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ISSN: 2329-6674
Enzyme Engineering Sarkar , Hussain, Enz Eng 2016, 2016, 5:1
DOI: 10.4172/2329-6674.1000143

Research Open Access

Photocytotoxicity of Curcumin and its Iron Complex

Tukki Sarkar and Akhtar Hussain*
Department of Chemistry, Handique Girls’ College, Guwahati 781001, Assam, India
*Corresponding Author: Akhtar Hussain, Department of Chemistry, Handique Girls’ College, Guwahati 781001, Assam, India, Tel: +91-84869948829; E-mail:
[email protected]
Rec Date: Jan 20, 2016, Acc Date: Mar 28, 2016, Pub Date: Mar 30, 2016
Copyright: © 2016 Sarkar T, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and source are credited

Abstract

There is currently strong interest in curcumin and its metal complexes as potential photocytotoxic agents.
Curcumin is a polyphenolic dye of root turmeric which can be isolated from the rhizome of the herb Curcuma longa.
Curcumin is known to show a wide range of biological activities. It shows anticancer activity against a wide range of
cancers. Unfortunately, it is unstable in aqueous medium and undergoes rapid hydrolytic degradation thereby
severely limiting its usefulness as anticancer drug. In a recent work, we have shown that complexation to iron(III) ion
arrests the hydrolytic instability of curcumin while retaining its photocytotoxic activity. Thus, a metal bound
formulation of curcumin could be photochemotherapeutically more effective and successful than curcumin alone.

Keywords Curcumin; Iron(III); Photocytotoxicity; Photodynamic range of medicinal properties as anticancer, antioxidant, anti-
Therapy; Apoptosis inflammatory, antimicrobial, anti-HIV and anti-diabetic agents [4-7].
The wide range of therapeutic activities of curcumin are attributed to
Abbreviations the fact that curcumin can interact with a number of molecular targets
in the body [3]. Curcumin shows potent anticancer activity against a
DCFDA: 2',7'- Dichlorofluoresceindiacetate; DMEM: Dulbecco’s variety of cancers and has entered into several clinical trials for the
Modified Eagle’s Medium; DMF: Dimethylformamide; FACS: treatment of cancer and other diseases [8-11]. The anticancer activity
Fluorescence Assisted Cell Sorting; HeLa: Human Cervical Carcinoma; of curcumin stems from its ability to induce apoptosis in cancer cells
MCF-7, Human Breast Adenocarcinoma; MTT: 3-(4,5- without being cytotoxic to normal cells [8-11]. Curcumin interferes
Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide; PDT: with the activity of the transcription factor NF-κB (a protein complex
Photodynamic Therapy; PI: Propidium Iodide; ROS: Reactive Oxygen that is involved in the transcription of DNA) which has been linked to
Species; TCM: Traditional Chinese Medicine a number of inflammatory diseases including cancer [11]. However,
the clinical applications of curcumin have been severely impeded by its
Introduction poor bioavailability and pharmacokinetic profiles due to its hydrolytic
instability under physiological conditions [5,12]. The presence of the β-
Curcumin (abbreviated Hcurc) is a polyphenolic dye found in root diketone moiety in its structure renders curcumin hydrolytically
turmeric and can be isolated from the rhizome of the herb Curcuma unstable [5]. To improve the aqueous stability and hence therapeutic
longa (Figure 1). It is used as dietary spice in India and in Traditional efficacy of curcumin, several modifications of curcumin have been
Chinese Medicine (TCM) to treat infections, bite, burns and skin synthesized and tested. One very recent and successful strategy to
diseases [1-3]. Curcumin (1,7-bis(4-hydroxy-3-methoxy phenyl)-1,6- address this problem takes advantage of curcumin’s metal binding
heptadiene-3,5-dione) consists of two feruloyl chromophores property [13-28]. Binding of curcumin to a metal ion via its β-diketone
connected by a methylene group. The two aryl rings possessing two moiety significantly reduces the tendency of curcumin to undergo
ortho-methoxy and phenolic hydroxyl groups are conjugated through hydrolysis in aqueous medium and hence could result in improved
a β-diketone moiety. After deprotonation of the acidic hydroxyl group bioavailability and therapeutic efficacy.
by base treatment, the β-diketone moiety with two chemically
equivalent oxygen atoms can act as a strong bidentate ligand for
chemically hard metal ions such as oxidovanadium(IV), iron(III),
Materials and Methods
cobalt(III) and lanthanide(III). The β-diketone functionality is also Tissue homogenates from archival breast cancer FFPE sections
quite reactive and responsible for the occurrence of the well known (6µm) were prepared according to the procedure as described in the
keto-enol tautomerism in curcumin [2]. Curcumin possesses a visible QuantiGene Sample Processing Kit for FFPE Tissues (Affymetrix Inc.,
absorption band near 420 nm with a shoulder around 450 nm. This Santa Clara, CA). Excess paraffin from the slides were removed by
band is responsible for curcumin’s bright orange-yellow colour [2]. soaking the slides in xylene for 5 minutes followed by soaking in 70%
Curcumin emits green fluorescence when excited around 430 nm and ethanol for 5 minutes. The slides were air dried and the tissue from the
the position of this emission band is dependent on the nature of the slides were removed using a clean razor blade and placed into 1.5 mL
solvent used. For example, the emission maximum (λem) of curcumin tube. 300 μL of homogenizing solution supplemented with 2 µL of
is centred at 524 nm in acetonitrile and 549 nm in ethanol [2]. proteinase K (50 µg/L) were added to the tubes. The tubes were
Curcumin has demonstrated negligible intrinsic toxicity and hence it is vortexed for 30 seconds and incubated at 65°C for 4 hours. The tissue
safe for oral administration to a limit of 10 grams a day [3]. Recent
interests in curcumin is attributable to the fact that it shows a wide

