Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer
Aim: Preclinical study of the specific anticancer pharmacological activity of the formulation containing active substance 3,3ʹ-diindolylmethane (DIM), cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E), in vivo in a xenograft animal model of LNCaP. Materials and Methods: The DIM, cod...
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| Опубліковано в: : | Experimental Oncology |
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| Дата: | 2014 |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
2014
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| Цитувати: | Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer / V.I. Kiselev, V.M. Drukh, E.L. Muyzhnek, I.N. Kuznetsov, O.I. Pchelintseva, M.A. Paltsev // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 90-93. — Бібліогр.: 20 назв. — англ. |
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Digital Library of Periodicals of National Academy of Sciences of Ukraine| _version_ | 1859714151518044160 |
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| author | Kiselev, V.I. Drukh, V.M. Muyzhnek, E.L. Kuznetsov, I.N. Pchelintseva, O.I. Paltsev, M.A. |
| author_facet | Kiselev, V.I. Drukh, V.M. Muyzhnek, E.L. Kuznetsov, I.N. Pchelintseva, O.I. Paltsev, M.A. |
| citation_txt | Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer / V.I. Kiselev, V.M. Drukh, E.L. Muyzhnek, I.N. Kuznetsov, O.I. Pchelintseva, M.A. Paltsev // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 90-93. — Бібліогр.: 20 назв. — англ. |
| collection | DSpace DC |
| container_title | Experimental Oncology |
| description | Aim: Preclinical study of the specific anticancer pharmacological activity of the formulation containing active substance 3,3ʹ-diindolylmethane (DIM), cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E), in vivo in a xenograft animal model of LNCaP. Materials and Methods: The DIM, cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E) formulation was intragastrically administered to BALB/c-nude (nu/nu) mice during 33 days post inoculation at the dose of 133 mg/kg/day. Antitumor activity of the test drug was estimated by the rate of tumor growth inhibition (T/C% — treated versus control), dividing the tumor volumes from treatment groups with the control groups. Results: Statistically significant tumor xenograft regressions have been shown in group which received the DIM, cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E) on the 37th day of observation post inoculation. The highest antitumor activity was achieved on the 39th day (T/C = 16,8%). Therapeutic effect lasts for 6 days after the end of therapy period. Conclusion: Our findings demonstrate inhibitory effect of the formulation on tumor development in the xenograft animal model due to the tumor growth rate reduction. Key Words: 3,3´-diindolylmethane, bioavailability, anticancer activity, xenograft model, LNCaP cell line, preclinical studies.
|
| first_indexed | 2025-12-01T06:39:59Z |
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90 Experimental Oncology 36, 90–93, 2014 (June)
PRECLINICAL ANTITUMOR ACTIVITY OF THE DIINDOLYLMETHANE
FORMULATION IN XENOGRAFT MOUSE MODEL OF PROSTATE
CANCER
V.I. Kiselev1, V.M. Drukh1, E.L. Muyzhnek2, I.N. Kuznetsov3, O.I. Pchelintseva1,*, M.A. Paltsev4
1Peoples’ Friendship University of Russia, Moscow 117198, Russia
2ZAO “MiraxBioPharma”, Moscow 121248, Russia
3Moscow State Medical Stomatological University (MGMSU), Moscow 127473, Russia
4National Research Centre (NRC “Kurchatov Institute”), Moscow 123182, Russia
Aim: Preclinical study of the specific anticancer pharmacological activity of the formulation containing active substance 3,3�-di-
indolylmethane (DIM), cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E), in vivo in a xenograft animal model
of LNCaP. Materials and Methods: The DIM, cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E) formulation was
intragastrically administered to BALB/c-nude (nu/nu) mice during 33 days post inoculation at the dose of 133 mg/kg/day. Anti-
tumor activity of the test drug was estimated by the rate of tumor growth inhibition (T/C% — treated versus control), dividing
the tumor volumes from treatment groups with the control groups. Results: Statistically significant tumor xenograft regressions
have been shown in group which received the DIM, cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E) on the 37th
day of observation post inoculation. The highest antitumor activity was achieved on the 39th day (T/C = 16,8%). Therapeutic effect
lasts for 6 days after the end of therapy period. Conclusion: Our findings demonstrate inhibitory effect of the formulation on tumor
development in the xenograft animal model due to the tumor growth rate reduction.
