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Soni et al., IJPSR, 2015; Vol. 6(11): 4588-4600. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4588
IJPSR (2015), Vol. 6, Issue 11 (Review Article)
Received on 14 May, 2015; received in revised form, 21 June, 2015; accepted, 30 August, 2015; published 01 November, 2015
REVISITING THE ROLE OF PHYCOCYANIN IN CURRENT CLINICAL PRACTICE
A. Soni *1, M. Dubey 1, M. Verma 2, R. Dhankhar 1, V. Kaushal 1, R. Atri 1 and R. Sabharwal 3
Department of Radiotherapy 1, Department of Biochemistry 2, PGIMS, Rohtak, Haryana, India.
Consultant Radiation Oncologist 3, Department of Health, Government of Haryana, Kurukshtra, Haryana
India.
ABSTRACT: C-phycocyanin (C-PC) is a biliprotein found in edible blue-green
algae. Its anti-cancer, anti-inflammatory, anti-proliferative and anti-oxidant activities
has been evidenced by many in vitro and in vivo studies. Anti-inflammatory activity
of C-PC demonstrated by free radical scavenging, inhibition of DNA damage, and
decreased ROS. Here, the effects of C-PC on cytotoxicity and cell signaling through
the apoptotic and other pathways were studied. Results indicated that anti-
proliferative effects of C-PC are mediated by inactivation of BCR-ABL signaling
and the downstream pathway PI3K/AKT. Phycocyanin induces apoptotic death, and
Bcl-2 expression inhibits it via generation of free radicals. C-PC exerted
antimelanogenic mechanisms by downregulating p38 MAPK-regulated CREB
pathway activation and upregulating MAPK/ERK-dependent degradation of MITF
protein. C-PC-mediated PDT (photodynamic therapy) is approved as a potential
therapy for cancer. Phycocyanin can be consumed as a dietary supplement or a food
component to obtain health benefits against CVD (cardiovascular disease) and
NAFLD (non-alcoholic fatty liver disease). These results suggest that phycocyanin
which had been obtained from blue green algae are potential medicaments in the
treatment of various kinds of human ailments and cancers.
INTRODUCTION: Phycocyanin extracted from
Spirulina was first marketed in 1980 by Dainippon
Ink and Chemicals under the brand name “Lina
Blue–A.1 Phycocyanin is a dietary supplement
dedicated to individuals who are undergoing
chemotherapy and radiation for cancer and is used
to ease negative symptoms during treatment as well
as rejuvenate post treatment.
Phycocyanin is an important molecule extracted
from Spirulina platensis, a 3.6 billion years old blue
green algae and its nutritional values and
therapeutic values are well documented.2, 3
QUICK RESPONSE CODE
DOI:
10.13040/IJPSR.0975-8232.6(11).4588-00
Article can be accessed online on:
www.ijpsr.com
DOI link: http://dx.doi.org/10.13040/IJPSR.0975-8232.6(11).4588-00
Spirulina is known to have nutritional advantages
of high-quality protein, minerals, vitamins,
essential amino acids, cyanocobalamin (B12),
tocopherols and essential fatty acids including β-
carotene and γ -linolenic acid (GLA).2, 3
Phycocyanin is a water soluble, natural and non-
toxic molecule with anticancer, antioxidant,
antiviral and anti-inflammatory activities.3,4
Phycocyanin is also a powerful agent for the
immune system in human and animals, and
provides protection from a number of diseases.3
The deep blue colour of Phycocyanin has been
widely used as a colorant in food industry for food
additive purposes.3 Various research studies also
support strong hepatoprotective, cytoprotective and
neuroprotective profile of phycocyanin.
Most of the studies are based on the laboratory
experimental results on mice and cultured cell
lines, and, still very less literature is available to
conclude any concrete result for Phycocyanin use
Keywords:
Anti-oxidant, apoptosis,
cancer, free radicals, Phycocyanin.
Correspondence to Author:
Dr. Abhishek Soni
Senior Resident, Department of
Radiotherapy, Post-graduate institute
of medical sciences, Rohtak, India –
124001
E-mail: abhisheksoni246@gmail.com
Soni et al., IJPSR, 2015; Vol. 6(11): 4588-4600. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4589
in current era of medical practice. Thus, this article
reviews the role of phycocyanin in today‟s clinical
practice.