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homogenate was separated from the debris by brief centrifugation, and water, 0.2 μL of proteinase K solution, 2 μL of blocking reagent, 5 μL of
then transferred to a new tube. probe set, 1 μL of magnetic Luminex beads; customised QuantiGene
Plex Set Panel). Hybridization was performed overnight for 18 hours at
Gene expression analysis was performed using a QuantiGene 10
54°C, with shaking at 600 rpm. The hybridization mixtures were then
Plex assay (Affymetrix Inc, Santa Clara, CA). The 12 genes measured
transferred to a 96-well flat bottom plate. An Affymetrix handheld
in this study included EN1, FOXC1, GABRP, CA12, AGR2, TTF3,
magnetic bead washer (Affymetrix P/N QP0702) was used to wash the
GATA3 ESR1 SCNN1A, ERBB2 and the housekeeping genes PPIB and
beads, thus removing all unbound materials. 100 μL of preamplifier
HPRT. Tissue homogenates were transferred to a 96 well hybridization
reagent was added to each assay well. The magnetic separation plate
plate containing QuantiGene Plex probe and Luminex beads sets. Each
was sealed with adhesive backed foil and incubated for 1 hour at 50°C
bead type was coated with a different single-strand DNAcapture probe
and 600 rpm. The unbound preamplifier reagent was removed, and
(CP). Several other components of the QuantiGene Probe set are also
beads were washed three times with 100 ml of wash buffer using the
comprised of single-strand DNA oligonucleotides including the
handheld magnetic washer. This was followed by similar incubation
capture extenders (CEs), label extenders (LEs), and blocking probes
and washing steps with 100 μL of Amplifier reagent, followed by 100
(BPs). Parts of CE oligonucleotides are complementary to the target
μL of Label Probe reagent, and finally followed by 100 μL SAPE
mRNA (covering ~500 bases). The QuantiGene Plex Assay was
working reagent. Signals from the beads were measured with a
performed according to the manufacturer’s manual with all of the
Luminex 200 (Luminex Corp., Austin, TX), after re-suspending the
reagents and consumables supplied by the manufacturer. (Quantigene
beads in 130 μL of SAPE wash buffer, using dd gate settings of 5,000–
Plex 2.0 Assay, Affymetrix Inc, Santa Clara, CA). For each well of the
25,000. Per target, 50–100 beads were measured in a sample volume of
96 well hybridization plate, 40 μL of tissue homogenate were
100 μL.
transferred to the plate where each well already contained 60 μL of
working bead mix (33.3 µL of lysis mixture, 18.5 μL of nuclease free

Figure 1: A partial Jablonski diagram showing the processes that take place during PDT of a tumor.