Key Words: 3,3´-diindolylmethane, bioavailability, anticancer activity, xenograft model, LNCaP cell line, preclinical studies.
3,3�-Diindolylmethane (DIM) — one of the most
prospective compound with antitumor and immu-
nomodulatory properties. A great number of studies
have revealed that DIM is able to block the multiple
molecular mechanisms which cause cancer in different
organs and tissues [1, 2]. In addition to the suppres-
sion of proliferation of transformed (tumor) cells and
stimulation of their apoptosis, DIM inhibits pathologic
angiogenesis and reduces the metastatic potential
of cancer cells by affecting targets which mediate
processes of cell migration and invasion [3, 4]. It has
been recently found that DIM is a selective inhibitor
of certain tumorigenic minor population of non-diffe-
rentiated cancer cells — the so-termed “cancer stem
cells” [5], which are the main source of recurrence
and metastasis according to modern ideas. DIM may
provide some protection against hormone-dependent
cancers by altering hormone levels, particularly due
to down-regulation of androgen receptors [2].
The only significant problem in creating DIM-
based anticancer drug is its low bioavailability and,
as a result, the inability to achieve the therapeutic
concentrations of active substance in target tissues.
Generally, DIM exhibits low solubility in physiological
fluids and has limited ability to permeate through mem-
brane barriers [6, 7]. Based on this, and taking into
account the uniqueness of the candidate substance
DIM, the drug DIM, cod liver oil, polysorbate 80 and
α-tocopherol acetate (vitamin E) was developed.
Drug formulation is enclosed in a capsule as solution
containing the active substance — DIM (150 mg),
as well as organic auxiliary components — cod liver oil,
polysorbate 80 and α-tocopherol acetate (vitamin E)
providing high bioavailability and storage stability
of the drug [8]. It is known that cod liver oil in combina-
tion with polysorbate significantly improves absorption
in the gastrointestinal tract and distribution in the body,
and vitamin E increases storage stability [8].
The new drug formulation, created by us on the ba-
sis of modern technological solution, contains DIM
in a dissolved state, whereby DIM quickly enters
the blood and the target organs, and reaches concen-
trations which manyfold exceed the concentrations
of crystalline forms [9]. It was revealed that 5-fold
higher concentration of DIM was observed in blood
plasma of rats who received the 2,000-fold lower
dose of liquid DIM formulation (the DIM, cod liver oil,
polysorbate 80 and α-tocopherol acetate (vitamin E))
compared to crystalline form and non-formulated
crystalline DIM. We decided to carry out preclinical
in vivo study of pharmacological activity of the formula-
tion as a therapeutic antitumor agent.
Prostate cancer (PC) is one of the most common
cancers in the world affecting men. PC in Europe
is 2nd/3rd cause of cancer deaths, in the USA — 1st.
PC leads to 29% of fatal causes among patients
with malignant tumors [10]. In the absence of orga-
nized mass screening programs of early detection
of PC disease in many cases becomes metastatic
and incurable.
Modern methods of treating PC — hormone-
dependent cancer — are primarily directed to total
androgen blockade (androgen deprivation therapy),
and may involve surgery (radical prostatectomy,
Submitted: March 27, 2014.
*Correspondence: E-mail: pchelintseva87@mail.ru
Abbreviations used: BR-DIM — bioresponse 3,3´-diindolylme-
thane; DIM — 3,3´-diindolylmethane; PC — prostate cancer.
Exp Oncol 2014
36, 2, 90–93
Experimental Oncology 36, 90–93, 2014 (June) 91
conservative surgery, orchiectomy (rarely)) or hor-
mone therapy using medications.
According to statistics, about 60% of newly diag-
nosed cases of PC aren’t localized, and, consequently,
most of patients first-time diagnosed with PC, should
not undergo surgical procedures. Hormone therapy
is considered the most effective treatment for non-
localized forms of PC, however it allows to control the
disease only for limited periods of time because hor-
monal resistance inevitably develops [11]. Hormone-
refractory prostate tumors are resistant to treatment,
highly aggressive and have a poor prognosis [12].