Structure:
Phycocyanin occurs as the major phycobiliprotein
in Cyanobacteria and as a secondary
phycobiliprotein in some red algae.2 C-
Phycocyanin (C-PC) is a natural compound.5 The
pigment is composed of two subunits, α and β,
which occur in equal numbers, but the exact
number may vary among the species. Both α and β
subunits contain only the PCB chromophore.2 The
structure of C-phycocyanin from the thermophilic
blue green algae Mastigocladus laminosus has been
determined at 3 Å resolution by X-ray diffraction
methods. The protein found to consist of three α-β
units arranged around a threefold symmetry axis to
form a disc with dimensions of 110 Å × 30 Å with
a central channel of 35 Å in diameter. Both
subunits, α and β, have a similar structure and are
related by a local twofold rotational axis.6 Its
molecular weight is between 70,000 and 110,000
Daltons. Phycocyanin has visible absorption
maximum between 615 and 620 nm and maximum
fluorescence emission at ~650 nm.2 Phycocyanin
accepts quanta from phycoerythrin by fluorescent
energy transfer in organisms in which it is present.2
The purity of C-PC is evaluated using the
absorbance ratio of A620/A280, and a purity of 0.7
is considered as food grade, 3.9 as reactive grade,
and more than 4.0 as analytical grade. Purity is
directly related to process costs, and, in general, the
more purified a product is, the more expensive to
obtain it.1
Fig.1 shows chemical structure of the bilin
chromophores in phycocyanin, which is very
similar to bilirubin, a heme breakdown product.2
FIG.1: CHEMICAL STRUCTURE OF PHYCOCYANIN
BILIN CHROMOPHORE (OPEN-CHAIN TETRAPYRROL) 2
Sources:
Phycocyanin can be extracted mainly from blue
green algae and may be from red algae
(rhodophytes) and cryptophytes.7 Main sources are
Spirulina platensis, Arthrospira platensis, Spirulina
maxima, Phormedium fragile, Nostoc muscorum,
Oscillatoria species, Nostoc humifusum, Anabaena
oryzae, Wollea saccata, Anabaena flous aquae,
Limnothrix and Porphyra haitanensis, thermophilic
cyanobacterium Mastigocladus laminosus,
Agmenellum quadruplicatum, Remyella
diplosiphon, Phanizomenon flos-aquae, marine
cyanobacterium Synechococcus sp. IO9201,
Galdieria sulphuraria (rhodophyte), Anabaena sp.
PCC 7120, Leptolyngbya species, Scytonema
julianum, Thermosynechococcus elongates,
Tolypothrix tenuis, Nostoc minutum, Klamath
algae, Acaryochloris marina, and Microcystis
aeruginosa.6-17
Extraction and Purification:
A number of drying methods like spray dried,
crossflow dried and oven dried methods, are used
for Spirulina processing, and results in
approximately 50% loss of phycocyanin. So fresh
biomass is suitable for extraction of phycocyanin.18
Blue green algae are grown in nutrient medium
(like Zarrouk‟s medium) containing different
amounts of nitrogen and salt. In Spirulina species,
Phycocyanin pigments increase from 12% to 22%
on increasing nitrogen levels.3 Spirulina has a wide
variety in composition of Phycocyanin pigments
ranging from R-phycocyanin (R-PC) from 5.75 to
12.35%, allophycocyanin (A-PC) from 2.53 to
6.11% and C-phycocyanin (C-PC) from 1.65 to
4.02% as a result of changing nitrogen contents and
salt stress.3, 19
The concentration of Phycocyanin pigment
including C-Phycocyanin (C-PC), allophycocyanin
(A-PC), and R-phycocanin (R-PC) are determined
spectrophotometrically at 618 and 650 nm, 650 and
618 nm, and 498, 615 and 650 nm respectively as
reported by Kursar and Alberte.20 Cyanobacteria
adjusts the contents and relative ratio of its
pigments with the light quality, like more
production under red or violet light.21 C-PC is a
natural blue pigment accounting for 14% of SP dry
weight.22 The increase in NaCl levels in nutrient
Soni et al., IJPSR, 2015; Vol. 6(11): 4588-4600. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4590
medium led to significant increase in production of
Phycocyanin contents and soluble protein in
Spirulina cells.23, 24 Phycocyanin production also
depends on iron concentration in the media.25 Thus,
Spirulina species grown under combined stress of
high NaCl and nitrogen deficient levels, produce
higher amount of Phycocyanin.3, 21, 26, 27
Many methods have been used for the separation
and purification of C-PC. C-PC is purified from
Spirulina platensis by ammonium sulfate
precipitation, ion-exchange chromatography,
modified flow cytometry and free-flow
electrophoresis (FFE).5, 28, 29 SDS-polyacrylamide
gel electrophoresis is performed to assess the
molecular weight and purity of C-PC. SDS-PAGE
analysis of the purified fraction clearly showed 2
protein bands corresponding to α and β subunits of
C-PC. The purity of C-PC, as judged by an
A620/A280 purity ratio greater than 4.0, is
sufficient for further testing. 5, 30 Femtosecond laser
spectroscopies are used to examine the electronic
structures of cyanobacteria.31
Table 1 shows the purity of C-PC after various
stages of purification which can be implied for
further analysis of grading the phycocyanin. The
table signifies that the purity can be increased and a
food grade phycocyanin was isolated.1
TABLE 1: PURIFICATION OF PHYCOCYANIN1
Sr. No.
Purification
process
Extraction
purity at
615/280nm
Phycocyanin
concentration
(mg/ml)
1
Crude
Phycocyanin
0.61
1.94
2
Ammonium
sulphate
precipitation
0.73
2.39
3
Membrane
filtration
0.89
2.64
4
Dialysis
0.99
2.90
Cell cytotoxicity was evaluated by the 2,3-bis[2-
methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-
carboxyanilide inner salt (XTT) assay. Western
blot analysis is used to study the expression and
phosphorylation of proteins in the PI3K/AKT
pathway.5 The oxygen radical absorbance capacity
(ORAC) assay is used to assess antioxidant activity
of phycocyanin.32 C-PC concentration from G.
