The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro
Aim: To evaluate the effect of cell oxygenation on photocytotoxicity of a novel tricarbocyanine indolenine dye covalently bound to glucose (TICS). Methods: HeLa cells were incubated with 5 µM TICS, 2 h later irradiated by laser at 740 nm with a light dose of 10 J/cm2, delivered at a power density of...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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irk-123456789-1375502018-06-18T03:04:05Z The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro Istomin, Y.P. Alexandrova, E.N. Zhavrid, E.A. Voropay, E.S. Samtsov, M.P. Kaplevsky, K.N. Lugovsky, A.P. Lugovsky, A.А. Short communications Aim: To evaluate the effect of cell oxygenation on photocytotoxicity of a novel tricarbocyanine indolenine dye covalently bound to glucose (TICS). Methods: HeLa cells were incubated with 5 µM TICS, 2 h later irradiated by laser at 740 nm with a light dose of 10 J/cm2, delivered at a power density of 10, 20, 25 or 30 mW/cm2, in air or in argon atmosphere, and then scored for viability. Results: The photocytotoxicity of TICS increased dramatically as the power density was reduced. Under hypoxia TICS-photosensitized cell death was determined but its value was lowered, compared to photoirradiation in the air. Conclusion: Photosensitizing effect of TICS is only partially dependent on the oxygenation of tumor cells. Цель: исследование влияния оксигенации клеток на фотоцитотоксичность нового трикарбоцианинового индоленинового красителя, ковалентно связанного с глюкозой (ТИКС). Методы: клетки HeLa инкубировали в среде, содержащей 5 мкМ ТИКС, а через 2 ч на воздухе или в атмосфере аргона облучили светом лазера с длиной волны 740 нм в дозе 10 Дж/см2 при плотности мощности 10, 20, 25 или 30 мВт/см2 . Затем была определена их жизнеспособность. Результаты: фотоцитотоксичность ТИКС значительно возрастала при уменьшении плотности мощности облучения. В условиях гипоксии гибель клеток, фотосенсибилизированная ТИКС, сохранялась, но несколько уменьшалась в сравнении с результатами фотооблучения на воздухе. Выводы: фотосенсибилизирующий эффект ТИКС только частично зависит от оксигенации опухолевых клеток. 2006 Article The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro / Y.P. Istomin, E.N. Alexandrova, E.A. Zhavrid, E.S. Voropay, M.P. Samtsov, K.N. Kaplevsky, A.P. Lugovsky, A.А. Lugovsky // Experimental Oncology. — 2006. — Т. 28, № 1. — С. 80-82. — Бібліогр.: 16 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/137550 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Short communications Short communications |
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Short communications Short communications Istomin, Y.P. Alexandrova, E.N. Zhavrid, E.A. Voropay, E.S. Samtsov, M.P. Kaplevsky, K.N. Lugovsky, A.P. Lugovsky, A.А. The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro Experimental Oncology |
| description |
Aim: To evaluate the effect of cell oxygenation on photocytotoxicity of a novel tricarbocyanine indolenine dye covalently bound to glucose (TICS). Methods: HeLa cells were incubated with 5 µM TICS, 2 h later irradiated by laser at 740 nm with a light dose of 10 J/cm2, delivered at a power density of 10, 20, 25 or 30 mW/cm2, in air or in argon atmosphere, and then scored for viability. Results: The photocytotoxicity of TICS increased dramatically as the power density was reduced. Under hypoxia TICS-photosensitized cell death was determined but its value was lowered, compared to photoirradiation in the air. Conclusion: Photosensitizing effect of TICS is only partially dependent on the oxygenation of tumor cells. |
| format |
Article |
| author |
Istomin, Y.P. Alexandrova, E.N. Zhavrid, E.A. Voropay, E.S. Samtsov, M.P. Kaplevsky, K.N. Lugovsky, A.P. Lugovsky, A.А. |
| author_facet |
Istomin, Y.P. Alexandrova, E.N. Zhavrid, E.A. Voropay, E.S. Samtsov, M.P. Kaplevsky, K.N. Lugovsky, A.P. Lugovsky, A.А. |
| author_sort |