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Photodynamic Therapy (PDT) radiationless decay to populate the lower energy triplet excited state
(T1) by a process known as intersystem crossing (ISC). This triplet
Photodynamic therapy (PDT) is a newly recognized successful excited state is of importance due to its longer lifetime [36]. In type 1
chemotherapeutic modality for the treatment of cancer. In PDT, a reaction, the triplet PS can react directly with a substrate, such as the
photoactivatable drug is administered to a cancer patient and the cell membrane or a molecule and in type 2 reaction, the triplet PS can
target tissue is exposed to specific light in the presence of molecular transfer its energy directly to molecular oxygen to form excited state
oxygen thereby resulting in the production of cytotoxic molecular singlet oxygen. Both type 1 and type 2 reactions can result in further
species [29,30]. PDT has many advantages over conventional cancer reactions resulting in the formation of ROS which are toxic to several
therapies such as its low systemic toxicity, selective drug action within vital cellular components and macromolecules such as DNA, lipids,
the photo-irradiated regions, very low level of invasiveness and ability polysaccharides and enzymes. Molecules and organelles that are
to overcome drug resistance [29-35]. Light of wavelength in the range proximally located within the area ROS production and hence the area
620-850 nm, also known as the PDT window, is ideally required in of PS localization, are directly influenced by PDT [36]. The various
PDT to activate the drug molecule [36]. Absorption of light by a processes that can undergo upon irradiation of a PS are described in a
photoactivatable drug, also called a photosensitizer (PS), causes an partial Jabłoński diagram (Figure 2). Photofrin® is the currently FDA
electronic transition promoting an electron from a singlet ground state approved organic PDT drug [37]. Unfortunately, the limitations such
to a singlet excited state. The singlet excited state is relatively short- as skin sensitivity and hepatotoxicity associated with Photofrin® have
lived (typically 10-12 to 10-6 s) and there exists several pathways for motivated chemists to search for its alternatives [36-38]. Thus, the
deactivation of this excited state. Initial excitation of the PS takes it to a photoactivatable metal complexes of non-porphyrinic ligands have
higher vibrational level of the first electronic singlet excited state. The emerged as potential candidates in the PDT of cancer [39-48]. Metal
molecule then reaches the lowest vibrational level of the first electronic complexes possess varying coordination geometries, versatile spectral
singlet excited state (called S1) by a process known as internal and redox properties and can induce cell death via photo-redox and/or
conversion (IC). At this stage, the PS may undergo further deactivation type-I pathways besides generating cytotoxic singlet oxygen species in
with the emission of a photon (fluorescence) and come back to the a type-II process [39–48].
ground state. Alternatively, the excited singlet (S1) state may undergo

Figure 2: Extraction of curcumin and its chemical structure showing the metal binding reactive β-diketone moiety.

