Review: UV protection and anticancer properties of lichen secondary metabolites

Abstract

Citation: Murugan M, Muthu S, Rajendran K, Ponnusamy P (2021) Review: UV protection and anticancer properties of lichen secondary metabolites. Sci Academique 2(2): 1-29. Abstract The organism consisting of algae and fungi together in one single thallus is called lichens, yet they are also the subject of study by the lichenologists because either the purified secondary metabolites or the crude extract of lichen have a wide variety of biological activities such as anticancer, antibiotic, anti-inflammatory, antioxidant, anti-fungal, anti-HIV, etc., The following review article focused primarily on scientific proof for the documented evidence of medicinal value of lichen compounds. The present article also made the review on the secondary metabolites of lichens from traditional drug research, ultraviolet radiation protection and anti-cancer treatment, and summarized the biological activities of the main functional compounds such as atranorin, calycin, pannarin, parietin and usnic acids, etc. Finally, it is concluded that these compounds have powerful sunscreen and anticytotoxic effects both in vivo and in vitro.

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Science Academique
Murugan M, et al.
Pages: 1-29
Volume 2; Issue: 02
Article ID: SA2115
Review Article
Review: UV protection and anticancer properties of lichen secondary
metabolites
Mariraj Murugan1*, Shenbagam Muthu1, Kalidoss Rajendran2, Ponmurugan Ponnusamy1
1Biomedical Research Lab, Department of Botany, Bharathiar University, Coimbatore, India
2Assistant professor, Department of Biotechnology, Sri Kaliswari College, Sivakasi, Tamil Nadu, India
*Correspondence to: Mariraj Murugan; msmariraj777@gmail.com
Citation: Murugan M, Muthu S, Rajendran K, Ponnusamy P (2021) Review: UV protection and anticancer
properties of lichen secondary metabolites. Sci Academique 2(2): 1-29.
Received: 04 May, 2021; Accepted: 26 May 2021; Publication: 31 May 2021
Abstract
The organism consisting of algae and fungi together in one single thallus is called lichens, yet they are also the
subject of study by the lichenologists because either the purified secondary metabolites or the crude extract of lichen
have a wide variety of biological activities such as anticancer, antibiotic, anti-inflammatory, antioxidant, anti-fungal,
anti-HIV, etc., The following review article focused primarily on scientific proof for the documented evidence of
medicinal value of lichen compounds. The present article also made the review on the secondary metabolites of
lichens from traditional drug research, ultraviolet radiation protection and anti-cancer treatment, and summarized the
biological activities of the main functional compounds such as atranorin, calycin, pannarin, parietin and usnic acids,
etc. Finally, it is concluded that these compounds have powerful sunscreen and anticytotoxic effects both in vivo and
in vitro.
Keywords: Sunscreen compound; Lichen secondary metabolites; anticancer
Introduction
Lichens comprises a group of organisms which are
fungus (mycobiont) in one hand and photosynthetic
eukaryotic algae (photobiont) or cyanobacteria on the
other [1] and sometimes actinobacteria [2]. By their
water retention property, fungi nurture algae with
water but their photosynthetic nature, the algae
cherish fungi with food. The association is referred to
as symbiosis. The fungi which occupy 90 per cent of
total lichen thallus while the algal (cyanobacteria or
blue green algae) layer occupies only 10 percent.
About 20,000 lichen species are found to be reported
all over the World. Nearly 8 percent of the land
surface of earth are covered with lichens. The most
distinguishing characteristic of this Lichen is its slow
growth rate of a few species which is indicated by the
growth of just 1 cm in 10 years. Therefore, the lichen
has to play a role in selecting variety of a growth forms
capable of thriving under extreme conditions such as
UV radiation, high temperature, excess salt, drought
environment. The nutraceutical value of lichens is also
known from the previous literature [1]. Most lichen
forms can produce chemical substances. These
substances can exert their biological activities,
regulation of the synergism between symbionts and
environmental interactions [3]. The chemical
substances are generally divided into primary and

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Murugan M, et al.
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Article ID: SA2115
secondary metabolites. Presence of primary
metabolites from both the symbionts necessarily
means that they are essential for structural functions
and cellular metabolism. Secondary metabolites are
generally fungal derived [4–7] and therefore stored in
different parts of lichen like upper cortex, lower
cortex, medulla, sexual and asexual fruiting bodies.
But, photobiont and mycobiont metabolites
interaction are needed to produce secondary
substances. Lichen secondary metabolite production
cannot be identified in a naturally occurring non
symbiotic state [8]. This has aroused further interest
in the study of the bioactive compounds of lichen
associated bacteria, especially Actinobacteria and
Cyanobacteria [9].
Sun which emits ultraviolet radiations which are the
type of electromagnetic non ionizing radiation. Both
UV B and UV A are the most damaging to living
things has been reported by the National Toxicology
program on Carcinogens. As many as 90% of total
skin cancer cases showed UV exposure due to solar
radiation [10]. Skin cancer causes uncontrolled
growth of skin cells. UV A and UV B radiations
considerably affect UV exposed skin cells as well as
induce genetic defects or mutation. It triggers
biochemical changes that lead the skin cells to form
malignant tumors. There are many skin cancers types.
These are Basal cell carcinoma (BCC), Squamous cell
carcinoma (SCC), and Melanoma. BCC and SCC are
not serious type cancer treatable but melanoma cancer
is a serious type of cancer treatment is crucial. There
were 1,80,78,957 persons affected by skin cancer as
of 2018 records and it causes considerable death
which raises to about 95,55,027 patients [11].
Nowadays, most are vulnerable to skin cancer
throughout the world. The ignorance of skin cancer is
a serious problem and it has been identified from
several cases that the affected are in great danger.
Thus, documentation of skin cancer is in need. The
case studies of death reports caused by Basal cell
carcinoma (BCC), Squamous cell carcinoma (SCC),
are very rare and It is estimated that almost 30% of
affected deaths are caused by aggressive Melanoma
type of skin cancer [12,13]. Lichens produce more
than 1000 secondary metabolites. There are very
useful biological activities such as anticancer,
antibiotic, anti-inflammatory, antioxidant, anti-
fungal, anti-HIV, etc., used for preventive measures in
medicine are known to be attributed to lichen
compounds [2, 14,15].
Besides many other applications, UV proof
metabolites such as Depsidone derivatives, Depside
derivatives, Xanthone derivatives, Orsellinic acid
derivatives, Pulvinic acid derivatives, Anthraquinone
derivatives, sctonemin, Mycosporine amino acids are
of great importance [3] to pharmaceutics in Medicinal
Industry [16]. This review article focused on the role
of lichen compound in UV protection and its
anticancer properties.
Lichens used in Traditional Medicine
The knowledge on importance of lichen compounds in
traditional medicines is known for several centuries as
it cures different ailments is presented in Table 1.
[17,18]. However, initial contributions to medicinal
uses of lichens were made during 1700-1800 BC from
Evernia furfuracea (L.) mann. [18,19]. It has been
evident from literature that these lichens display wide
applications in Siddha, Ayurvedic and Unani systems
for common ailments and cure many diseases like
heart disease, wound, asthma, leprosy, bronchitis,
stomach disorders, skin disease, etc., [20].
S. N
Lichen Name
Disease
Country
Reference
1
Usnea ceratina Ach.
Coughs, inflamed lungs, tuberculosis, headache,
injury, snakebites
China
[115]
2
Usnea sikkimensis
Biswas sp. nov.
Asthma, wound, hair strengthen, lung troubles, treat
blisters
India
[116]

