCl3-soluble phase (per os (p.o.)) and
damnacanthal (p.o.). The times spent in licking, biting and
shaking behaviors were measured during 0 to 5 min (early
phase) and from 5 to 30 min (late phase) after formalin injec-
tion.
Histamine-Induced Paw Edema Histamine (0.5 m mol,
10 m l) was injected intraplantarly (i.pl.) into the right hind
paw to induce acute inflammation.9) The thickness of the in-
jected hind paw was measured every 10 min or 60 min for
300 min after histamine injection (i.pl.). The intraperitoneal
administration of diphenhydramine (30 mg/kg), a histamine
H1 receptor antagonist, was used as a positive control in the
test. The area under the curve (AUC) value for the effect of
restraining paw edema on each mouse was then calculated.
Histamine H1 Receptor Binding Assay The histamine
H1 receptor binding affinity assay was conducted at Cerep In-
corporated (Celle l’Evescault, France), according to an estab-
lished method.10) The influence of damnacanthal (109—
103 M) on histamine H1 receptors was tested in a radioligand
binding assay with HEK-293 cells transfected with the
human recombinant histamine H1 receptor using [3H]-pyril-
amine (1 nmol/l; incubation time, 60 min at 22 °C). Bound
radioactivity was measured with a scintillation counter. The
histamine H1 binding assay was done in duplicate. Non-spe-
cific binding was defined using 1 m M unlabeled pyrilamine.
Statistical Analyses Data are meanS.E.M. The statis-
tical significance of differences between the control and
CHCl3 soluble phase-treated group and damnacanthal-treated
group were analyzed using one-way ANOVA followed by
Scheffe’s multiple-comparison test for the acetic acid writh-
ing test and formalin test. p0.05 was considered signifi-
cant.
RESULTS
Effect of the MeOH-, CHCl3- and BuOH-Soluble Phase
of the Noni Root on the Chemical Nociceptive Stimuli in
the Formalin Test The CHCl3-soluble phase (3 g/kg) did
not reduce pain response time in the early phase, but signifi-
cantly suppressed pain-related behavior in the late phase
(p0.01) of the formalin test. Similarly, indomethacin
(50 mg/kg) as a positive control significantly attenuated pain-
related behavior in the late phase of the formalin test, but not
the early phase. However, the MeOH (3 g/kg)- and BuOH
(3 g/kg)-soluble phase had no effect in the formalin tests
(Fig. 2).
Effect of NLX on CHCl3 Soluble Phase-Induced An-
tinociception The antinociceptive effect in the late phase
of the CHCl3-soluble phase (3 g/kg) was not affected by pre-
treatment with NLX (1 mg/kg). On the other hand, morphine
(5 mg/kg) significantly attenuated pain-related behavior in
the early and late phase in a NLX-reversible manner (Fig. 3).
Effect of the CHCl3-Soluble Phase of the Noni Root on
Histamine-Induced Paw Edema The saline-injected hind
January 2011 105

Fig. 2. Effect of the MeOH-, CHCl3- and BuOH-Soluble Phase of the

Noni Root on Chemical Nociceptive Stimuli in the Formalin Test
The cumulative nociceptive response time of biting, licking and shaking of the in-
jected hind paw was measured during 30 min after injection (i.pl.) of formalin at 5%
(V/V). Responses were measured at 0—5 min (early phase) and 5—30 min (late phase)
after formalin injection. Indomethacin was used as a positive control. Each column in-
dicates meanS.E.M. (n5—15) ** p0.01, * p0.05 vs. Vehicle, Scheffe test.
Fig. 4. Effect of the CHCl3-Soluble Phase of the Noni Root on Histamine-
Induced Paw Edema
The thickness of the injected hind paw was measured between 0 min and 300 min.
The thickness measured every 10 min or 60 min for 300 min after the histamine injec-
tion (i.pl.) at 0.5 m mol is described in the Materials and Methods. The area under the
curve (AUC) was calculated. Diphenhydramine was used as a positive control. Each
column indicates meanS.E.M. (n5—6). ** p0.01, * p0.05 vs. HistamineVehi-
cle, ## p0.01 vs. SalineVehicle, Scheffe test.