Future prospects of PC treatment involve che-
motherapy combining anti-androgenic effects with
the targeted inhibition of multiple signaling pathways
that activate procarcinogens in the prostate gland.
The purpose of this investigation was to study
specific pharmacological preclinical antitumor activity
of the new drug — DIM, cod liver oil, polysorbate 80 and
α-tocopherol acetate (vitamin E) in vivo in a xenograft
mouse model of PC.
MATERIALS AND METHODS
Reagents. Drug formulation containing DIM, cod
liver oil, polysorbate 80 and α-tocopherol acetate
(vitamin E) (ZAO “MiraxBioPharma”, Russia) was pre-
pared according to special patented technology [8].
The crystalline DIM (3,3΄-methandiilbis(1H-indol)) (Alexis
Corporations, Switzerland), cod liver oil and polysor-
bate 80 (Sigma-Aldrich, USA) were used. The solvent
used in the experiment was a mixture of cod liver oil and
polysorbate 80 in the same proportions as developed
drug formulation.
Cell culture. The LNCaP (androgen-sensitive
human PC cells) was obtained from a collection of tu-
mor strains from the N.N. Blokhin Cancer Research
Center. All manipulations with cells were performed
under sterile conditions under a laminar flow hood
(NuAire, USA). LNCaP cells were maintained in RPMI
1640 (Gibco, USA) supplemented with 10% FBS (Hy-
Clone, USA), 2 mM L-glutamine and penicillin/strepto-
mycin (100 MU/mL) (Pan Eco, Russia) in an incubator
at 37 °С and 5% СO2 (Shel Lab, USA). On reaching
80–90% confluence, the cells were passaged. Cells
were washed twice with Versen solution, 0.025%
trypsin (Pan Eco, Russia) was added to the cells and
incubated for 10 min at 37 °C. After full cell separation
10 ml of growth medium were added and aggregated
cells were resuspended. Suspended cells was trans-
ferred for the following cells inoculation.
Animals. LNCaP cell inoculation. Study was car-
ried out using 60 immunodeficient male Balb/c-nude
(nu/nu) mice (4–5 weeks) which were purchased from
Charles River GmbH (Germany). The length of qu-
arantine was 14 days. During this time daily inspections
of behavior and general condition of each animal were
undertaken.
The animals were housed in standard cages
(Techniplast, Italy), connected to the air conditioning unit
TouchSLIM Plus® (Techniplast, Italy), 4–8 mice/cage.
The following microclimate parameters were maintained:
light conditions: 12 h — light, 12 h — dark; air tempera-
ture 24–26 °С; relative humidity 30±70%; air exchange
8–10 room volumes per hour. The animals had free ac-
cess to distilled water and food (PMI LabDiet® 5K67).
Food and water were pre-sterilized (autoclaving).
All animals were inoculated with LNCaP cells sub-
cutaneously along the spine (in left scapular region)
after adaptation period. LNCaP cell line inoculation
was carried out by injection of 0.2 ml of tumor suspen-
sion in sterile solution of PBS (Sigma, USA), containing
5 mln cells (25•106 cells/ml). All manipulations with
animals were approved by the local Animal Care and
Use Committee.
Treatment protocols. At 3 days after LNCaP cell
inoculation, animals which met criteria for inclusion
were randomized and individually labeled. Two groups
of animals were formed: control and experimental
(animals treated with the formulation) — 30 mice
each. In experimental group animals were adminis-
tered with the formulation twice daily (in the morning
and evening) with an interval of 8–9 h intragastrically
at a dose of 133 mg/kg/day (per DIM) by atraumatic
gavage for 33 days. The control group treated with
the same amount of solvent (cod liver oil + polysorbate)
on the same schedule. Tumor growth was monitored
for a further 6 days after the end treatment period.
In the days of administration of drug/solvent animals
were inspected at a specified time prior to and two
hours after administration.
Euthanasia was carried out by CO2-inhalation.