Photocytotoxicity of curcumin with visible light (Luzchem photoreactor, 400-700 nm, 10 J cm-2). It
was found to be significantly less toxic (IC50 = 85 μM) to the cell line in
The photophysical and photochemical properties of curcumin have the absence of light (4 h incubation in the dark). The dark toxicity of
recently been reviewed [2]. In India, turmeric is well known to protect Hcurc was reported to be 18 μM on 48 h incubation in the same cell
skins from sunburns and used as remedy for skin related diseases such line. The free curcumin, however, was found to undergo rapid
as leprosy and psoriasis [49]. Curcumin was shown to be genotoxic to hydrolytic degradation in culture media. The green emission of the
bacterial systems following photo irradiation with visible light of 420 curcumin ligand was used to study its cellular localization in HeLa
nm [50]. Dahl and co-workers found that curcumin was toxic to both cells. Curcumin was found to accumulate slightly within 2hr of
gram-positive and gram negative bacteria as well as mammalian cells incubation as evidenced from the intensity of the green fluorescence
in the presence of light and oxygen [51]. Similarly, the inside the cells. Upon increasing the incubation time to 4 h the
photocytotoxicity of curcumin was observed in NPC/CNE2 cell lines fluorescence intensity decreased substantially and the cells were no
when irradiated with visible light [52]. The mechanism of cell death longer seen, possibly due to the degradation of free curcumin molecule
was shown to be apoptotic thereby indication that curcumin could act in culture media. When the curcumin ligand was allowed to bound to
as a photochemotherapeutic agent. The phototoxicity of curcumin has an oxidovanadium(IV) moiety, not only the photocytotoxicity but also
been attributed to the generation of singlet oxygen and ROS during the fluorescence intensity increased significantly as a result of
photoexcitation [53,54]. Recently, the PDT effect induced by curcumin increased hydrolytic stability of curcumin on complexation to the
on cancer cells has also been investigated [55,56]. Very recently, the VO2+ moiety.
photocytotoxicity of curcumin has been investigated by Chakravarty
and coworkers [25, 26]. Curcumin was found to be photocytotoxic to
HeLa cells yielding an IC50 value of 8.2 μM when irradiated for 1 h

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Photocytotoxicity of curcumin when bound to iron (III) method. The complex was found to be a dinuclear species with a
distorted octahedral FeN3O3 core formed by the tridentate N,N,N-
As discussed above, free curcumin rapidly decays hydrolytically to donor phdpa, bidentate O,O-donor acac and the bridging oxo ligands.
its degradation products in aqueous buffer and this degradation of Absorption spectral study on complex 2 in Dulbecco's Modified Eagle's
curcumin can be cleverly arrested if the cheating β-diketone moiety is medium (DMEM) showed that the complexes were stable even after 48
engaged in bonding to a metal centre such as iron(III). While hours [57].
numerous studies on the anticancer and other biological properties of
curcumin and its metal complexes are reported, the photodynamic The photocytotoxicity and hence the anticancer activity of the
effect of metal complexes of curcumin in cancer cells remains complexes was studied by the well-known MTT assay in two human
unexplored despite curcumin’s rich photophysical and photochemical cancer cell lines, viz., HeLa and MCF-7 in the presence of visible light.
properties [2,13-28]. Earlier reports on cobalt (III), oxidovandium(IV), The photoactive complex 2 gave an IC50 value of 3.1 μM when
lanthanide(III), copper(II), zinc(II) and Ir(III) complexes have also irradiated with visible light of 400–700 nm (10 J cm-2) in HeLa cells
shown that the hydrolysis of curcumin gets suppressed upon binding (Table 1). Under identical conditions, the same complex gave an IC50
to a metal ion [13-28]. Using this strategy, we have recently reported an value of 4.9 μM in MCF-7 cells. Interestingly, the complex was
oxo-bridged iron(III) complex of curcumin that shows negligibly toxic to both the cell lines in the dark (IC50 > 50 µM). The
photocytotoxicity in HeLa and MCF-7 cancer cells in visible light control complex 1, lacking a curcumin unit, was neither
(Luzchem photoreactor, 400-700 nm, 10 J cm-2) [57]. In the reported photocytotoxic nor dark toxic in these cell lines under similar
work, two complexes of formulation [{Fe(phdpa)(acac)}2(μ-O)](ClO4)2 experimental conditions (Table 1). This result indicates that curcumin
(1) and [{Fe(phdpa)(curc)}2(μ-O)](ClO4)2 (2), where phdpa is bis-(2- is responsible for the observed photocytotoxicity of complex 2. The free
pyridylmethyl)-benzylamine, acac is acetylacetonate and curc is the curcumin ligand is known to give IC50 values of 8.2 μM and 19.9 μM,
monoanion of curcumin (bis(4-hydroxy-3-methoxyphenyl)-1,6- respectively, in HeLa and MCF-7 cells in visible light [20,25]. Hence,
diene-3,5-dione) were prepared in good overall yield and characterized an increase in activity of curcumin with respect to free curcumin was
by a number of physico-chemical techniques such as elemental observed in both the cell lines on binding to iron(III). The
analysis, IR, conductivity, electrochemical, mass spectral, UV-Visible, photocytotoxicity but negligible dark toxicity displayed by complex 2 is
emission and magnetic measurements (Figure 3). The crystal structure interesting considering the chemistry of iron based PDT agents [57].
of complex 1 was established by single crystal X-ray diffraction