Fig. 3. Effect of Naloxone on CHCl3 Soluble Phase-Induced Antinocicep-
tion in the Formalin Test
The cumulative nociceptive response time of biting, licking and shaking of the in-
jected hind paw was measured during 30 min after injection (i.pl.) of formalin at 5%
(V/V). (a) Responses were measured at 0—5 min (early phase) and 5—30 min (late
phase) after formalin injection. Morphine was used as a positive control. Each column
indicates meanS.E.M. (n9—11) ** p0.01, * p0.05 vs. Vehicle, ## p0.01 vs.
Morphine. Scheffe test. NLX: naloxone, n.s.: not significant.
Fig. 5. Effect of Damnacanthal on Chemical Nociceptive Stimuli in the
Formalin Test
The cumulative nociceptive response time of biting, licking and shaking of the in-
jected hind paw was measured during 30 min after injection (i.pl.) of formalin at 5%
(V/V). Responses were measured at 0—5 min (early phase) and 5—30 min (late phase)
after formalin injection. Indomethacin was used as a positive control. Each column in-
dicates meanS.E.M. (n4—11). ** p0.01, * p0.05 vs. Vehicle, Scheffe test.

paws used as control showed no increase of paw volume dur-

ing the entire experiment; on the other hand, hind paw edema
was successfully induced by intraplantar injection of hista-
mine. Administration of the CHCl3-soluble phase showed
significant inhibition of the edema. Diphenhydramine
(30 mg/kg) significantly inhibited the paw edema (Fig. 4).
Effect of Damnacanthal on Chemical Nociception in
the Formalin Test Damnacanthal (10—100 mg/kg) did not
reduce pain response time in the first phase, but significantly
suppressed pain-related behavior in the second phase
(p0.01). Damnacanthal (30—100 mg/kg) exhibited a sig-
nificant antinociceptive effect in a dose-dependent manner.
Indomethacin (50 mg/kg) significantly reduced pain-related
behavior in the second phase (Fig. 5).
Effect of Damnacnthal on Histamine-Induced Paw
Edema Administration of damnacanthal (100 mg/kg) and Fig. 6. Effect of Damnacanthal on Histamine-Induced Paw Edema
diphenhydramine (30 mg/kg) showed significant inhibition of The thickness of the injected hind paw was measured between 0 min and 300 min.
histamine-induced paw edema (Fig. 6). The thickness measured every 10 min or 60 min for 300 min after the histamine injec-
tion (i.pl.) at 0.5 m mol is described in the Materials and Methods. The area under the
Effects of Damnacanthal in the Displacement of [3H]- curve (AUC) was calculated. Diphenhydramine used as a positive control in the test.
Pyrilamine in Human HEK293 Cells Damnacanthal dis- Each column indicates meanS.E.M. (n5—6). ** p0.01 vs. Vehicle, Scheffe test.
106
Fig. 7. Displacement of [3H]-Pyrilamine Binding by Damnacanthal or
Histamine
Histamine H1 radioligand ([3H]pyrilamine) displacement curves for drugs using
HEK293 cells. Displacement of [3H]pyrilamine binding to the histamine H1 receptor by
different concentrations of [3H]pyrilamine. The data, shown as percentage of specific
binding, fit according to a one-site ligand–receptor model.
placed [3H]-pyrilamine binding to human HEK293 cells in a
concentration-dependent manner. Similarly, histamine also
displaced [3H]-pyrilamine binding to human HEK293 cells in
a concentration-dependent manner. Specific binding of [3H]-
pyrilamine was displaced with increasing concentrations of
unlabeled pyrilamine (Fig. 7).