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3
Cladonia gracilis (L.)
Willd.
Dizziness, painful urination, nose bleeding,
impetigo, pink eye, drink decoction
China
[115]
4
Pertusaria pertusa
(weigel) Tuck.
Fever, kill worms, toothache
Europe
[117]
5
Parmelia nepalense
(Talyor) Hale
Toothache, sore throat,
Nepal
[118]
6
Thamnolia vermicularis
(Schwartz) Ach.
antiseptic
India
[119]
7
Cetraria islandica (L.)
Ach.
Tuberculosis, chronic bronchitis, diarrhea,
inflammation, ulcer, feed for deer and pigs
Iceland
[120]
8
Xanthoparmelia
conspersa (Ehrh. ex
Ach.) Hale
Syphilis eruptions, known and suspected snakebites,
scarify bite
South Africa
[121]
9
Parmotrema zollingeri
(Hepp) Hale
Used as medicine for children high fever and let the
child smell the fumes
Philippines
[122]
10
Punctelia borreri (Sm.)
Krog
Used for blurred vision, bleeding from uterus,
bleeding from external injuries and swelling and
chronic dermatitis. Drink decoction or apply
powdered lichen to affected area
China
[115]
11
Evernia divaricata (L.)
Ach.
Used for coughs, pneumonia, hepatitis, headaches,
infection due to trauma, inflammation of the breasts,
and snake bites.
China
[115]
12
Ramalina capitata
(Ach.) Nyl.
Drunk as tea to relieve symptoms of asthma
Spain
[123]
13
Lobaria pulmonaria
(L.) Hoffm.
It was mainly used in lung ailments (e.g
tuberculosis, asthma, coughs, spitting blood)
stimulant diarrhea, and stop bleeding. It was usually
boiled water or milk and drunk or made ointment
for external use.
England,
Germany, Sweden
[124,125]
14
Pseudocyphellaria
aurata (Ach.) Vain.
Used as tea to treat indigestion
Madagascar
[126]
15
Peltigera aphthosa (L.)
Wild.
Used to improve digestion
China
[115]
16
Cladonia subtenuis
(Abbayes) Mattick
Lichen used to relieve the pain of insect stings.
USA
[127]
17
Bryoria fremontii
(Tuck.) Brodo & D.
Hawksw.
Boiled and used as poultice for arthritis, Good for
upset stomach, indigestion, and diarrhea
USA
[128]
18
Usnea longissima Ach.
Used to treating cancer, tuberculosis and ulcers,
treating heal bone fractures. Washed, air-dried,
soaked overnight in salted water, and placed over
affected part
Turkey, China,
Indo-Tibetan
Himalayas
[129–131]
19
Letharia vulpina (L.)
Hue
Used for Wolf poison. Pulverized, mixed with fat
and flesh, wolf will die within 24 h of ingestion.
Sweden
[125]

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20
Heterodermia
diademate (Taylor) D.
D Awasthi
Used for cuts and injuries
India
[132]
21
Lobaria spp. (Schreber)
Hoffm.
Pulverized and made into a paste to cure skin
diseases, Whole lichen used to treat indigestion.
Bhutan, Tibet
[133]
22
Peltigera membranacea
(Ach.) Nyl.
Used as antiseptic and to stop bleeding. thalli made
into paste and put on cuts
Sikkim, India
[134]
23
Lasallia papulosa
(Ach.) Llano
Lichen used for urinary problems
Canada
[135]
Table 1: Medicinal applications of Lichens.
Role of Lichen compounds in medicine and drug
discovery
Recent advancement in the medical field has endowed
a limited number of lichen compounds with amazing
biological activities both in vitro and in vivo (Table 2).
Usnic acid has a potential antimicrobial activity
against Streptococcus mutants bacteria [21,22].
[23,24] The widely occurring lichen compounds such
as diffractaic acid, norstictic acid, hypostictic acid,
protocetraric, Barbatic acid were identified to inhibit
the bacterial growth. In literature, most of the lichen
compounds have been compiled which gives fair
information regarding the anti-viral [25],
antimicrobial property against both Gram positive and
Gram negative bacteria [16]. Critical investigation on
anti-prolifetative and cytotoxic activity of following
lichen compounds parietin, atranorin, gyrophoric acid,
usnic acid were carried out against HaCat, K-562,
HEC-50, L1210, HeLa, A 2780, SK-BR-3, HCT-116,
p53, HT-29, MCF-7 and proved its biological
activities [26–29]. Several studies have confirmed
antioxidant and pro-oxidant properties of lichen
compounds which prevent oxidative damage [30–33].
It was noteworthy to identify that lichen compounds
displayed antiviral activity against HIV [34,35],
Papilloma virus, polyomavirus, influenza virus A
(H1N1), polio virus, [25,36,37] protozoans [38,39].
The growth rate of cancer cells found arrested at s-
phase or sub-G1 might probably be the reason for the
cancer regulation control in lichen compound [40,41],
Various lichen compounds such as usnic acid,
atranorin, n-Butyl orsellinate, Lecanoric acid, 16-O-
acetyl -leucotylic acid, diffractaic acid, divaricatic
acid, retigeric acid, olivetoric acid, pannarin,
gyrophoric acid , parietin are effective against
following cancer cell lines such as A431, HCT-116,
HL-60, HeLa, HaCaT, DU-145, HT-29, MCF-7,
LNCaP, MM98, DU 145, T-47D, PC-3, H1299, K-
563, A549, M14, and RCB-0461 [29,40–50].
Similarly, dichloromethane solvent fraction of
following lichen acids from Heterodermia indica,
Heterodermia microphylla, Heterodermia leucomela,
Heterodermia podocarpa, Heterodermia diademata,
Heterodermia punctifera and Heterodermia speciosa
showed 80% mortality of cell lines in brine shrimp
assay [51]. [52] showed ethyl acetate extract
Heterodermia species had strong DPPH and TEAC
(Trolox equivalents activity capacity) scavenging
activity. Compounds like atranorin and Lobaric acid
compounds extracted from Heterodermia obscurata
were screened for analyzing immunomodulatory
activity on respiratory burst of WBCs, isolated human
PMN leukocytes and macrophages from murine using
lucigenin-based chemiluminescence of luminol
probes [53]. (Protocetraric acid exhibited cytotoxic
effects against human melanoma and human colon
carcinoma with an IC50 value of 58.68 µg/ml and
60.18 µg/ml respectively [54]. Protolichesterinic acid
showed antitrypanosomal activity against
Trypanosoma brucei with a MIC value of 12.5 µM.
The molecular docking studies displayed its
hydrophobicity property favors its free infiltration into
pathogen cells [55]. Cytotoxicity analysis of
protolichesterinic acid exhibited effective activity at
the concentrations as high as 5 µM against human