Assessment of antitumor activity. Tumor vo lume
measurements began at the initiation of tumor growth
and continued twice a week. Tumor volumes were
measured with caliper and were calculated by the fol-
lowing formula (Vt):
Vt (mm3) = L • W2/2,
where L — the longest tumor diameter,
W — the shortest tumor diameter.
Antitumor activity of the DIM formulation was esti-
mated by tumor growth inhibition ratio (Т/C%), where
T and C represent the means of the tumor volumes
of the control (VC) and treatment mice (VI) in each ex-
periment day (VI/VC • 100%). Another value of inhibition
ratio (D%) was reckoned by the formula:
D% = (VC−VI)/VC • 100%.
Behavior and general condition of animals have
been registered both in experimental and control
groups. Animals were weighted 2–3 times a week.
Statistical analysis. Statistical differences in tu-
mor growth inhibition ratio (Т/C%) between treated
and untreated groups were determined using Stu-
dent’s t-test by means of GraphPad Prism 5 software.
Differences were statistically significant at p < 0.05.
RESULTS AND DISCUSSION
Study of the antitumor activity of the formula-
tion in subcutaneous LNCaP xenografts. The effect
of the DIM formulation on tumor growth dynamics
was evaluated by measuring changes in tumor size
92 Experimental Oncology 36, 90–93, 2014 (June)
in response to treatment in immunodeficient mice
Balb/c-nude (nu/u) subcutaneously implanted with
human PC line LNCaP. Figure shows the average tumor
sizes in control and experimental groups of animals
in each study day.
-100
100
300
500
700
12 22 32 42
Day post inoculation
Tu
m
or
v
ol
um
e,
m
m
3
Solvent
Pharmaceutical composition of DIM
Figure. Dynamics of tumor growth in PC3 xenograft mouse model
in experimental (after intragastrically administration of the DIM for-
mulation for 33 days at a dose of 130 mg/kg/day) and control groups
The average tumor volumes of the treated
mice were not significantly different (ns) from that
of the control group till the 33-rd day post tumor cell
inoculation. Subsequently, however, the antitumor
effect of injected drug has become more evident. Sta-
tistically significant size reduction of the tumors treated
with the formulation compared with the control tumors
have registered since 37 day. As a result within 42 days
post inoculation the average volume of full-grown xe-
nograft tumors in control group reached ~ 600 mm3,
by comparison only ~100 mm3 in experimental group
(animals treated with the formulation). Therapeutic ef-
fect lasts for 6 days till study ends after the cessation
of the formulation administration (36th day after cell
inoculation). We suggest that this is result of stable
positive changes, caused by multiple targeted action
of the active substance on the molecular intracellular
mechanisms that mediate tumor growth.
According to the data, the highest antitumor effect
of the DIM formulation was observed on the 39th day
of experiment (37th day of observation post inocula-
tion), when the T/C% ratio, which was calculated by di-
viding the average tumor volumes of experimental ani-
mals by the control values, reached 16.8%. In the same
day of the experiment the value of inhibition ratio (D%)
was 83.2%. The values of these parameters remained
unchanged until the end of experiment.
Besides, we’ve registered dynamics of animals’
weight. It was shown that animals in both groups had
weight loss after the drug/solvent administration,
however weight and general condition of animals be-
came stable through about a week.
Thus the average volume of xenograft tumors in ex-
perimental group which was treated with the formula-
tion was 6-fold less than in group treated with original
DIM and T/C ratio reached 16.8% on day 42.
It should be noted that anticancer activity of crys-
talline DIM, and bioresponse-DIM (BR-DIM) formula-
tion (“BioResponse” LLC, USA), which contains DIM
combined with pegylated vitamin E and phosphatidyl
choline, has been successfully studied by different
authors in xenograft model of PC [2, 13–15], and
other cancers [3, 16–19]. However, bioavailability
of DIM in BR-DIM formulation compared with crystal-
line DIM was enhanced only in 1,5- to 2-fold, which
demon strate that administration of BR-DIM formu-
lation (per os) doesn’t ensure peak concentrations
of the active substance (DIM) and, consequently, de-
sired therapeutic effect. This could help to explain why
no significant clinical effect was achieved with BR-DIM
formulation in treatment of cervical dysplasia [20].