sulphuraria is low than cyanobacteria.33
Uses:
The spray-drying method is used to load
chitosomes with C-phycocyanin for colonic drug
delivery.34 Phycocyanin extracted from Spirulina
platensis displayed favorable health benefits such
as improving immune function, promoting zooblast
regeneration and inhibiting the growth of cancer
cells.35 Since phycocyanin is photosensitive, it has
been proposed as a new photosensitizer for
photodynamic therapy.36 C-phycocyanin is
endowed with various biological and
pharmacological properties.5 C-phycocyanin
possesses significant antioxidant activities and can
enhance immunity and inflammatory responses.5
Studies have shown that C-phycocyanin can induce
apoptosis in cancer cells such as a mouse
macrophage cell line (RAW 264.7), prostate cell
line (LNCaP), breast cell line (MCF-7), and
erythromyeloid leukemia cell line (K562).5
Phycocyanin is used in treatment of hepatocellular
carcinoma, rectal cancer, leukemia, melanoma and
used in food industry, biomedicine and cosmetics
industry. Subashini et al demonstrated that C-
phycocyanin induced apoptosis in K562 cells is
mediated by cytochrome c release, PARP cleavage,
and Bcl-2 down-regulation.5 C-phycocyanin could
be used for treating ischemia-reperfusion injury
through the activation of ERK pathway and
suppression of p38 MAPK pathway.37, 38
Phycocyanin is a potent antioxidant as well as
herbicidal agent, and possesses significant immune
enhancing and antiviral properties.1, 39, 40 It‟s
enhancing biological defense activity against
infections disease reduces allergies inflammation
by the suppression of IgE antibody.
The phycocyanin is used as coloring agent in food
item like jellies, chewing gums, ice sherbaths, and
dairy products, and it enhances antioxidant capacity
of food and beverages.1, 41 In Japan, China, and
Thailand, phycocyanin is used in cosmetics like
lipstick and eyeliners.1 It is used in biomedical
research and pharmaceutical industries.1, 42, 43 It is
used in immune diagnostic applications.1 C-PC
selectively stimulates the lymphocyte antioxidant
defence system of occupationally exposed subjects.
The activation of the antioxidant protective
mechanisms as part of the early radiation response
Soni et al., IJPSR, 2015; Vol. 6(11): 4588-4600. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4591
is probably related to the chronic low-dose
occupational exposure. The modulating capacity of
C-PC at the molecular level may be of interest for
the protection of occupationally exposed persons.44
Antioxidative Properties of Phycocyanin:
Antioxidant activity of Phycocyanin is
demonstrated by ascorbate/iron/H2O2 assays,
DPPH (2,2 diphenyl-1-picrylhydrazyl) assay and
ABTS (2,2‟-azino-bis ethylbenzthiazoline-6-
sulfonic acid) assay.8, 45 Oxidative stress, mainly
characterized by reactive oxygen species (ROS),
damages tissues and therefore is associated with
several pathological conditions, such as
atherosclerosis, nonalcoholic steatohepatitis
(NASH), and aging. 46 Hydroxyl and peroxyl
radicals are associated with oxidative damage to
lipids and DNA.46 Human studies have reported the
protective effects of BGA against oxidative damage
in vivo and in vitro.
SP supplementation of 8 grams per day for 12
weeks significantly decreased plasma levels of
MDA (malondialdehyde), a biomarker of oxidative
stress, in diabetic patients. Similarly, healthy
elderly Korean subjects who consumed 8 grams per
day of SP for 16 weeks showed a decrease in the
lipid peroxidation level, whereas the total
antioxidant status and levels of antioxidant
enzymes, such as SOD and GPx, were elevated in
plasma, indicating that SP supplementation was
able to improve antioxidant status in the human
subjects. C-PC markedly inhibited the production
of alkoxyl radicals that are generated by the
reaction of tert-butyl hydroperoxide with ferrous
ions in the presence of luminol. In addition, C-PC
prevented DNA damage and scavenged hydroxyl
and peroxyl radicals. Furthermore, C-PC inhibited
peroxyl radical-induced oxidative hemolysis and
lipid peroxidation in normal human erythrocytes.46,
47
C-PC from AFA extract demonstrated protective
effects against cupric chloride-induced lipid
oxidation in human plasma samples. Cysteine-rich
cyanopeptide beta 2 isolated from C-PC of SF
demonstrated free radical scavenging, inhibition of
DNA damage, and decreased ROS production.48
Selenium-containing allophycocyanin (Se-APC)
extracted from selenium-enriched SP inhibited
2,20-azobis-2-methylpropanimidamide,
dihydrochloride (AAPH)-induced oxidative
hemolysis, and morphological changes in human
erythrocytes.49 Se-APC, furthermore, inhibited
AAPH-induced intracellular ROS production and
MDA accumulation.46 Treatment with C-Pc
protects the rats from Tributyltin (TBT) induced
thymic atrophy, but not proved in humans for such
a role.50 Phycocyanin may inhibit atherosclerosis by
activating heme oxygenase-1.51 Phycocyanin helps
in displacing fluoride, facilitating antioxidant
formation, reverses sodium fluoride-induced
thyroid changes, improves behaviour and protects
Purkinje cells. Phycocyanin supplementation
during pregnancy may reduce the risk of fluoride
toxicity to offspring.52
Lipid-Lowering Effect of Phycocyanin:
In human clinical trials, supplementation with
Spirulina Platensis (SP) exhibited lipid-lowering
effects. In patients with type 2 diabetes, subjects
who consumed 2 grams per day of SP for 2 months
showed significantly lower plasma triglyceride
(TG) concentrations as well as a significant
reduction in ratios of total cholesterol : HDL-C and
LDL-C : HDL-C.46 Eight grams per day of SP
supplementation for 12 weeks significantly reduced
plasma triglyceride concentrations and blood
pressure in type 2 diabetic patients with higher
initial triglyceride levels, whereas subjects with
high initial total cholesterol and LDL-C showed
significant reductions in the plasma lipids. In