DISCUSSION
We examined the antinociceptive effect of the MeOH-,
CHCl3- and BuOH-soluble phase in a model of acute inflam-
matory pain induced by formalin. In general, the early phase
(0—10 min) of formalin-induced pain behavior is produced
by direct stimulation of primary afferent nerves, whereas
pain behaviors associated with the late phase (10—30 min)
are related to the sensitization of dorsal horn neurons due to
the initial barrage of primary afferent input during the early
phase or the formalin-induced inflammatory reaction.8) In the
present study, we obtained evidence that the CHCl3-soluble
phase exhibited a significant antinociceptive effect on chemi-
cal nociceptive stimuli. In particular, the CHCl3-soluble
phase reduced pain-related behavior in the late phase. The
antinociceptive effect of the CHCl3-soluble phase may there-
fore be (at least in part) due to attenuation of the central sen-
sitization induced by certain inflammatory substances.
It is well known that opioidergic nervous systems regulate
the various types of pain. The activation of opioid receptors
has a pivotal role in the production of analgesic effects in an-
imal and human. Some researchers have shown that the aque-
ous extracts of the fruit and roots of the Noni plant have an
antinociceptive effect via opioid receptors.11,12) In the present
study, these effects were not inhibited by pretreatment of
NLX on the antinociceptive effect of the CHCl3-soluble
phase. The CHCl3-soluble phase may therefore produce an
antinociceptive effect without acting on opioid receptors.
This discrepancy may be dependent upon the main ingredi-
ents of the Noni root.
The CHCl3-soluble phase may have an anti-inflammatory
effect because administration of indomethacin attenuated
pain-related behavior in the late phase of the formalin test.
To examine the anti-inflammatory effect of the CHCl3-solu-
ble phase, we evaluated histamine-induced paw edema in
mice. Histamine is a potent mediator of acute inflamma-
Vol. 34, No. 1
tion.13) It is produced in the early phase of acute inflamma-
tion to increase vascular permeability. The CHCl3-soluble
phase significantly suppressed the paw edema induced by
histamine. This test was inhibited by treatment with diphen-
hydramine, so this response seems to be partly mediated by
the histamine H1 receptor. Therefore, we suggest that the
CHCl3-soluble phase exerts anti-inflammatory effects by
mechanisms similar to those of histamine.
Histamine activates polymodal nociceptors and produces
pain.14) The role of histamine in pain is different in the cen-
tral nervous system and peripheral nervous system. In the
former, histamine H1 and H2 receptors are involved in the
modulation of pain sensations.15—17) In the peripheral ner-
vous system, it is reported that pyrilamine (histamine H1 re-
ceptor antagonist) and cimetidine (histamine H2 receptor an-
tagonist) show analgesic effects in the formalin test.18) In ad-
dition, anti-histaminic drugs show antinociceptive effects on
formalin-induced stimuli.19—21) Thus, histamine seems to be
involved in the stimulation of nociceptive fibers, and its an-
tagonists show antinociceptive effects, considering histamin-
ergic neurons are important for pain modulation.22)
We demonstrated that damnacanthal is the major compo-
nent in the CHCl3-soluble phase of the Noni root.5)
Damnacanthal has been reported to inhibit: selective tyrosine
kinase activity,23) activation of nuclear factor kappa-B,24) pro-
gression of cancer,25,26) and the human immunodeficiency
virus (HIV).27) However, there is no evidence that damnacan-
thal has an antinociceptive and anti-inflammatory effect on
chemical nociceptive stimuli. Here, we found that damnacan-
thal possesses antinociceptive and anti-inflammatory effects.
Therefore, in the present study, damnacanthal may have been
one of the active components of the CHCl3-soluble phase of
the Noni root. Interestingly, damnacanthal was weakly bound
to the histamine H1 receptor. Damnacanthal may therefore
exert its antinociceptive and anti-inflammatory effects
through binding to in part the histamine H1 receptor.
In conclusion, we demonstrated that the CHCl3-soluble
phase of the Noni root has antinociceptive and anti-inflam-
matory effects. In addition, damnacanthal was shown to be
the main active component through in part a histamine H1 re-
ceptor-mediated system in the production of these effects in
the CHCl3-soluble phase.
Acknowledgments Parts of this study was “Academic
Frontier” Project, Cooperative Research Center of Life Sci-
ences.
REFERENCES
1) Wang M. Y., West B. J., Jensen C. J., Nowicki D., Su C., Palu A. K.,
Anderson G., Acta Pharmacologica Sin., 23, 1127—1141 (2002).