However, animal in vivo experiments revealed that
crystalline DIM and BR-DIM formulation — by various
routes of administration — demonstrate significant
dose-dependent antitumor effect. They induced
a reduction in tumor volume which was established
by implantation of PC3 cells, and/or reduce the amount
of newly formed metastases. According to the study
in a SKOV-3 xenograft tumor model of ovarian cancer
Т/C ratio was 47.2%, in other study this value was
51.63% (PC3 xenograft tumor model of PC) (Т/C values
were calculated according to the original experimental
data reported in these publications).
Our findings confirm inhibitory effect of the new for-
mulation containing DIM, cod liver oil, polysorbate 80 and
α-tocopherol acetate (vitamin E) on tumor development
in the xenograft animal model and complement previ-
ously obtained experimental data.
ACKNOWLEDGMENTS
Research and experimental studies were carried
out at the FGBOU VPO Peoples’ Friendship University
of Russia in the context of Project “Production of drugs
based on biotechnology for the treatment of socially
significant diseases”, financed by Presidential Grant
of The Russian Ministry of Education and Science
in compliance with Russian Government’s decree
№ 218.
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Copyright © Experimental Oncology, 2014
|
| id | nasplib_isofts_kiev_ua-123456789-145337 |
| institution | Digital Library of Periodicals of National Academy of Sciences of Ukraine |
| issn | 1812-9269 |
| language | English |
| last_indexed | 2025-12-01T06:39:59Z |
| publishDate | 2014 |
| publisher | Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| record_format | dspace |
| spelling | Kiselev, V.I. Drukh, V.M. Muyzhnek, E.L. Kuznetsov, I.N. Pchelintseva, O.I. Paltsev, M.A. 2019-01-20T16:36:21Z 2019-01-20T16:36:21Z 2014 Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer / V.I. Kiselev, V.M. Drukh, E.L. Muyzhnek, I.N. Kuznetsov, O.I. Pchelintseva, M.A. Paltsev // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 90-93. — Бібліогр.: 20 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/145337 Aim: Preclinical study of the specific anticancer pharmacological activity of the formulation containing active substance 3,3ʹ-diindolylmethane (DIM), cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E), in vivo in a xenograft animal model of LNCaP. Materials and Methods: The DIM, cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E) formulation was intragastrically administered to BALB/c-nude (nu/nu) mice during 33 days post inoculation at the dose of 133 mg/kg/day. Antitumor activity of the test drug was estimated by the rate of tumor growth inhibition (T/C% — treated versus control), dividing the tumor volumes from treatment groups with the control groups. Results: Statistically significant tumor xenograft regressions have been shown in group which received the DIM, cod liver oil, polysorbate 80 and α-tocopherol acetate (vitamin E) on the 37th day of observation post inoculation. The highest antitumor activity was achieved on the 39th day (T/C = 16,8%). Therapeutic effect lasts for 6 days after the end of therapy period. Conclusion: Our findings demonstrate inhibitory effect of the formulation on tumor development in the xenograft animal model due to the tumor growth rate reduction. Key Words: 3,3´-diindolylmethane, bioavailability, anticancer activity, xenograft model, LNCaP cell line, preclinical studies. Research and experimental studies were carried out at the FGBOU VPO Peoples’ Friendship University of Russia in the context of Project “Production of drugs based on biotechnology for the treatment of socially significant diseases”, financed by Presidential Grant of The Russian Ministry of Education and Science in compliance with Russian Government’s decree № 218. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Original contributions Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer Article published earlier |
| spellingShingle | Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer Kiselev, V.I. Drukh, V.M. Muyzhnek, E.L. Kuznetsov, I.N. Pchelintseva, O.I. Paltsev, M.A. Original contributions |
| title | Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer |
| title_full | Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer |
| title_fullStr | Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer |
| title_full_unstemmed | Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer |
| title_short | Preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer |
| title_sort | preclinical antitumor activity of the diindolylmethane formulation in xenograft mouse model of prostate cancer |
| topic | Original contributions |
| topic_facet | Original contributions |
| url | https://nasplib.isofts.kiev.ua/handle/123456789/145337 |
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