patients with a hyperlipidemic nephritic syndrome,
1 gram per day of SP supplementation for 2 months
significantly decreased plasma total cholesterol,
LDL-C, and triglyceride concentrations. Up to
now, BGA dosages used in human clinical trials
have ranged from 1 to 8 grams per day for up to 24
weeks, whereas 5 gram per day is generally
recommended by the manufacturers.46
Although individual cases of discomfort or
unpleasant condition have been reported with BGA
supplementation from time to time, Dietary
Supplements Information Expert Committee (DSI-
EC) of the United States Pharmacopeial
Convention has awarded Spirulina (SM and SP) a
grade A safety rating and agreed that Spirulina is
generally safe to be consumed.53 Concern over
using BGA during pregnancy and breast feeding is
Soni et al., IJPSR, 2015; Vol. 6(11): 4588-4600. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4592
not clearly defined in humans. However, numerous
animal studies indicated that SP consumption
during pregnancy and lactation did not induce signs
of maternal intoxication.46
In contrast, Kapoor and Mehta had demonstrated
that SP supplementation could improve iron status
during pregnancy, as evidenced by a higher
hemoglobin count, serum iron, and serum ferritin.54
Further study is necessary to evaluate the effect of
BGA supplementation in humans during specific
nutrition status and pathological conditions.46
Morcos et al perfused atherosclerotic artery
segments obtained within 5 hours postmortem with
0.1 mg/ml phycocyanin in oxygenated Krebs
Ringer solution at 30 mmHg for five minutes
followed by washout with Phycocyanin free Krebs
for ten minutes. Histologically, on light and
fluorescence microscopy, artery section revealed
fluorescence localization within the plaque
particularly at the site of elastic lamina and also at
the internal elastic lamina but not in the medial
muscle layer.
These properties suggested therapeutic use of
Phycocyanin for plaque localization and
regression.55 Both C-PC and CD59 inhibit the
process of atherosclerosis, and the anti-
atherosclerotic properties of C-PC might be due to
promoting CD59 expression, preventing
proliferation of smooth muscle cell and the
apoptosis of endothelial cells, reducing lipid levels,
and finally inhibiting atherosclerosis.56
Phycocyanin prevents hypertension and endothelial
dysfunction related disease like metabolic
syndrome.57
Effect of C-PC on Lipid Peroxidation:
ROS initiate the peroxidation of membrane lipids,
leading to the accumulation of lipid peroxides and
leakage of cytosolic enzymes into circulation.46
Bhat and Madyastha reported C-PC inhibited
nearly 95% of peroxyl radical-induced lipid
peroxidation. C-PC with a reduced chromophore
can efficiently inhibit peroxyl radical-induced lipid
peroxidation in a dose-dependent manner.58
Anti-Inflammatory Effects of Phycocyanin:
Oxidative stress plays important roles in lung
disease, gastrointestinal dysfunction, endothelial
dysfunction and atherosclerosis.45 Anti-oxidative
and anti-inflammatory effects can be demonstrated
by non-alcoholic steatohepatitis model.59 C-
phycocyanin suppresses inflammation by inhibiting
the expressions of inducible cyclooxygeanase-2
(COX-2) and nitric oxide synthase, and by
inhibiting the production of pro-inflammatory
cytokines. Also, Phycocyanin scavenges free
radicals, including alkoxyl, hydroxyl and peroxyl
radicals; inhibits liver microsomal lipid
peroxidation, decreases prostaglandin E(2)
production, reduce myeloperoxidase production,
decreases nitrite production, inhibits platelets
aggregation, and uppresses the activation of nuclear
factor-κB (NF-κB) via preventing degradation of
cytosolic IκB-α. These all effects lead to anti-
inflammatory activity of Phycocyanin.60 Upto now,
the antinociceptive properties of phycocyanin have
been less thoroughly investigated.45
Consumption of BGA has been demonstrated to
promote immunity and to protect against
inflammatory diseases, such as colitis, arthritis, and
allergic rhinitis in animal and human studies.61 SP
organic extracts markedly decreased the secretion
of proinflammatory cytokines, including the
granulocyte-macrophage colony stimulating factor,
IL-6, MCP-1, and TNFa. Moreover, translocation
of NF-jB from cytoplasm to nucleus was also
inhibited. Anti-inflammatory effects of BGA have
been shown in cell studies, animal studies, and
human studies. Furthermore, understanding of the
effect of BGA on acute or chronic inflammatory
pathways is necessary because although the two
pathways share some of common mediators,
protective effects against chronic inflammation at a
low degree for a long period of time are more
relevant and beneficial to the prevention of
metabolic diseases such as CVD and NAFLD.46
Several components of BGA, including GLA and
PC, have been implicated in their anti-
inflammatory effects. SP contains 1.3% GLA. An
anti-inflammatory effect of SP is also often
associated with antioxidant and antiviral properties
of C-PC and R-PC.46 Phycocyanin supplementation
significantly reduces the salicylate-induced tinnitus
in mice.62
Antibacterial Role:
Soni et al., IJPSR, 2015; Vol. 6(11): 4588-4600. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4593
The antibacterial activity of S. maxima extracts
were assayed against five bacterial strains (P.
aeruginosa, B. subtilis, S. aureus, E. coli and
Streptococcus sp.) by evaluation of the inhibition of
zones. Generally, all S. maxima extracts were
found to be effective with antibacterial activity and
were dose dependant. This phenomenon was in
agreement with that found by Ozdemir et al.63 The
data in Table 2 showed that the most susceptible
bacteria were Streptococcus sp. and B. subtilis to S.
maxima with highest inhibition zones ranged 6–13
mm at concentrations 100–400 µl/disk. It is of
interest to note that all S. maxima extracts
manifested similar degrees of susceptible towards
both Gram-positive and Gram-negative bacteria.
