Critical Reviews in Microbiology

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Endophytic fungi with antitumor activities: Their occurrence and anticancer compounds Ling Chen, Qiao-Yan Zhang, Min Jia, Qian-Liang Ming, Wei Yue, Khalid Rahman, Lu-Ping Qin & Ting Han To cite this article: Ling Chen, Qiao-Yan Zhang, Min Jia, Qian-Liang Ming, Wei Yue, Khalid Rahman, Lu-Ping Qin & Ting Han (2016) Endophytic fungi with antitumor activities: Their occurrence and anticancer compounds, Critical Reviews in Microbiology, 42:3, 454-473 To link to this article: http://dx.doi.org/10.3109/1040841X.2014.959892

Published online: 24 Oct 2014.

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Date: 05 December 2016, At: 22:56

http://informahealthcare.com/mby ISSN: 1040-841X (print), 1549-7828 (electronic) Crit Rev Microbiol, 2016; 42(3): 454–473 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/1040841X.2014.959892

REVIEW ARTICLE

Endophytic fungi with antitumor activities: Their occurrence and anticancer compounds Ling Chen1*, Qiao-Yan Zhang1*, Min Jia1, Qian-Liang Ming2, Wei Yue1, Khalid Rahman3, Lu-Ping Qin1, and Ting Han1 1

Department of Pharmacognosy, School of Pharmacy, Second Military Medical University, Shanghai, China, 2Department of Pharmacognosy, School of Pharmacy, Third Military Medical University, Chongqing, China and 3Faculty of Science, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK Abstract

Keywords

Plant endophytic fungi have been recognized as an important and novel resource of natural bioactive products, especially in anticancer application. This review mainly deals with the research progress on the production of anticancer compounds by endophytic fungi between 1990 and 2013. Anticancer activity is generally associated with the cytotoxicity of the compounds present in the endophytic fungi. All strains of endophytes producing antitumor chemicals were classified taxonomically and the genera of Pestalotiopsis and Aspergillus as well as the taxol producing endophytes were focused on. Classification of endophytic fungi producing antitumor compounds has received more attention from mycologists, and it can also lead to the discovery of novel compounds with antitumor activity due to phylogenetic relationships. In this review, the structures of the anticancer compounds isolated from the newly reported endophytes between 2010 and 2013 are discussed including strategies for the efficient production of the desired compounds. The purpose of this review is to provide new directions in endophytic fungi research including integrated information relating to its anticancer compounds.

Anticancer activity, Aspergillus, bioactive metabolite, endophyte, medicinal plant, Pestalotiopsis

Introduction Cancer is a collective term used for a group of diseases that are characterized by the loss of control of growth, division and the spread of cells, leading to primary tumors that invade and destroys adjacent tissues. It is one of the most serious health threats worldwide, with an estimated 12.7 million new cases and 7.6 million cancer-related deaths each year (Jemal et al., 2011). At least three important classes of genes play key roles in tumor initiation: proto-oncogenes, tumor suppressor genes and genes involved in DNA repair mechanisms (Berit & Rolf, 2007). DNA damage is considered to be the primary cause of cancer (Wiseman et al., 1995) and a variety of environmental and genetic factors cause DNA damage in a coordinated or sequential manner, thus activating oncogenes and/or tumor suppressor genes. This leads to changes in apoptosis regulating genes and/or DNA repair genes, thus causing abnormal expression levels resulting in the

*Ling Chen and Qiao-Yan Zhang equally contributed to this manuscript; both should be considered as first author. Address for correspondence: Professor Ting Han, School of Pharmacy, Department of Pharmacognosy, Second Military Medical University, Shanghai, China. Tel, Fax: (+86) 021-81871306. E-mail: than927@163. com; [email protected] Dr. Lu-Ping Qin, School of Pharmacy, Department of Pharmacognosy, Second Military Medical University, Shanghai, China. Tel, Fax: (+86) 021-81871300. E-mail: [email protected]

History Received 30 June 2014 Revised 26 August 2014 Accepted 27 August 2014 Published online 24 October 2014

transformation of target cells (Croce, 2008; Knudson, 2001). Through a long process of cellular proliferation and together with additional mutations, subclones with different characteristics are formed after the amplification of every clone, leading to invasion and metastasis and eventually cancer (Fearon & Vogelstein, 1990; Wood et al., 2007). The aim of most cancer chemotherapeutic drugs in clinical use is to destroy malignant tumor cells by inhibiting some of the mechanisms implied in cellular division. However, cancer chemotherapy is a very difficult task due to non-specific toxicity and severe drug resistance of most anticancer drugs (Nygren & Larsson, 2003). In addition, the research and development of anticancer drugs is expensive which places a high financial burden on individual healthcare costs and government budgets. The extracts or natural products from medicinal plants are of great value in the control of malignancies in view of their low cytotoxic activities and drug resistance (Mbaveng et al., 2011). For example, camptothecin, taxol, combretastatins, are plant-derived drugs and play a dominate role in the treatment of the cancer (Srivastava et al., 2005). The research and discovery of new antitumor drugs is mostly based on the modification of the natural products or the specific isolation of anticancer compounds from medicinal plants (Srivastava et al., 2005). However, the resources of medicinal plants are being reduced significantly due to over-harvesting, illegal exploitation and destruction of ecological habitat (Kala,

