Review: UV protection and anticancer properties of lichen secondary metabolites

Mariraj Murugan^1*, 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

Citation: Murugan M, Muthu S, Rajendran K, Ponnusamy P (2021) Review: UV protection and anticancer properties of lichen secondary metabolites. Sci Academique 2(1): 68-96.

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 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].

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 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].

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.

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_* transitionspresence 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, 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].

E_λ is solar spectral irradiance expressed in W∙/(m­­²∙nm¹) at wavelength λ and dλ is the wavelength interval used in the summation. S_erλ is an erythema reference action spectrum and K_er 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-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 Sor 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 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 G_I50 value of 2.2-72.4 µm on B16-F10, K562 and 786-0 G_I50 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 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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Table 3: UV screening compounds from lichens.

Table 4: Anticancer activity of lichen secondary metabolites.