The lower inhibition zone ranged from 6 to 9 mm
of extracts obtained for S. maxima.1
TABLE 2: ANTIBACTERIAL ACTIVITY OF
PHYCOCYANIN1
Sr.
No.
Microorganism
Zone of inhibition at various
concentrations of C-PC (mm)
100µl
200µl
300µl
400µl
1
Streptococcus
9
11
12
13
2
Pseudomonas
8
10
11
12
3
Bacillus
8
10
11
13
4
Staphylococcus
6
7
8
9
5
E. coli
7
9
10
11
Sarada et al showed that phycocyanin was able to
markedly inhibit the growth of drug resistant
bacteria Escherichia coli, Klebsiella pneumonia,
Pseudomonas aeruginosa and Staphylococcus
aureus while no activity was recorded
in Acinetobacter baumanii and Enterococcus
durans.64
Phycocyanin as Immune System Modulator:
The regular intakes of phycocyanin boost immune
responses.65-67 When used as an adjuvant to
chemotherapy Phycocyanin boost immune
system to fight cancer spread, improved cancer
response to chemotherapy and decreased risk that
chemotherapy may give rise to a new cancer.
Phycocyanin affects the stem cells in the bone
marrow, which produce white blood cells that make
the immune system and red blood cells that
oxygenate the body. Phycocyanin emulates the
affect of erythropoetin, which regulates red blod
cells production. Phycocyanin suppresses allergic
IgE antibody response and enhances secretary IgA
antibody response in mice. The immune cells
involved in cancer control, NK cells and cytotoxic
T lymphocytes, function more effectively with
intake of Phycocyanin.65, 68
Phycocyanin Mediated Apoptosis
COx-2 play a significant role in promoting tumor
growth in multiple organ systems and is
overexpressed in human lung, breast, colorectal and
prostrate tumors. C-phycocyanin from S. platensis
is a specific COx-2 inhibitor. Phycocyanin
generates free radicals, which induce damage at
macromolecular level, leading to apoptotic cell
death.60 Pardhasaradhi et al demonstrated
Phycocyanin inability to induce apoptosis in Bcl-2
transfectants which correlated well with significant
decrease in production of ROS (reactive oxygen
species) in these cells.60 Z-VAD, a pancaspase
inhibitor, inhibits phycocyanin-mediated apoptosis,
which indicates some role of caspases in apoptotic
death of BC-8 cells (monoclonal cells of rat
histiocytic tumor). Phycocyanin downregulates
Bcl-2 expression in BC-8 cells, thereby make them
vulnerable to apoptotic death. Since many tumors
are resistant to apoptosis due to Bcl-2 expression,
therefore, Phycocyanin treatment leading to Bcl-2
down-regulation, may make them sensitive to other
anticancer agents that kill the tumor cells via
apoptosis. Pardhasaradhi et al showed that
phycocyanin induce apoptosis in tumor cells via
ROS production, which is suppressed by Bcl-2.60
Anti-Cancer Effects:
Shanab et al showed that Spirulina Platensis
showed higher antioxidant activity and moderate
anticancer efficiency among various algal species
due to its total phycobiliprotein pigments, and
secondary metabolites.8 Shalaby et al revealed that
Spirulina platensis shows highest antioxidant
activity under salt stress conditions.69 Wang et al
reported that c-phycocyanin interact with the
membrane associated glyceraldehydes-3-phosphate
dehydrogenase (GADPH) and B-tubulin, causing
polymerization of microtubules and actin filaments
leading to arrest the cell cycle at G0/G1 phase, thus
exhibiting higher antiproliferative activity.70
The anticancer potential of C-PC extracted from
Spirulina platensis is very well known.71
Phycocyanin induces apoptosis in the existing as
well as proliferating cancer cells. Various
mechanisms of its anticancer activity are clear from
Table 3.71
Soni et al., IJPSR, 2015; Vol. 6(11): 4588-4600. E-ISSN: 0975-8232; P-ISSN: 2320-5148
International Journal of Pharmaceutical Sciences and Research 4594
TABLE 3: VARIOUS MECHANISMS OF ANTITUMOR
ACTIVITY OF C-PC ISOLATED FROM SPIRULINA
PLATENSIS 71
Sr.
No.