Istomin, Y.P. |
| title |
The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro |
| title_short |
The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro |
| title_full |
The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro |
| title_fullStr |
The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro |
| title_full_unstemmed |
The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro |
| title_sort |
effect of hypoxia on photocytotoxicity of tics tricarbocyanine dye in vitro |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2006 |
| topic_facet |
Short communications |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/137550 |
| citation_txt |
The effect of hypoxia on photocytotoxicity of TICS tricarbocyanine dye in vitro / Y.P. Istomin,
E.N. Alexandrova, E.A. Zhavrid, E.S. Voropay, M.P. Samtsov, K.N. Kaplevsky, A.P. Lugovsky, A.А. Lugovsky // Experimental Oncology. — 2006. — Т. 28, № 1. — С. 80-82. — Бібліогр.: 16 назв. — англ. |
| series |
Experimental Oncology |
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2025-07-10T02:34:52Z |
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2025-07-10T02:34:52Z |
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| fulltext |
80 Experimental Oncology 28, 80–82, 2006 (March)
In most human malignancies, oxygen delivery to
the neoplastic and stromal cells is reduced as a result
of structural and functional abnormalities of tumor
microcirculation and limited diffusion. Hypoxia in solid
tumors may restrict tumor curability, as hypoxic cells
have been shown to be resistant to standard radio-
therapy and chemotherapy [1].
Photodynamic therapy (PDT) of malignant tumors is
based on the activation of tumor-localizing photosensi-
tizing agents by specific light. With most photosensitiz-
ers (PS) under investigation, the PDT effect is mediated
by singlet oxygen and so is also oxygen-dependent.
Indeed, direct cell phototoxicity of Photofrin is reduced
at oxygen concentration of 0.5% [2]. Photocytoto-
xicity of Foscan under anoxic conditions was almost
completely inhibited [3]. Cytotoxic effects induced by
photoactivated hypericin [4] or phthalocyanines [5]
are also completely oxygen-dependent. The tumor
cell response to aminolaevulinic acid-based PDT was
abolished by hypoxia, as a result of both reduced pro-
toporphyrin IX synthesis and reduced PDT toxicity [6].
However, in the case of bacteriochlorophyll-serine, a
phototoxic effect was also seen under hypoxic condi-
tions [7]. Some other PS (psoralens, kryptocyanines)
can act in the absence of oxygen [8].
PDT treatment efficacy may be reduced not only
by pre-existing tumor hypoxia but also by oxygen de-
pletion during the therapy itself as a result of oxygen
consumption by photooxidative reactions, especially
with high rate of light delivery (power density) [9].
Therefore, it is important to know if the applied PS is
oxygen-dependent and to use an oxygen-conserv-
ing regimen of light treatment that determines the
outcome of malignant tumor PDT [10].
Tricarbocyanine indolenine dye covalently bound to
glucose (TICS) is a novel promising PS for PDT. TICS has
strong light absorption in the long-wave region, low toxi-
city in the dark, accumulates in tumor cells and tissues,
and was proved to be an effective PS in HeLa tumor cells
culture and in rats with transplanted tumors [11, 12]. In the
present study we investigated the impact of cell oxygena-
tion and rate of light delivery on TICS photocytotoxicity,
in comparison with chlorin e6 which acts as PS due to a
predominantly singlet oxygen mechanism [13].
Chemicals. Symmetrical tricarbocyanine indolenine
dye with 4-chlorosubstituted conjugate heptamethine
chain and with glucose connected to nitrogen (TICS)
has been developed and synthesized at Spectroscopy
Laboratory of A. N. Sevchenko Research Institute of
Applied Physical Problems (Minsk, Belarus) [12]. The
stock solution (10 mM) was prepared by dissolving the
dye in ethanol and stored at 4o C at dark until use.