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keratinocyte cell line [28]. Protolichesternic acid
induces Cell apoptosis by inhibiting Hsp 70 protein
expression and a redox-sensitive mechanism was
indicated in LNCaP and DU-145 prostate cancer cell
lines [56].
Patent No
Lichen metabolites and application
Reference
US4424373A
Preparation of secalonic acids used for innovative
antibacterial agents
[136]
DE3229086A1
Cetraria islandica use in veterinary medicine for horses
[137]
US4556651A
Secalonic acid derivatives as antitumor agents
[138]
US4536474A
Tissue culture of lichens
[139]
US5169783A
Increasing nucleation activity with lichens and fungi
[140]
US5260053A
A Herbal deodorant composition for a key bactericide
[141]
EP0560227A2
Acetone extract of Nephromopsis ornata showing antiviral
properties on Epstein-Barr virus
[142]
US5447721A
Superoxide elimination activity of acetone extracts of
Nephromopsis ornate and Vulpicida canadensis for
cosmetic application
[143]
FR2756182B1
Crude extract of Cetraria islandica used to prevent and
treat asthma
[144]
WO1999020793A1
Usnic acid and Vulpinic acid used to inhibit eukaryotic
protein kinase for tentative and therapeutic uses.
[145]
US6811835B1
Lichen on rock camouflage pattern
[146]
US20030068294A1
Extract for Cetraria islandica used for veterinary medicine
(ex. ear hygiene)
[147]
KR100453679B1
A hair color composition containing Tuckermannopsis
ciliaris as a auxiliary component
[148]
CN1500520A
Ethanol extract of lichen Parmelia tinctorum containing
atranorin, salazinic acid and norstictic acid produced for
antibiotics
[149]
US20040198815A1
Antimicrobial and Anticancer properties of Methyl-Beta-
Orcinolcarboxylate from Lichen (Everniastrum cirrhatum)
[150]
WO2006125857A1
A polymer mixture established from lichen polysaccharides
and other polymers for capsule coatings
[151]
WO2008077997A1
Cetraria islandica lichen based wood protection and
impregnation product
[152]
RU2358750 C2
Pharmaceutical compositions based on barbate lichen
(Usnea barbata) and common st john’s wort (Hypericum
perforatum) and application thereop
[153]
US20120329868A1
A mixture of lichesterinic acid and protolichesterinic acid
or their derivative compound used for stimulating
pigmentation of skin and appendages
[154]
WO2012085559A1
Antibacterial and anti-acne skin care formulations contain
usnic acid or usnate
[155]

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JP2013253060A
A process to produce a lichen extract for skin whitening
agent
[156]
US20150105459A1
Lichesterinic acid and derivative compound to inhibit the
skin pigments
[157]
US9139694B1
High temperature materials with low moisture uptake made
from lichen metabolites
[158]
US9328202B1
High temperature materials with low moisture uptake made
from lichen metabolites
[159]
US9539227B2
Pharmaceutical composition for the prevention or treatment
of inflammatory diseases or immune diseases containing
ramalin
[160]
US20190072494
A1
PH color indicator for use with agricultural compounds
[161]
Table 2: List of Patents in Lichen metabolites and its applications.
UV Radiation
The sun emits electromagnetic UV radiation. This
radiation has different frequency and wavelength
(Figure 1). They are shorter than visible light and
longer than x rays. UV radiation is classified into three
types. When the wavelength is between 100-280 nm
these radiations are called shortwaves represented as
UV C. When the wavelength is from 280 – 315 nm
they are called a medium wave denoted as UV B
which is partially absorbed by the ozone layer. When
the radiation range is beyond 315 but less than 400 nm
they are called longwave, regarded as UVA which
reaches earth directly as ozone does not absorb UVA
[57]. The radiation UV C is widespread in the ozone
layer as the latter traps UVC from sunlight and hence
it does not reach earth. Shortwave UV radiation
damages the DNA.
Figure 1: Different wavelengths of Ultraviolet radiation.