Compound HeLa MCF-7

Light / µM Dark / µM Light / µM Dark / µM

[{Fe(phdpa)(acac)}2(μ-O)](ClO4)2 (1) 58.1 ± 1.1 79.4 ± 1.3 70.4 ± 1.7 >100

[{Fe(phdpa)(curc)}2(μ-O)](ClO4)2 (2) 3.1 ± 0.4 >50 4.9 ± 0.5 >50

Curcumin 8.2 ± 0.2 85.4 ± 0.6 19.9 ± 1.4 90.3 ± 4.9

a References 25 and 57.

Table 1: Cytotoxicity (IC50 values) of the complexes and curcumin in HeLa and MCF-7 cells in the presence of visible light (400-700 nm, 10 J
cm-2) and in dark.a

To know about the mechanism of cell death, the authors carried ROS only on exposure to visible light by complex 2 and not in the dark
out Annexin V-FITC/PI assay using HeLa cells treated with complex 2 [57].
under illuminated conditions. The results showed induction of
The green fluorescence of the free curcumin ligand retained upon
apoptosis in ~52% of the cell populations upon irradiation with a slight
binding to Fe(III) and this property was exploited by the authors to
occurrence of necrosis (~4% of the cells). No effect of the complex on
study the cellular uptake and localization of the complex in the HeLa
the cells was seen in the absence of light. To further confirm the above
and MCF-7 cells using fluorescence microscopy. Uptake of complex 2
result, the authors carried out propidium iodide (PI) staining
could be seen in both the cell lines after 2 h of incubation which
experiment with complex 2. Propidium iodide (PI) stains only the cell’s
increased substantially after 4 hr of incubation. Dual staining
nucleus. HeLa cells treated with complex 2 and incubated 4 hours
experiment with Hoechst 33342, which is known to stain only cell’s
followed by photo-exposure to visible light of 400-700 nm for 1 h
nucleus with its characteristic blue emission, showed primarily
exhibited irregular nuclear morphology on staining with propidium
cytosolic localization of complex 2 as evidenced from the merged
iodide as revealed from the fluorescence microscopy images.
fluorescence images [57].
Chromatin condensation of nuclei, which is a characteristic feature of
cells undergoing apoptosis, was observed. No such changes were seen
in the complex untreated and photo unexposed cells suggesting that Conclusions
the complex remained harmless inside the cells in the absence of light. There is currently a surge of research interest in curcumin and its
Intracellular ROS are the key players in inducing apoptosis by redox metal complexes as an anticancer agent. Recent work has shown that
active metal complexes [58, 59]. To detect ROS, 2',7'- the main drawback of curcumin, which is its poor bio-availability due
dichlorofluoresceindiacetate (DCFDA) assay was performed by FACS to its hydrolytic instability, can be successfully overcome by taking
analysis. The results showed generation of cytotoxic apoptosis inducing advantage of curcumin’s metal binding property. In most cases an

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increase in anticancer activity of curcumin has been observed on photochemotherapeutic agent. There is lot of future scope to design
binding to a metal. Our recent work on iron (III) complex of curcumin and develop metal complexes of curcumin with enhanced efficacy and
has shown that curcumin, when bound to iron(III), is a potential selectivity towards cancer cells.

Figure 3: Schematic drawing of the complexes [{Fe(phdpa)(acac)}2(μ-O)](ClO4)2 (1) and [{Fe(phdpa)(curc)}2(μ-O)](ClO4)2 (2).

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Enz Eng 2016, Volume 5 • Issue 1 • 143

ISSN:2329-6674 EEG, an open access Journal