2) Kamiya K., Tanaka Y., Endang H., Umar M., Satake T., J. Agric. Food
Chem., 52, 5843—5848 (2004).
3) Harada S., Hamabe W., Kamiya K., Satake T., Yamamoto J.,
Tokuyama S., Biol. Pharm. Bull., 32, 405—409 (2009).
4) Kamiya K., Hamabe W., Harada S., Murakami R., Tokuyama S., Sa-
take T., Biol. Pharm. Bull., 31, 935—938 (2008).
5) Kamiya K., Hamabe W., Tokuyama S., Hirano K., Satake T., Kuma-
moto-Yonezawa Y., Yoshida H., Mizushina Y., Food Chem., 118,
725—730 (2010).
6) Choi J., Lee K. T., Choi M. Y., Nam J. H., Jung H. J., Park S. K., Park
H. J., Biol. Pharm. Bull., 28, 1915—1918 (2005).
7) Kim I. T., Park H. J., Nam J. H., Park Y. M., Won J. H., Choi J., Choe
January 2011
B. K., Lee K. T., J. Pharm. Pharmacol., 57, 607—615 (2005).
8) Hunskaar S., Hole K., Pain, 30, 103—114 (1987).
9) Amann R., Schuligoi R., Lanz I., Donnerer J., Eur. J. Pharmacol., 279,
227—231 (2005).
10) Smit M., Timmerman H., Hijzelendoorn J., Fukui H., Leurs R., Br. J.
Pharmacol., 117, 1071—1080 (1996).
11) Basar S., Uhlenhut K., Högger P., Schöne F., Westendorf J., Phytother.
Res., 24, 38—42 (2010).
12) Younos C., Rolland A., Fleurentin J., Lanhers M., Misslin R., Mortier
F., Planta Med., 56, 430—434 (1990).
13) Rosenthal S. R., J. Invest. Dermatol., 69, 98—105 (1971).
14) Glick S. D., Crane L. A., Nature (London), 15, 547—549 (1978).
15) Malmberg-Aiello P., Lamberti C., Ipponi A., Bartolini A., Schunack
W., Life Sci., 63, 463—476 (1998).
16) Hough L. B., Nalwalk J. W., Leurs R., Menge W. M., Timmerman H.,
Life Sci., 64, 79—86 (1999).
17) Galeotti N., Malmberg-Aiello P., Bartolini A., Schunack W., Ghelar-
dini C., Neuropharmacology, 47, 295—303 (2004).
18) Parada C. A., Tambeli C. H., Cunha F. Q., Ferreira S. H.,
107
Neuroscience, 102, 937—944 (2001).
19) Rumore M., Schlichting D., Life Sci., 36, 403—416 (1985).
20) Yeh S. Y., Pharmaco.l Biochem. Behav., 24, 925—930 (1986).
21) Olsen U., Eltorp C., Ingvardsen B., Jørgensen T., Lundbaek J., Thom-
sen C., Hansen A. J., Eur. J. Pharmacol., 435, 43—57 (2002).
22) Hough L. B., Jackowski S., Eberle N., Gogas K. R., Camarota N. A.,
Cue D., Biochem. Pharmacol., 15, 4707—4711 (1988).
23) Faltynek C. R., Schroeder J., Mauvais P., Miller D., Wang S., Murphy
D., Lehr R., Kelley M., Maycock A., Michne W., Biochemistry, 34,
12404—12410 (1995).
24) Kang J. L., Jung H. J., Lee K., Kim H. R., Toxicol. Sci., 90, 470—477,
(2006).
25) Hiramatsu T., Imoto M., Koyano T., Umezawa K., Cancer Lett., 73,
161—166 (1993).
26) Palsson E., Popoff M., Thelestam M., O’Neill L., J. Biol. Chem., 275,
7818—7825 (2000).
27) Kamata M., Wu R., An D., Saxe J. P., Damoiseaux R., Phelps M.,
Huang J., Chen I., Biochem. Biophys. Res. Commun., 348, 1101—
1106 (2006).