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Sunburn is formed by the intense impact of UV A on
skin surface and to cause skin cancer suntan. Some
regions are normally devoid of ozone and therefore,
the C radiation can be greatly found reaching through
the ozone hole. Human retina, eye lens and cornea and
were unable to see UV rays but rarely some children
and young adults could see the UV rays [58,59]. UV
radiations were visible to some mammals, insects and
birds [60]. Over exposure of Ultraviolet radiation can
cause not only sunburn, but other harmful effects such
as skin cancer and eye damage [61].
UV A induces DNA damage and melanoma. Mutation
alone accounts for 92% of the total UV exposed cells
and melanoma cancer represents the effect of mutation
[62]. The short wavelength range of UV C radiation
causes contrary effects of mutation and carcinogenic
damages [63].
Features of UV Radiation protecting chemicals
Aromatic and heteroaromatic rings are chief electron
acceptor or donor regions in lichen compound and
possessing UV absorbing capacity [64]. Among
various UV absorbing compounds, lichen metabolite
is represented by aromatic and heteroaromatic
compounds such as benzene derivatives, biphenyl
derivatives, indole derivatives, imidazole derivatives,
purine derivatives, and naphthalene derivatives. Apart
from these general views, unsaturated bonds (π) are
significant and have been the specific receptor site in
most UV absorption. Further, other compounds have
heteroatoms like halogens, oxygen, sulfur or nitrogen
and with unpaired electrons will excite to σ*, π*
transitions presence of heteroatom with a double bond
affect absorption maximum [64]. UV B and UV A
radiations are potential agents to irradiate molecules.
Poly unsaturated hydrocarbons like β-carotene
absorbs UV-visible light absorption maximum at 452
nm and high intensity (ε=15.2 104 L mol-1cm-1) [64].
Nguyen et al (2013) reported lichens have UV
protectant metabolites such as depsidone derivatives,
depside derivatives, xanthone derivatives, orsellinic
derivatives, anthraquinone derivatives, scytonemin,
pulvinic acid derivatives and mycosporine amino acid
(Table 3). Lichen cyanobacteria produces non-
aromatic compounds like Mycosporines and
Mycoporine amino acids responsible for UV
protection and play a vital photo-antioxidant role
[65,66]. Some studies reported that high amount of
phenolic compounds distributed mainly in the upper
parts exposed under direct sunlight which effectively
absorb UV B radiation [57,67]. Moreover,
depsidones, depsides, dibenzofuranes, diphenyl ethers
and chromones are representative agents to control
UV B radiation while xanthones, pulvinic acid
derivatives control the UV A radiation, absorb energy
10,000 L mol-1cm-1. The depside derivatives such as
atranorin, barbatic acid [68] divaricatic acid,
diffractaic acid, evernic acid, gyrophoric acid,
isosphaeric acid and sphaephorin are reported to
screen UV radiations [69,70].
The depsidones derivatives like pannarin,
chloropannarin, salazinic acid, fumarprotocetraric
acid, lobaric acid, variolaric acid, vicanicin, diploicin,
scensidin, dechlorodiploicin, methyldiploicin are
lichen compounds display UV B and UV A radiation
absorbing properties [71–73]. Diploicin absorbs
wavelengths of λ max= 320nm, dechlorodiploicin (λ
max=315nm), and 4-O-methyldiploicin (λ max=
324nm) Millot reported [73].
Dechlorodiploicin has cyto-toxic effect on HaCaT cell
lines [74]. Dibenzofurans derivatives, chromones, and
xanthone compounds such as usnic acid, lepraric acid,
placodiolic acid, epiphorellic acid, buellin and
lichexanthone are reported to have the UV proof
features. Usnic acid is the most common therapeutic
lichen compound known to filter UV B radiation (λ
max= 287nm) and ε=18 600 L mol-1 cm-1 [70]. There
are few chromones isolated from lichens known to
filter radiations.
Lepraric acid is one of the chromones, occurs in
cortical and medullary layers of Roccella fuciformis
[75]. The anthraquinone compounds influence UV B
and blue light absorbing features in lichen species and.
Similarly, anthraquinone and perylenequinone
derivatives such as parietin [76], russulone,

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haematommone, isohypocrellin and elsinochrome
respond to filter UV radiation [77]. Pulvinic acid
derivatives display absorption of UV B and UV A are
calycin, rhizocarpic acid, and vupinic acid [70,78].
The pulvinic acid derivative has to play a vital role in
moderate UV protection but stable photo-protection
[79]. These compounds are relatively lacking in
energy transfer and therefore preventing DNA
damage [71].
Mycosporines and Mycosporine amino acid (MAA)
are polar, low molecular and water soluble
compounds found in many marine lichens. The lichen
symbiotic partner cyanobacteria synthesize
mycosporines and MAA derivative such as
mycosporine-glycine, mycosporine-taurine,
mycosporine serinol, mycosporine
hydroxyglutamicol, shinorine, mycosporine-2-
glycine and euhalothece. These secondary compounds
have high photostability and the ability to prevent the
DNA damage caused by UV A and UV B radiation.
However, a major limitation is its availability of low
concentration of these compounds in marine
organisms so isolation is difficult [80–82].
Scytonemin is a shikimic acid derivative synthesized
in outer thallus of cyanobacterial lichens of some
genera exposed under direct sunlight are
Gonohymenia, Peltula and Collema species [83].
Scytonemin related compound dimethoxyscytonemin
produced by cyanobacteria under uv exposed
condition synthesize tetramethoxyscytonemin by the
scytonemin reduction mechanism. These compounds
have the ability to absorb in UV A, UV B and UV C
radiation [84,85]. The carotenoid pigments of lichens
have also displayed UV screening and photoprotective
features [64,86]. The melanin, widely present in all
species of fungi to humans, is a complex group of
biological origin pigment to have UV protecting
ability [87]. Accordingly, strong UV B absorbing
melanin pigment has been harvested from lichen
thallus of Cetraria islandica [88].
UV protectant mechanism
As a result of exposure of UVA (320-400 nm)
radiation, skin cells produce ROS (reactive oxygen
species) and reactive nitrogen species (RNS). The sun
screen compounds are concerned with the interaction
of antioxidants. These antioxidants are naturally
found in lichen compounds. In fact, application of
sunscreen paste having antioxidant substances which
solves the misery associated with skin cancer as it
protects the skin from formation of free radicals.
Eventually, it protects skin from the toxic effects of
ROS and RNS [89].
UV index
The Global Solar UV index is a reference action
spectrum formulated for UV induced erythema on
human skin defined by the International commission.
It quantifies the amount of UV radiation which is
relevant to induce effect for the horizontal surface. UV
index is a unit less calculation represented by the
formula [90].
     