Chlorin e6 (Chl) was obtained from Photochemis-
try Laboratory of Byelorussian Academy of Sciences
(Minsk, Belarus) [14] and dissolved in saline solution.
Further PS dilutions were made in 199 culture medium.
199 medium, fetal calf serum and Hanks’ balanced
salt solution were obtained from Research Institute of
Epidemiology and Microbiology (Minsk, Belarus).
Cell culture. HeLa cells (human cervical epithe-
lioid carcinoma) were obtained from the cell culture
collection of Research Institute of Epidemiology and
Microbiology (Minsk, Belarus). The cells were cultured
as a monolayer in 199 medium supplemented with 10%
fetal calf serum and 100 µg/ml kanamycin.
Photocytotoxicity study. For the experiments,
HeLa cells were plated at 1×105 cells in 2 ml of culture
medium into glass flasks (with diameter of 3 cm2), al-
lowed to get attached to the bottom and grow for 72 h
before being tested. All the experiments were carried
out on exponentially growing cells. On the day of the
experiment, 100 µl of TICS at a concentration of 100
µM or Chl at a concentration of 40 µM were added into
the flasks with cell monolayer in order to obtain a final
concentration of 5 µM TICS or 2 µM Chl. After incuba-
THE EFFECT OF HYPOXIA ON PHOTOCYTOTOXICITY OF TICS
TRICARBOCYANINE DYE IN VITRO
Y.P. Istomin1,*, E.N. Alexandrova1, E.A. Zhavrid1, E.S. Voropay2, M.P. Samtsov2,
K.N. Kaplevsky2, A.P. Lugovsky2, A.А. Lugovsky2
1N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus
2A.N. Sevchenko Research Institute of Applied Physical Problems, Minsk, Belarus
Aim: To evaluate the effect of cell oxygenation on photocytotoxicity of a novel tricarbocyanine indolenine dye covalently bound to
glucose (TICS). Methods: HeLa cells were incubated with 5 µM TICS, 2 h later irradiated by laser at 740 nm with a light dose of
10 J/cm2, delivered at a power density of 10, 20, 25 or 30 mW/cm2, in air or in argon atmosphere, and then scored for viability.
Results: The photocytotoxicity of TICS increased dramatically as the power density was reduced. Under hypoxia TICS-photosen-
sitized cell death was determined but its value was lowered, compared to photoirradiation in the air. Conclusion: Photosensitizing
effect of TICS is only partially dependent on the oxygenation of tumor cells.
Key Words: photosensitizers, cyanine dyes, HeLa cells, photodynamic therapy, hypoxia.
Received: January 23, 2006.
*Correspondence: E-mail: Istomin@users.med.by
Abbreviations used: Chl – chlorin e6; PDT – photodynamic therapy;
PS – photosensitizer; TICS – tricarbocyanine indolenine dye
covalently bound to glucose.