DOI: 10.3109/1040841X.2014.959892

2000). Thus, it is urgent to conserve endangered medicinal plants and to develop new alternative resources for harvesting anticancer compounds from plants. Endophytes (or endophytic fungi and fungal endophyte) are organisms that inhabit living plants at some stage in their life, without causing apparent harm to the host. These include some surface saprophytes, latent pathogens and mycorrhizal fungi which also inhabit the living plants at certain stages of their life cycle (Petrini & Fisher, 1990). Endophytes provide a broad variety of bioactive secondary metabolites with unique structures, including alkaloids, benzopyranones, chinones, flavonoids, phenolic acids, quinones, steroids, terpenoids, tetralones, xanthones and others (Tan & Zou, 2001). The bioactive metabolites are used for a wide range of applications such as agrochemicals, antibiotics, immunosuppressants, antiparasitics, antioxidants and anticancer agents (Gunatilaka, 2006). Although the bioactive natural compounds produced by endophytic fungi have potential in safety and human health concerns, there is still significant demand from the drug industry for these synthetic products due to economic reasons (Strobel et al., 2004). The endophytic fungi have been recognized as a possible useful source of bioactive secondary metabolites, especially in anticancer application (Kharwar et al., 2011; Schulz et al., 2002; Strobel et al., 2004). In a detailed analysis of anticancer agents derived from fugal endophytes over the period 1990–2010, Kharwar et al. (2011) carefully described each compound in terms of its biological activity, the source of microorganism and the plant host. In this review, the data obtained between 1990 and 2013 have been integrated and summarized to include the taxonomy of endophytes and the diversity of the species of the genera of endophytes. Besides, the newly reported endophytes and the structures of the anticancer compounds isolated from the endophytes between 2010 and 2013 have been systematically introduced in Table 1 and Figure 1, respectively. The criteria for selecting the most relevant references in this study were: (i) secondary metabolites or bioactive components of endophytic fungi must be detectable by high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), mass spectral (MS) or X-ray crystallography analysis, (ii) the determination of antitumor activities was based on cytotoxicity of each compound against specific cancer cell lines. Some strategies available for the efficient production of the desired compounds, as well as their future potential applications are also discussed.

Classification of endophytic fungi producing antitumor components Integrated with the data in review by Kharwar et al. (2011), the references from 1990 to 2013 were collected to show that about 46 genera and 111 species of endophytic fungi producing antitumor components have been reported. Taxonomically, nearly all genera belong to Ascomycotina (96%), involving Sordariomycetes (56%), Eurotiomycetes (22%), Dothideomycetes (14%) and Pezizomycetes (1%); others belong to Basidiomycota (3%) and Glomeromycota (1%; Figure 2). The genera contained two or more species of antitumor producing endophytic fungi, namely, Pestalotiopsis (14), Aspergillus (11), Chaetomium (9), Fusarium (7),