Mechanism
Study
Year
1
Interference of DNA
synthesis in the tumor cells
Wang et al
2001
2
Activation of caspase-
dependent programmed cell
death pathways (apoptosis)
Pardhasaradhi et
al
Li et al
Roy et al
Li et al
2003
2006
2007
2010
3
Inhibition of tumor cell
growth by membrane
destruction, leading to
increased leakage of cell
constituent
Abd El-Baky
2003
4
Inhibition of tumor cell
growth by stimulation of
expression level of the proto-
oncogene c-myc
Liu et al
2000
5
Improvement of host immune
functions
Hayashi et al
Li et al
2006
2010
Gantar et al demonstrated that in contrast to the C-
PC of Spirulina platensis, the C-PC from the
cyanobacterium Limnothrix species exhibited low
activity.72 Previous studies have reported that
phycocyanin from Spirulina platensis inhibited the
growth of human hepatocellular carcinoma cell line
SMMC-7721, human rectal cancer cell line
HR8348, and human leukemia HL-60, as well as
K562 and U937 cell line. Phycocyanin from
Porphyra haitanensis was also reported to inhibit
the growth of HL-60 cells. Phycocyanin inhibits the
growth of Ehrlich Ascites Carcinoma Cells
(EACC) in a dose dependent manner, by a pathway
other than the apoptosis, by membrane destruction,
which led to increase in the leakage of cell
constituent and increase in GST and LDH enzyme
activities.3 Spirulina maxima and its protein extract
mainly C-phycocyanin provided moderate
genotoxic protection (~30%) against hydroxyurea
and some protection against the hydroxyurea
induced cytotoxicity in mice.73
C-phycocyanin attenuates cisplatin-induced
nephrotoxicity in mice.74 Hence, Phycocyanin have
antitumor activity and may be used as a
chemopreventive agent.3
Effect on Prostate Cancer:
Gantar et al reported that when only 10% of
standard dose of topotecan was combined with C-
PC, the prostate cancer cells (LNCaP) were killed
at a higher rate than when topotecan was used
alone at full dose. C-PC induce apoptosis through
generation of ROS and activation of caspase-9 and
caspase-8.72
Melanogenesis Inhibitor:
C-phycocyanin is a potential melanogenesis
inhibitor. C-phycocyanin inhibits melanin
biosynthesis by dual mechanisms; the promoted
MITF protein degradation via MAPK/ERK
signaling pathway upregulation, and the suppressed
activation of CREB via the p38 MAPK pathway
down-regulation as is clear from Table 4.37, 75
TABLE 4: PATHWAY INVOLVED FOR C-PHYCOCYANIN
AS MELANOGENESIS INHIBITOR37, 75
Negative impact
Positive impact
-C-phycocyanin may also
exert its negative impact on
p38 phosphorylation
-to restrict activation of the
CREB
-resulting in restricted MITF
gene expression
-C-phycocyanin elevates the
cellular abundance of cAMP
-which triggers the activation
of down-stream MAPK/ERK
pathway
-leading to the reduction of
MITF proteins
-activation of ERK1/2
resulted in the
phosphorylation of MITF at
S73
-induced the subsequent
ubiquitin-dependent
proteasomal degradation of
MITF
The structure resemblance of C-phycocyanin
constituents to MAPK pathway modulators (like
SB203580 and bilirubin), account for its
antimelanogenic effect.37 SB203580 [4-(4‟-
fluorophenyl)-2-(4‟- methylsulfinylphenyl)-5-(4‟-
pyridyl) imidazole] acts as a competitive inhibitor
of ATP binding of MAP kinase homologues p38a,
p38b and p38b2, and blocks a-MSH induced
melanogenesis in B16 cells.76 The prosthetic group
of C-phycocyanin, phycocyanobilin might possess
similar pyridinyl imidazole structural features to
that of SB203580, so, sharing comparable
inhibitory mechanisms.37 In constrast, a structurally
related molecule of phycocyanobilin, bilirubin,
have an anticancer activity through the
MAPK/ERK pathway activation.77
C-phycocyanin was found to be at nucleus at the
early stage of entrance and afterwards accumulated
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International Journal of Pharmaceutical Sciences and Research 4595
at the cytoplasm.37 Phycocyaniobilin, could
function as either or both an ERK activator and a
p38 MAP kinase inhibitor to regulate melanin
synthesis.37
Hematological Role:
In chronic leukemias, including chronic myeloid
leukemia (CML), Philadelphia negative
myeloproliferative neoplasms (MPNs), and chronic
lymphocytic leukemia (CLL), evidence of defects
in the regulation of cellular signaling pathways has
been reported. Currently, treatment of a CML
patient is usually based on a potent protein-tyrosine
kinase inhibitor such as imatinib. Imatinib inhibits
the kinase activity of the BCR-ABL oncoprotein,
thus hindering cell proliferation. Although imatinib
is an effective medication, drug resistance is a
problem. Therefore, an alternative medicine is
needed.5 Phycocyanin is an antioxidant protector of
human erythrocytes against peroxyl radicals.78
The anticancer effects of C-PC appear to mediated
by various mechanisms such as an increase in the
proapoptotic Fas rotein, down-regulation of Bcl-2,
and selective inhibition of COX2. The pathway
through which C-PC exerts its activities will enable
its application as a therapeutic agent for MPNs.5
Tantirapan et al found that C-PC at a micromolar
level exhibited a cytotoxic effect on human
erythromyeloid leukemia cell line (K562 cells).5
Subhashini et al demonstrated a decrease to
approximately 65% of the control growth of K562
cells treated with C-PC. Decrease in the cell growth
is a result of apoptosis via downregulation of anti-
apoptotic Bcl-2, release of cytochrome c into the
cytosol, and cleavage of poly(ADP) ribose
polymerase (PARP). C-PC induce apoptosis and
inhibit proliferation of cancer cells by altering
signal transduction related to both apoptosis
enhancement and terminated proliferation in cancer
cells, possibly through the Ras/Raf/Mek/ERK,
JAK/STAT, MAPK and PI3K/AKT pathways in
K652 cells.5
Hepatocellular Carcinoma (HCC):
Roy et al demonstrated a 50% decrease in
proliferation of doxorubicin sensitive (S-HepG2)
and doxorubicin resistant (R-HepG2) HCC cell
lines with phycocyanin. C-PC also enhanced the
sensitivity of R-hepG2 HCC cells to doxorubicin.