 󰇛󰇜
Eλ is solar spectral irradiance expressed in W∙/(m-
2∙nm1) at wavelength λ and dλ is the wavelength
interval used in the summation. Serλ is an erythema
reference action spectrum and Ker are the constant
equal to 40 m2/w.
The UV Index can be determined through
measurements or model calculations. Two
measurement approaches can be considered: the first
is using a spectro-radiometer to calculate the UV
index using the above formula.
The second uses a broadband detector which
calibrates to give the UV index directly. Prediction of
the solar model that requires the input of the aerosol
optical properties and total ozone. The total ozone is
predicted using a regression model which calculates
the input from ground-based ozone Spectro-

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radiometers or from satellites (Figure 2). A good cloud
parameterization is also required unless only clear sky
values will be reported [90].
Figure 2: Global solar index Map [90].
Anticancer properties in lichens
Cancer is the deadliest and common disease leading to
death around the world. Due to its medicinal
significance, it has become a trend that many countries
are on the lookout for agents from bacteria, marine
microorganisms, fungi, plants, etc., and focusing on
extraction of novel anticancer drugs.
Lichens belong to the plant kingdom. The application
of lichen secondary metabolites as anti-tumour drugs
dates back to the 1960s when the activity of lichen
sugars against cancer cells was initially discovered
[91]. An extensive research of many lichen
compounds extracted on many different malignant
cell lines showed a strong effect of cytotoxicity (Table
4) [28,92,93]. Structural slight modification of lichen
compounds is found to increase cytotoxic potency of
many lichen metabolites [43,50]. Various lichen
compounds have been found to inhibit the growth of
cancer cells at the S or sub -G phase of the cell cycle
[26,40,41]. The mechanism of cytotoxicity in cancer
cell lines is caused by lichen metabolite induced
apoptosis [26,92]. It has been evident from previous
investigations reported that increase in the level of the
Bax protein was associated with reduce in the Bcl-2
protein (Bax/Bcl-1:2 ratio) can induce the release of
mitochondrial protein cytochrome c into the
cytoplasm, as a result in the induction of caspase-3
which acts as an inducer of apoptosis [94,95]. Liches
primary and secondary metabolites such as β-glucan
and galactomannan have shown strong anticancer
agents [96]. Recently cancer research studies
indicated the use of lichen polysaccharides as
immune-stimulants and they play a vital role against
cancer cell lines [97,98]. Usnic acid evaluation of
anticancer potency and associated with molecular
alterations against human lung carcinoma A549 cell
lines study reported that it inhibits cell growth and
involving G0/G1 phase cell cycle arrest and induces
cell death via mitochondrial membrane depolarization
and induction of apoptosis in human lung carcinoma
cell lines [99]. [48] Reported that usnic acid has anti-
proliferative activity against the wild type TP53
nonfunctional breast cancer cell lines, and lung cancer
cell line H1299 and is null for TP53. Lichen

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Murugan M, et al.
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Article ID: SA2115
compound usnic acid as non-genotoxic anticancer
agent studies in TP53 independently support to
suppress tumor cells [48]. The cytotoxic mechanism
of action of parietin, atranorin, gyrophoric acid and
usnic acid was showed against A2780 and HT-29
cancer cells [100]. [101] Reported that usnic acid
effectively inhibited in vivo angiogenesis in chicken
embryos. Mouse tumor model usnic acid suppressed
Bcap-37 breast tumor growth and angiogenesis. [26]
evaluated sensitivity of various cancer cell line
A2780,HeLa, SK-BR-3, HT-29, HCT-116, HCT-116,
MCF-7, HL-60 for the anti-proliferative and cytotoxic
effects of four lichen secondary compounds atranorin,
parietin, gyrophoric acid and usnic acid. [43] Reported
that usnic acid induced apoptosis on L1210 cell lines.
Cetraria islandica lichen species produced a
antiproliferative protolichesterinic acid against
fourteen cancer cell lines and most of them showed
IC50<10 µg/ml [102,103]. Pannarin and shpaerophorin
are also reported to inhibit cell growth and induce
apoptosis in human prostate carcinoma DU-145 and
human melanoma M14 cell line [49,104]. Recently
antiproliferative assays were carried out on A431
vulvar carcinoma, MM98 malignant mesothelioma
cell line compared to HaCat keratinocytes with
vulpinic, usnic, gyrophoric, salazinic, and evernic
acids and confirmed the strong activity of usnic acid
and showed interesting results about the disconnection
of cell proliferation stimulation and mitosis inhibition
[46]. (−)Usnic acids In vivo assays showed weak
antitumoral effect against Lewis Lung carcinoma and
P388 leukemia [29,46,105]. [46,106] reported
salazinic acid had lower significant activity against
MM98, HacaT, A431, HCT-8 MDA-MB435, and SF-
295 cancer cells. According to [107], hypostictic acid
had anticancer and antiproliferative activity against,
MCF7, HT-29, HepG2, K562, NIH/3T3, PC-03, 786-
0, B16-F10, cell lines. Hypostictic acid showed
cytotoxic activity in following cell lines tested with
GI50 value of 2.2-72.4 µm on B16-F10, K562 and 786-
0 GI50 value of 2.2-13.8 and 14.2 µm. Lichen
metabolite such as salazinic acid and hypostictic acid
induced cell death by apoptosis at concentrations more
than 25 µg/ml at 24 and 48 h of UV exposure. [108]
Investigation reported that the cytotoxic activities of
methyl orsellinate and tenuiorin extracted from
Peltigera leucophlaebia lichen species tested on
human breast T-47D, pancreatic PANC-1, and colon
WIDR cancer cell lines, showed a mild to significant
activity of tenuiorin on the pancreatic and colon cell
lines, whereas methyl orsellinate had no effect.
Depsidones and depsides extracted from Antarctic
lichens were investigated with colchicine in in vitro
cell lines of lymphocytes or with usnic acid for their
apoptotic and cytotoxic activity on liver cell lines
[109]. Lichen glucans did not show cytotoxic actions
with the IC50 values on cancer cells as exemplified by
the galactomannose substituted glugan extracted from
Cladonia furcate IC50 500-800 µg/ml. Apoptosis
induction and a telomerase activity diminution
demonstrated their potential in anticancer adjuvants
[110]. According to [111] physodic acid showed high
activity with the IC50 value of 26.7 µm against
melanoma cancer cells. [112] Reported that
depsidones derivative such as protocetraric acid,
norstictic, and psoromic acid and depside derivatives
of divaricatic and perlatolic acids showed strong
activity against UACC-62 melanoma cells and 3T3
normal cells.
Molecular mechanisms and anticancer activity of
Lichen metabolite atranorin exhibited antitumorigenic
activity in a mouse xenograft tumor. Further
investigation revealed that nuclear Ki-67 level
reduction and expression of nuclear protein occurred
in cancer cells in all phases of the active cell cycle
[113]. [114] Vulpinic acid showed cytotoxicity at a
concentration with the IC50 value is 23.8 µm against
HepG2 cancer cell line and this study reported that
vulpinic acid could be used as a novel drug source in
the pharmaceutical industry.
Conclusion
Activities of lichen metabolites are illustrated in-detail
and at this juncture, it is realized that these lichen
compounds are the least explored agents among
anticytotoxic sunscreen drugs. The challenge here is
lack of rapid in vitro culture methods in undertaking
the commercial production of lichen compounds and