Exp Oncol 2006
28, 1, 80–82
SHORT COmmuNICATIONS
Experimental Oncology 28, 80–82, 2006 (March) 81
tion at 37 oC at a dark for 2 h with TICS or for 3 h with Chl
for maximal accumulation of PS in cells, the medium
containing PS was removed, cell monolayers were
washed three times with ice-cold Hanks’ balanced
salt solution, and the flasks were refilled with fresh
medium without PS. To perform experiments in argon
atmosphere with exclusion of oxygen, the monolayer
of cells was covered with deoxygenated (by bubbling
99.99% argon gas with 50 ml/min for 2 h) medium, and
then further saturated with argon by bubbling argon
gas with 6 ml/min through the medium for 30 min. In
such conditions the oxygen content in the medium was
below 0.1–0.2 µg/ml [4]. Phototreatment of the cell
monolayer was carried out at 0–4 oC with semiconduc-
tor laser (740 nm, Lotis, Belarus, in the case of TICS; or
668 nm, BioSpec, Russia, in the case of Chl). The size
of a light spot adjusted by diaphragm was 2 cm in diam-
eter. At the surface of the flask bottom the power den-
sity was of 10, 20, 25 or 30 mW/cm2, as measured by
LM-2 power meter (Carl Zeiss, Jena, Germany). Im-
mediately after irradiation the hypoxic medium was
removed and replaced with fresh normoxic culture
medium. Treated and control cells were cultured for
additional 20 h and scored for viability by determining
the number of viable cells in the flasks. This involves
dispersal of cells with 0.02% versen (DIALEK, Belarus)
for 10 min at 37 oC, pipetting and counting in Gory-
aev’s chamber under phase-contrast microscope. All
manipulations were carried out in reduced light. The
results are presented as the percentage of cell survival
relative to the controls. The mean ± standard deviation
was calculated from three experiments.
PS accumulation in cells. Cell content of TICS
or Chl was measured by a fluorimetric assay. HeLa
cell monolayers cultured in glass flasks over 72 h, as
for cytotoxicity evaluation, were incubated with 5 µM
TICS or 2 µM Chl at 37 °C at dark as described above.
After incubation with PS, the medium containing PS
was removed and cell monolayers were washed three
times with ice-cold Hanks’ balanced salt solution
without phenol red. The cells were removed from the
flask bottoms with 0.02% versen (10 min at 37 °C),
counted in Goryaev’s chamber and suspended in
butanol for dye extraction [14] in the case of TICS or
were dissolved in 2% Triton X-100 detergent solution
in phosphate buffer at pH 7.4 in the case of Chl [15].
Fluorescence intensity of the samples was measured
by Fluorolog Spex fluorescence spectrophotometer
(USA) at 750 nm (excitation wavelength, 715 nm) in the
case of TICS or at 668 nm (excitation wavelength, 500
nm) in the case of Chl. Just before measurements of
the samples spectrofluorimeter was calibrated using
standards of known PS concentration. All manipula-
tions were carried out in reduced light.
To eliminate oxygen from the cell monolayer, the
culture medium was saturated with argon by bubbling
argon gas through the medium with continuous stir-
ring. To compare the photodynamic activity of TICS
and Chl in hypoxic condition, we used isoeffective
amounts of each PS and light (near 10% survival)
under normal oxygenation. Thus, under normoxia, the
survival of HeLa cells after incubation with 5 µM TICS
followed by light irradiation at 740 nm with 10 J/cm2
(25 mW/cm2) was 12 ± 3%, and after incubation with
2 µM Chl with subsequent light irradiation at 668 nm
with 3 J/cm2 (25 mW/cm2) was 7 ± 2%. In hypoxic con-
dition, the same phototreatment resulted in 24 ± 4%
cell survival with TICS and 97±4% cell survival with
Chl (Fig.1). No differences in viability were noticed
when cells were incubated with 5 µM TICS or 2 µM Chl
without phototreatment or when cells were irradiated
with light in the absence of PS, both under normoxic
and hypoxic conditions.
Fig.1. Survival of HeLa cells after photodynamic treatment
with TICS or Chl in normoxic and hypoxic conditions. The
cell monolayers were incubated with 5 µM TICS or 2 µM Chl,
exposed to light under normoxia or hypoxia and scored for
viable cell number 20 h later. Each data point represents the
mean ± standard deviation of three experiments
Thus, at the attained level of hypoxia most of the Chl
photocytotoxicity was lost, while phototoxic effect of
TICS was partly retained. PS content in cells just before
phototreatment was 4.6 ×107 molecules/cell for TICS
and 5.7 × 107 molecules/cell for Chl, and it did not de-
pend on the oxygenation level. Hence the differences
between normoxic and hypoxic conditions could not
be ascribed to intracellular PS concentration.