They showed downregulation of the anti-apoptotic
protein Bcl-2 and upregulation of the pro-apoptotic
Bax protein in the R-HepG2 cells.79 Nishanth et al
reported a significant down regulation of MDR1
(multidrug resistance-1) expression in C-PC treated
HepG2 cells through cyclooxygenase-2 (COX-2)
and reactive oxygen species mediated pathways. In
a concentration dependent manner, C-PC increased
the doxorubicin accumulation in HepG2 cells and
enhanced cells sensitivity to doxorubicin by 5
folds. Further studies reveal the involvement of
AP-1 and NF-κB in the C-PC induced down
regulation of MDR1. The inactivation of the signal
transduction pathways involving ERK, Akt, p38
and JNK by C-PC was also observed.80
Ou et al produced hepatoprotective activity of C-
phycocyanin against carbon tetrachloride-induced
hepatocyte damage in vivo and in vitro.
Mechanisms involved through C-PC‟s scavenging
ability and ability to block inflammatory infiltrate
through its anti-inflammatory activities by
inhibiting HGF and TGF-β1 expression.81
Phycocyanin being COX-2 inhibitor, significantly
inhibits liver microsomal lipid peroxidation hence
protecting the liver by preventing oxidative stress
in hepatocytes.82 Phycocyanin inhibits microsomal
lipid peroxidation induced by Fe+2 – ascorbic acid
or the free radical initiator 2, 2‟ azobis (2-
amidinopropane) hydrochloride (AAPH).83 C-PC
extracted from Porphyra yezoensis could develop
to new photosensitizers for cancer photodynamic
therapy.84
Colon Carcinoma:
Lu et al reported that the recombinant α-subunit of
C-phycocyanin (CpcA) inhibited the growth of
human colon carcinoma COLO 205 cells. The
apoptotic process was associated with the Bax/Bcl-
2 ratio up-regulation, mitochondrial membrane
depolarization, cytochrome c release, and caspase-9
activation. It was proven that CpcA induced the
death of COLO 205 cells through intrinsic
apoptotic pathway.85
Breast Cancer:
Phycocyanin is an ideal photosensitizer which
accumulates in breast cancer tissue and attracts He-
Ne laser to target at tumor tissues. Being natural
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International Journal of Pharmaceutical Sciences and Research 4596
and non-toxic, phycocyanin is a good substitute to
highly toxic photosensitizers or chemotherapeutic
drugs. It also causes inhibition of MCF-7 cell
proliferation and morphological changes like
chromatin condensation, blebs formation and loss
of microvilli. C-PC-mediated photodynamic
therapy activates immune system, induce pro-
apoptotic Fas genes activation, cause apoptotis of
cancer cells and down-regulates anti-apoptotic
protein expression such as P53, Bcl-2, NF-kB and
CD44 mRNA. Hence, Phycocyanin could be the
new potential anticancer drug for therapy of
Human Breast Cancer.86
Cervix Cancer:
Treatment of Human cervical cancer cell line
(HeLa) cells with Phycocyanin increases
hypodiploid cells population and DNA
fragmentation. Phycocyanin reduces antiapoptotic
proteins Bcl-2 level and promote death receptor
genes expression like Fas/FasL and ICAM.
Caspases play a central role in all apoptotic
pathways and a higher level of caspases are seen in
phycocyanin treated cells. Hence, Phycocyanin
might be the new potential anticancer agent for
Cervical Cancer therapy.87
Phycocyanin and Laser Therapy:
In this photochemical method, Phycocyanin is
injected into a patient suffering from
atherosclerosis or cancer. After being injected,
phycocyanin is taken up selectively into the
atherosclerotic plaques or the cancer cells.
Destruction of the atherosclerotic plaques or the
cancer cells occurs on subsequent irradiation.
Phycocyanin has several advantages over prior art
chemicals used for similar purposes. First, it is only
marginally sensitive to ultraviolet part of the
spectrum; consequently the patients can be
irradiated without taking concern that they will be
sensitized to subsequent sunlight exposure. Second,
phycocyanin is taken up selectively into the
atherosclerotic plaques, with little or no uptake by
the surrounding normal cells. This ensures that
upon subsequent irradiation, atherosclerotic
plaques are selectively destroyed with little or no
damage to surrounding cells or tissue.88
Effect on Pancreas:
Li et al demonstrated that cleavage of poly (ADP-
ribose) polymerase (PARP) and activation of
caspase-3 was blocked by Phycocyanin in hIAPP-
treated cells. Also, PC significantly prevented the
hIAPP-induced overproduction of malondialdehyde
(MDA) and intracellular ROS, as well as changes
in activities of glutathione peroxidase (GSH-Px)
and superoxide dismutase (SOD) enzymes.