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Volume 2; Issue: 02
Article ID: SA2115
rediscovery of effective drugs to cure the potential
disease cancer. The study targeted the deleterious
effect of UV radiation in western countries and
importance of UV proof sunscreen lichen compounds.
However, in the current decade, most of the
advancements in microbiology not only solves the
cultivation problem but also helps in production of
lichen compounds with great success. There are many
UV screening compounds produced by various lichen
species. They are grouped under poly functionalized
aromatic compounds. Atranorin, calycin, pannarin,
parietin and usnic acids were the most investigated
UV screen compounds derived from lichens. Based on
the review, it is concluded that these lichen
compounds exhibited strong in vitro and in vivo
anticancer activities and hence, it can be used as a
novel sunscreen drug source in the drug industry.
Acknowledgement
Authors express their gratitude to Dr. A. Rajendran,
Prof. & Head, Department of Botany, Bharathiar
University, Coimbatore for providing excellent help
throughout this research work. We are thankful to
UGC SAP and DST FIST, Government of India for
financial support to carry out this study.
Conflict of Interest: The authors declare that they
have no conflict of interest.
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and their major metabolites as possible natural
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Table 3: UV screening compounds from lichens

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Table 4: Anticancer activity of lichen secondary metabolites

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Lichen
compound/extracts
Cell lines tested
Major finding
Refe
renc
es
Usnic acid derivatives
L1210 Lewis lung
carcinoma
Seven out of eleven usnic acid derivatives
completely inhibited L1210 cell growth at 1.4x10-7
mol/ml and it was found that the lipophilicity and
β-triketone moiety of usnic acid were responsible
for its cytotoxicity.
[29]
Lobaric acid
Protolichesterinic acid
T-47D & ZR-75-1
Breast cancer cell, K-
563 Erythro-leukemia
Significant apoptosis in cell lines were examined at
20 and 30 µg/ml concentrations of
protolichestericnic acid and lobaric acid
respectively. At higher concentrations
proliferation, DNA synthesis and survival of
fibroblasts in normal skin cells were unaffected.
[103]
Cladonia convoluata
Cladonia rangiformis
Evernia prunastri
Parmelia perlata
Parmelia caperata
Ramalina cuspidata
Usnea rubicunda
extracts.
3LL Murine Lewis
lung carcinoma, L1210
Murine lymphocytic
leukaemia, Human
chronic myelogenous
leukaemia, MCF7
Human breast
adenocarcinoma,
DU145 Human brain
metastasis of prostate
carcinoma, RCB-0461
Human glioblastoma,
African green monkey
kidney cell vero
3 different solvent extracts such as diethyl ether,
methanol and n- and hexane, of 8 species were
evaluated for antiproliferative activity against
seven cell lines with an IC50 value of <20µg/ml for
one solvent extracts of each lichen species. Crude
extracts of C. convoluta, C. rangiformis, P.
caperata, P. glauca, and R. cuspidata were found
to have high selectivity indices which suggests a
vital role as anti-cancer agents.
[162]
Depsidones-Vicanicin,
Pannarin, 1-
chlotropannarin,
Salazinic acid, Stictic
acid, Variolaric acid,
Psoromic acid,
Fumarprotocetraric
acid, Lobaric acid
Depsides-Atranorin,
Sphaerophorin,
Divaricatic acid,
diffractaic acid,
gyrophoric acid
Usnic acid
Hepatocytes from rat
Among 15 different lichen compounds analyzed,
the cytotoxicity activity of usnic acid was higher
with an IC50 value of 21 µg/ml after 20 h and lactic
acid dehydrogenase was used for this purpose.
Psoromic acid, stictic acid, and salazinic acid,
showed concentration-dependent apoptosis of liver
cell lines. The stictic acid showed higher apoptotic
activity.
[109]
Sphaerophorin
Pannarin
Epiphorellic acid-1
DU 145 Human
prostrate carcinoma,
All lichen compounds are nontoxic to normal
prostatic human epithelial cells. On the basis of
antiproliferative activity, the compounds such as
Sphaerophorin, Pannarin and Epiphorellic acid-1
showed excellent cytotoxicity activity against DU-
145 cells at a concentration of 6-50 µ mol/l results.
[49]

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Among these 3 compounds, Pannarin showed the
maximum activity at a minimum inhibition
concentration ranges between 12 and 25 µmol/I.
The results showed that necrosis was induced at a
higher concentration with the value greater than 50
µmol/I. The reason was due to the effect of lactic
dehydrogenase induction. The examination of
DNA fragmentation in DU 145 cells were higher at
a dose of 12 and 25 µmol/I concentration. The
effect of lichen compound to induce apotptosis was
evident at this concentration that caused DNA
damage. No such activities were seen at a
concentration greater than 50 µmol/I.
(+) Usnic acid
(-) Usnic acid
V79 Lung fibroblast,
A549 Human lung
carcinoma
The time and dose dependent cytotoxicity of usnic
acid are involved to inhibit V79 and A549 cell
lines. Cytotoxicity was less pronounced in V79
than A549.
[47]
Cetraria aculeata
extract
HeLa Human uterus
carcinoma, A549
Human lung
carcinoma, F2408 Rat
embryonic fibroblasts,
5RP7 c-H-ras
transformed rat
embryonic fibroblast.
The extract of Cetraria aculeata was found to be
antiproliferative against A549 and HeLa with an
IC50 value of 500 and 200 µg/ml respectively.
Significant cytotoxic activity 5RP7 with IC50
values ranges between 80 and 280 µg/ml was found
on F2408 cell line with the extract of Cetraria
aculeata..
[93]
Lethariella
zahlbruckneri extract
HT-29 Human colon
cancer cell
The crude methanolic and acetone extracts of L.
zahlbruckneri reduced cell proliferation in both a
dose and time dependent manner while an
methanolic extract displayed lower cytotoxicity
than the acetone extract. The acetone extract
induced apoptosis by increasing cell proliferation
in the sub-G1 phase, as well as the observation of
nuclear condensation and apoptotic bodies while
such results were not observed with methanolic
extract. The induction of apoptosis by the acetone
extract was mitochondria mediated in a caspase
dependent and caspase independent mechanism. It
was found that there is decreased level of the Bcl-2
protein and increased level of Bax.
[41]
16-O- Acetyl-
leucotylic acid
Leucotylic acid
HL-60
16-O- Acetyl-leucotylic acid was found to possess
cytotoxic activity against HL-60 cell line with an
EC50 value of 21µM. But the leucotylic acid,
showed higher EC50 value. The higher cytotoxic
activity of these two compounds were due to
modification of its structure. Lesser cytotoxic
activity was observed in Leucotylic acid than 16-
O- Acetyl-leucotylic acid.
[163]