The photocytotoxicity of TICS under normal oxy-
genation was greatly dependent on the rate of light
delivery (Fig. 2). As the power density was reduced
from 25 mW/cm2 to 20 mW/cm2 or 10 mW/cm2, the cell
survival was markedly diminished (from 12.4 ± 2.2% to
2.6 ± 0.9% or 1.7 ± 0.3%, respectively) with an applied
fixed light dose of 10 J/cm2. Cell survival following the
same light dose of 10 J/cm2 administered at a power
density of 30 mW/cm2 was 28.0 ± 4.3% under normoxic
conditions. Thus, with increasing the rate of light de-
livery, the photocytotoxicity of TICS was dramatically
decreased under normoxic conditions, while under hy-
poxic conditions similar phenomenon was less marked.
It should be noted that survival of cells treated with the
highest light delivery rate (30 mW/cm2) under hypoxic
conditions, was determined as 35.9 ± 4.7%. This value
did not significantly differ from those in normoxic con-
ditions 28.0 ± 4.3%, and most likely indicated that the
decrease of TICS photocytotoxicity under normal oxy-
genation with increase of light delivery rate was caused
by oxygen consumption within phototreatment. Similar
82 Experimental Oncology 28, 80–82, 2006 (March)
results with light-delivery rate effect on cell survival were
obtained in Colo 26 multicell spheroids photosensitized
by meta-tetra (hydroxyphenyl) chlorin and irradiated at
5, 30 or 90 mW/cm2 [16].
Fig.2. Survival of HeLa cells after TICS-PDT as a function of
light delivery rate and oxygenation conditions. The cell mono-
layers were incubated with 5 µM TICS, exposed to light irradia-
tion at 10 J/cm2, delivered at 10, 20, 25 or 30 mW/cm2 under
normoxia or hypoxia and scored for viable cell number 20 h later.
Points: means ± standard deviation of three experiments
Obtained results allow to suggest that molecular oxy-
gen is involved in TICS-sensitized cell photo inactivation
under normal oxygenation. The photocytotoxicity of TICS
under the hypoxia condition was retained but lowered, in
contrast to the loss of the phototoxic effect of Chl. Thus,
we can assume that the mechanism of the photosensitiz-
ing effect exhibited by TICS is only partly dependent on
oxygen. TICS ability for photodynamic activity in hypoxic
conditions makes it possible to overcome the resistance
of hypoxic cells in malignant tumors to PDT.
ACKNOWLEDGmENTS
This work was supported by Byelorussian Republic
Foundation for Basic Research and by INTAS.
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ВЛИЯНИЕ ГИПОКСИИ НА ФОТОЦИТОТОКСИЧНОСТЬ
ТРИКАРБОЦИАНИНОВОГО КРАСИТЕЛЯ ТИКС IN VITRO
Цель: исследование влияния оксигенации клеток на фотоцитотоксичность нового трикарбоцианинового индоленинового
красителя, ковалентно связанного с глюкозой (ТИКС). Методы: клетки HeLa инкубировали в среде, содержащей 5 мкМ
ТИКС, а через 2 ч на воздухе или в атмосфере аргона облучили светом лазера с длиной волны 740 нм в дозе 10 Дж/см2 при
плотности мощности 10, 20, 25 или 30 мВт/см2. Затем была определена их жизнеспособность. Результаты: фотоцитотоксичность
ТИКС значительно возрастала при уменьшении плотности мощности облучения. В условиях гипоксии гибель клеток,
фотосенсибилизированная ТИКС, сохранялась, но несколько уменьшалась в сравнении с результатами фотооблучения на воздухе.
Выводы: фотосенсибилизирующий эффект ТИКС только частично зависит от оксигенации опухолевых клеток.
Ключевые слова: фотосенсибилизаторы, цианиновые красители, клетки HeLa, фотодинамическая терапия, гипоксия.
Copyright © Experimental Oncology, 2006
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