Furthermore, hIAPP triggered mitogen-activated
protein kinases (MAPKs) activation, but these
effects were effectively suppressed by PC.89,90 So,
the study reported that PC protects INS-1E
pancreatic beta cells of rat insulinoma against
hIAPP-induced apoptotic cell death through
attenuating oxidative stress and modulating c-Jun
N-terminal kinase (JNK) and p38 pathways.89 This
is not proved in humans till now. PC may have a
potential to treat type-2 diabetes mellitus as it
enhances insulin sensitivity, regulates glucolipide
metabolism and ameliorates insulin resistance of
peripheral target tissues.91
Ischemia Reperfusion Injury:
C-phycocyanin could be used for treating ischemia-
reperfusion injury through the activation of ERK
pathway and suppression of p38 MAPK pathway.38
Phycocyanin may be used to treat ischemic stroke
as phycocyanobilin has an effective influence on
major inflammatory mediators of acute cerebral
hypoperfusion.92
Cardiovascular Disease (CVD) and Non-
Alcoholic Fatty Liver Disease (NAFLD):
Chronic diseases, such as CVD and NAFLD, are
highly related to impaired lipid metabolism,
oxidative stress, and inflammation. Phycocyanin
provides multiple health-promoting properties:
inhibition of inflammation via decreased nuclear
factor kappa B (NF-kB) activity; lowering plasma
lipid concentrations by decreasing intestinal
cholesterol absorption and hepatic lipogenesis; and
prevention of oxidative stress by blocking lipid
peroxidation and increasing free radical
scavenging.46,93 In conclusion, Phycocyanin can be
consumed as a dietary supplement or a food
component to obtain health benefits against CVD
and NAFLD.46
Neuroprotective Effects:
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International Journal of Pharmaceutical Sciences and Research 4597
The anti-inflammatory, antioxidant and immune-
modulatory properties contribute to the
neuroprotective effects of Phycocyanin. Either the
therapeutic or prophylactic application of
Phycocyanin is able to significantly reduce the
infarct volume, and also protect hippocampal
neurons from death, induced by cerebral ischemia
or reperfusion injury. Phyocyanin is platelet
aggregation inhibitor with a potential to hamper
arterial thromboembolism.94
Nephroprotective Effects:
Phycocyanin protects the renal cell integrity by
stabilizing lipid peroxidation and protecting against
oxalate induced nephro injury. Lipid peroxidation
produce aldehydes like malondialdehyde (MDA)
that are extremely active and can diffuse within or
even escape from the cell and attack targets far
from the site of the original free radical initiated
event, resulting in cell damage and therefore act as
„cytotoxic second messengers'. Phycocyanin pre-
treatment decreased the lipid peroxidation and
reversed the effects of oxalate on oxidative stress
parameters by interacting with hydroxyl radical and
by rebalancing the GSH content, catalase and
G6PD activity in oxalate treated animals.95
Acute Lung Injury:
Acute lung injury (ALI) is characterized by damage
to the epithelial and endothelial cells in lungs,
mediated by several pro-inflammatory mediators
and finally impairs respiratory function.
Phycocyanin exhibits its anti-inflammatory activity
by inhibiting inducible nitric oxide synthase
(iNOS) expression and NO production possibly by
suppressing nuclear transcription factor-kB (NF-
kB) activation, a key transcription factor promoting
proinflammatory gene expression. Leung et al
reported that posttreatment of ALI model with C-
PC significantly reduces the tissue permeability,
and protein concentration in bronchoalveolar
lavage fluid (BALF) and improves pulmonary
histological alterations.96
Wound Healing:
Phycocyanin directly enhances wound repair by its
anti-oxidant property and scavenging destructive
free radicals mechanism. Secondly, stimulation of
keratinocyte is one mechanism by which
phycocyanin might enhance wound repair
process.97
Side Effects: Phycocyanin is usually non-toxic, but
may cause liver damage, stomach pain, nausea,
vomiting, weakness, thirst, rapid heartbeat, shock,
and death. Phycocyanin may cause systemic
anaphylaxis, urticaria, labial edema, asthma,
diarrhea and diffuse erythema.98
CONCLUSION: Phycocyanin is a natural product
from cyanobacteria and is a rich source of
antioxidants. In view of current practice,
antioxidant properties of phycocyanin have been
investigated for their anti-inflammatory, anti-
proliferative and anti-cancer effects. The results
revealed for the first time that the C-phycocyanin
activities and its antitumor actions such as in
leukemia, colon cancer, pancreatic cancer etc.
could be a promising natural antitumor agent with a
potential for future pharmacological and medical
applications. In the future, these marine algae-
derived materials or compounds will be used more
often in pre-clinical studies for drug discovery. In
our review article, like other anti-cancer agents,
phycocyanin being a natural product, should be
more acceptable as an anticancer compound.
ACKNOWLEDGEMENTS: The authors are
thankful to Pubmed, BioMed Central and Google
database for providing the detailed parameters of
the articles.
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How to cite this article:
Soni A, Dubey M, Verma M, Dhankhar R, Kaushal V, Atri R and Sabharwal R: Revisiting the Role of Phycocyanin in Current Clinical
Practice. Int J Pharm Sci Res 2015; 6(11): 4588-00.doi: 10.13040/IJPSR.0975-8232.6(11).4588-00.