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Evernia prunastri
extract
Xanthoria parietina
extract
P3X63 Murine
myeloma
Significant cytotoxic effect was observed in a crude
solvent extracts of Xanthoria parietina in a dose
dependent manner while similar activities were not
seen with Evernia prunastri. The considerable
activity of X.parietina extract could be due to its
higher antioxidant content viz., superoxide
dismutase and peroxidases
[163]
Lecanoric acid
Orsellinate derivatives
MCF-7 Breast
carcinoma, 786-0
Kidney carcinoma,
HEP-2 Larynx
carcinoma, B16-F-10
Murine melanoma cell
Increase in antiproliferative activity of lecanoric
acid was found in its modified structures. The
compound is a derivative of orsellinates. The IC50
Value of orsellinate was found to be lesser than
than lecanoric acid, The IC50 values of n-Butyl
orsellinate showed its range between 7.2 and 14.0
µg/ml. The orsellinate activity was found higher
corresponding to its lengthy chain. The results of
lipophilicity was found to be higher in lengthy
chain of orsellinate .
[44]
Olivetoric acid
Rat adipose tissue
Dose dependent anti-angiogenic activities was
investigated with Olivetoric acid and it showed
strong antiproliferative activity and degenerated
endothelial tube development in adipose tissue.
Accordingly, Olivetoric acid triggers dose
dependent inhibition of actin stress fibres was
examined.
[164]
Retigeric acid A
Retigeric acid B
PC-3, DU 145, Human
Pca LNCaP, KB
Human epidermoid
cancer, 3-AO Human
ovarian cancer,
RWPEI Human benign
prostate epithelial
Lichen metabolites such as retigeric acid A (RA)
and retigeric acid B (RB) displayed
antiproliferative activity at a concentration more
than 100µm and RA was less effective than RB.
Structural relationship of RA and RB is -COOH
substitution in RB. Lichen acids of RB were found
to induce a concentration dependent accumulation
of cells on PC-3 cell lines during the S phase of cell
cycle followed by decrease in cyclin B, and
increase in cyclin E and cyclin A. The results
showed that caspase independent and dependent
pathways activated apoptosis.
[40]
Usnic acid
Atranorin
Gyrophoric acid
Parietin
A2780 Human ovarian
carcinoma
HT-29 Human colon
adenocarcinoma
Usnic acid and atranorin treated HT-29 cells cell
lines showed caspase-3 activation and decreased
mictochondrial membrane potential. Both test
substances caused an externalization of
phosphatidylserine in cell lines. Significant cell
deaths in A2780 and HT-29 were observed. This
may be due to mitochondrial pathway.
[100]
Diffractaic acid
Vicanicin
Lobaric acid
Variolaric acid
Protolichesterinic acid
Usnic acid
MCF-7 Human breast
adenocarcinoma,
HCT-116 Human
colon adenocarcinoma,
HeLa Human cervix
adenocarcinoma
Lichen acids displayed different antiproliferative
action with higher cytotoxicity in HCT-116 but less
activity in MCF-7. Of six compounds examined,
vicanicin did not show any activity, while usnic
acid and diffractaic acid were active against all 3
cancer cell lines. Protolichesterinic acid showed
[45]

Science Academique
Murugan M, et al.
Pages: 1-29
Volume 2; Issue: 02
Article ID: SA2115
apoptosis induction after 72 h of treatment and a
significant (3.27%) increase of caspase-3 activity
was observed
Protolichesterinic acid
SK-BR-3, T-47D
Human breast cancer
cell lines
Ptotolichesterinic acid displayed significant cell
deaths in cell lines of SK-BR-3, T-47D cell lines
were observed with the IC50 values of 10.8, 11.7
µM.
[165]
Atranorin
Fumarprotocetraric
acid
Fem-x Human
melanoma and LS174
Human colon
carcinoma cell line
Fumar protocetraric acid and atranorin were
evaluated for cytotoxicity against FemX and LS174
cells. Atranorin was most active with an IC50 value
was 28.27, 20.88 µg/ml. The cytofluorimetric
analysis was carried out for this purpose using
propidium iodide labelled DNA.
[166]
Stereocaulon paschale
extract
Fem-x Human
melanoma and LS174
Human colon
carcinoma cell line
Extract has strong anticancer activity against
LS174 Human colon carcinoma and Fem-x Human
melanoma cell line cell lines with the IC50 values of
40.22 and 23.52 µg/ml respectively.
[167]
Cetraria islandica
extract
Fem-x Human
melanoma and LS174
Human colon
carcinoma cell line
Methanolic extract of C. islandica showed
cytotoxic effects on LS174 and FemX cell lines
with the IC50 values of 33.74 and 22.68 µg/ml.
[168]
Xanthoparmelia
chlorochroa
Tuckermannopsis
ciliaris
and 15 Lichen species
extracts
Burkitt’s lymphoma
cells
The extract of 14 species showed cytotoxicity
activity against lymphoma cells. Both test
substances of X. chlorochroa and T. ciliaris caused
a significant decrease in cell proliferation and p53
upregulation. The extract of T. ciliaris upregulated
TK1 expression but the extract of X. chlorochroa
did not show TK1 gene expression.
[169]
Parmelia sulcata
extract
MCF-7 and MDA-
MB-231 Breast cancer
cell line
P. sulcata extract showed significant anticancer
activity against MDA-MB-231 and MCF-7 cell
lines with the IC50 values of 16.5 µg/ml and 39.1
µg/ml respectively. The extract activiated apoptosis
probably through the caspase independent pathway
in these cells or involvement of caspase-3
mechanism.
[170]
Physciosporin
compound and
Pseudocyphellaria
coriacea extract
A549, H1650 and
H1975 Human lung
cancer cells
The lichen metabolite physciosporin showed
significant inhibitory activity against human lung
cancer cells. Physciosporin treated cells showed
both mRNA and protein levels of N-cadherin with
significant decrease in the levels of epithelial-
mesenchymal transition markers such as snail and
twist.
[171]
Parietin compound and
Xanthoria parietina
extract
MCF-7 and MDA-
MB231 breast cancer
cells
The extract of Xanthoria parietina showed
antiproliferation activity and induced apoptosis.
Further investigation on the effects of parietin on
MCF-7 and MDA-MB231 breast cancer cells was
accompanied by alteration on expression of
regulating genes such as P16, p27, cyclin D1 and
cyclin A.
[172]

Science Academique
Murugan M, et al.
Pages: 1-29
Volume 2; Issue: 02
Article ID: SA2115
Cetraria islandica,
Vulpicida canadensis
extracts
HepG2 Hepatocellular
carcinoma, MCF-7
breast adenocarcinoma
The lichen extracts of Cetraria islandica, and
Vulpicida canadensis exhibited potent anticancer
activity against MCF-7, HepG2 cell lines with the
IC50 Values of and 19.51, 148.42 µg/ml.and 181.05,
58.02 µg/ml respectively.
[173]
Olivetoric acid,
Physodic acid and
Psoromic acid
GBM and U87 MG
Human brain cancer
cells, PRCC Primary
rat cerebral cortex cells
Antiproliferative analysis using MTT assay showed
that the metabolites exhibited higher susceptibility
in cancer cells at a concentration of 40 mg/ml.
Olivetoric acid showed strong cytotoxic effects for
U87 MG and PRCC cells. Physodic acid showed
less effective cytotoxic activity for both cells.
[174]
Lecanoric acid and 2’-
O-methyl anziaic acid
compounds, Melanelia
subaurifera, Melanelia
fuliginosa extracts
Hela Human epithelial
carcinoma, A549
Human lung cancer,
LS174 Human colon
carcinoma
M. subaurifera extract was found to be cytotoxic
against Hela, LS174, A549 cells with the IC50
values were 31.25, 9.88, 31.64 µg/ml repsectively.
The lichen compounds lecanoric acid and 2’-O-
methyl anziaic acid displayed less activity.
[175]
Alectoria samentosa,
Flavocetraria nivalis,
Alectoria ochroleuca,
Usnea florida, Usnic
acid compound
A549 Lung cancer cell
Usnic acid caused significant reduction in H1650
and H1975 cell lines at a concentration of 5 µM.
The extract of Flavocetraria nivalis showed 60%
cytotoxic effect.
[176]
Xanthoria parietina,
Caloplaca pusilla and
Protoparmeliopsis
muralis lichen
mycobiont extracts
PC-3 Human prostate
cancer, MCF-7 Human
breast
adenocarcinoma, HeLa
Human cervix
adenocarcinoma
The extract of Caloplaca pusilla increased the
cytotoxicity in HeLa, MCF-7, PC-3 with IC50
Values of 6.57, 7.29, 7.96 µg/ml-1 respectively. The
mycobiont extract of Protoparmeliopsis muralis
mycobiont did not display any anticancer activity.
[177]
Ramalin
HCT116 Human
colorectal cancer cell
line
Ramalina extract showed significant cell deaths
and observed apoptosis in HCT116. The extract of
Ramalina caused a significant increase in the
expression of its downstream gene CDKN1A and
TP53 while reduction in the expression of and
CCNB1 and CDK1 on the basis of concentration
dependent manner.
[178]
Atranorin
Gyrophoric acid
Physodic acid
A375 Human
melanoma cell line
The test substance caused a significant antitumour
activity at a concentratopn of 12.5-50µM.
Atranorin and gyrophoric acid displayed lower less
activity. Physodic acid activity has been found to
increase Hsp70 expression a likely consequence of
its interaction with regulatory elements and induces
apoptosis.
[111]
Atranorin, Lecanoric
acid, Caperatic acid,
Physodic acid,
Squamatic acid and
Salazinic acid
HCT116, DLD-1
Colorectal carcinoma
and HaCaT cells
HCT116 cells were sensitive to the Lecanoric and
Caperatic acid and decreased Auxin 2 expression.
Physodic acid effectively reduced Axin2
expression in HCT116 cells and less in DLD-1
cells.
[179]
Lobaric acid,
Lobarstin
HeLa Human cervix
adenocarcinoma and
Extracts of lichen compounds such as lobaric acid
and lobarstin exhibited cytotoxic activity in
[180]

Science Academique
Murugan M, et al.
Pages: 1-29
Volume 2; Issue: 02
Article ID: SA2115
HCT116 Colon
carcinoma
HCT116 and HeLa cancer cells and induce
apoptosis at the G2/M phase.
Parmotrema
tinctorum, Usnea
rubrotincta, Usnea
nipparensis, Lobaria
pulmonaria and 10
lichen extracts.
MCF-7 Human breast
adenocarcinoma, MO-
91 Acute myelogenous
leukemia cells
The methanolic extract of Usnea nipparensis
showed strong antiproliferative activity against
MCF-7 cell lines with the IC50 values of 34.27
mg/ml-1. All the other tested lichen extracts showed
different cytotoxic activity against MO-91 cell with
the IC 50 value ranges between 10.50 and 50
mg/ml-1.
[181]
Parmelia tinctorum,
Parmelia cetrata,
Candelaria fibrosa,
Clodonia scabriuscula,
Teloschistes flavicans
and 4 lichen extracts
Vero normal cell,
MCF-7 breast cancer,
HeLa cervical cancer
cell, WiDr colon
cancer cells
The methanolic extract of Cladonia scabriuscula
was effective against MCF-7 and HeLa IC50 Values
of 324 and 474 µg/ml respectively.
[182]