Endophytic fungi with antitumor activities

455

Penicillium (6), Alternaria (5), Phomposis (5), Acremonium (2), Ceriporia (2), Colletotrichum (2), Cytospora (2), Emericella (2), Eurotium (2), Eutypella (2), Guignardia (2), Hypocrea (2), Periconia (2), Stemphylium (2), Talaromyces (2), Thielavia (2) and Xylaria (2; Figure 3). These endophytes represent an alternative source of specific secondary metabolites which can be manipulated to increase the yields of desired metabolites. The genera of Pestalotiopsis and Aspergillus as well as the taxol producing endophytes have been highlighted in this review. The genus Pestalotiopsis The data obtained from the genera of the endophytes isolated between 1990 and 2013 (Figure 3) show that the species associated with the genus Pestalotiopsis is higher than that of other genera and accounted for 14 strains. Among these strains of genus Pestalotiopsis, five strains can produce taxol, and the rest of the nine strains of the endophytes produce other chemicals with antitumor activity. Thus, it is of great importance to study this genus in relation to the development of antitumor drugs. The genus Pestalotoiopsis belongs to the Amphisphaeriaceae (Coelomycetes) family and is an appendage-bearing conidial anamorphic form (Barr, 1975; Kang et al., 1998, 1999). And, it is monophyletically based on molecular studies (Jeewon et al., 2002, 2003, 2004). Some Pestalotiopsis species are saprobes in soil (Agarwal & Chauhan, 1988), degraders of plant materials (Okane et al., 1998; Osono & Takeda, 1999; Tokumasu & Aoiki, 2002) or organisms growing on decaying wild fruits (Tang et al., 2003), while others are either plant pathogens (Kohlmeyer & Volkmann-Kohlmeyer, 2001; Zhang et al., 2003; Zhu et al., 1991) or reside as endophytes in plant leaves and twigs (Ding et al., 2009; Liu et al., 2009a,b,c). To date, numerous newly discovered compounds with medicinal potential (Aly et al., 2010; Ding et al., 2008a,b; Strobel et al., 1996a, 2002; Xu et al., 2010) including alkaloids, terpenoids, isocoumarin derivatives, coumarins, chromones, quinones, semiquinones, peptides, xanthones, xanthone derivatives, phenols, phenolic acids and lactones, have been reported from Pestalotiopsis species, making this genus a particularly rich source for bioprospecting receiving much attention from the scientific community, especially the taxol-producing species. Other compounds may also be important as future drugs for the treatment and control of human and plant diseases, since several antioxidants, immunosuppressants, anticancer agents and others, have been identified from this genus (Li et al., 2001; Strobel et al., 1996a). Pestalotiopsis versicolor Various references have identified a strain of endophyte of Pestalotiopsis, Pestalotiopsis versicolor, in which the maximum amount of taxol concentration has been identified as 478mg/l. This amount of taxol is 9560-fold higher than that found in the culture broth of earlier reported fungus, Taxomyces andreanae (Kumaran et al., 2010). Pestalotiopsis versicolor are common species recorded in either decaying leaves or bark. Some species of Pestalotiopsis have also been isolated from extreme environments and these isolates also produce bioactive metabolites. The pathogenic fungus

Bidens pilosa (Asteraceae), stem Taxus cuspidate (Taxaceae) leaves and inner bark Aquilaria sinensis (Thymelaeaceae) stem Melaleuca quinquenervia (Myrtaceae) stem

Current-year phloem of Annona squamosa Leaves of Annona muricata

Old inner bark of T. chinensis var. mairei Infected fruit of Capsicum annuum by Colletotrichum capsici Laurencia sp.

Botryosphaeria rhodina

Xylarialean sp. A45

Didymostilbe sp.

Radix of Pongamia pinnata

Healthy plant of Avicennia marina

Aspergillus tubingensis GX1-5E

Aspergillus niger MA-132

Penicillium chrysogenum QEN-24S

Colletotrichum capsici

Periconia sp.

Pestalotiopsis sp.

Pestalotiopsis versicolor, Pestalotiopsis negle Nodulisporium sp.

Smallanthus sonchifolius (Asteraceae)

Host plant(s) (family), plant part or tissue

Papulaspora immersa

Endophytic fungal strain

(2R*,4R*)-3,4-dihydro4-methoxy-2-methyl2H-1-benzopyran-5-ol Pestalactams A

Xinyi, Guangdong Province, P. R. China

Asnipyrones A

Nigerapyrones E,

Pyrones

Pyrones

TMC 256 A1

Nigerapyrones B Nigerapyrones D,

Steroids

Diterpenes

Taxol

Penicisteroids A

Diterpenes

Triterpenes

Triterpenes

(+)-(3S,6S,7R,8S)periconone A, ()-(1R,4R,6S,7S)-2caren-4,8-olide Taxol

Xylariacins A–C

Alkaloids

Pyrans

Diterpenes

HeLa (15 mg/ml), SW1990 (31 mg/ml), NCI-H460 (40 mg/ml) MCF-7 (31.89 mm), MDA-MB-435 (19.92 mm), Hep3B (43.87 mm), Huh7 (36.44 mm), SNB19 (47.98 mm), U87MG (39.52 mm) HepG2 (62 mm), MCF-7 (121 mm), HepG2 (81 mm), A549 (81 mm), SW1990 (38 mm), MDA-MB-231 (48 mm), A549 (43 mm) A549 (62 mm)

Liver cancer cell line BEL7402 MCF-7, HL 251, HLK 210

HCT-8, Bel-7402, BGC-823, A549, A2780, MCF-7

MCF-7 (64.4 ± 3.0 mm), NFF (20.2 ± 9.2 mm) MCF-7 (58.5 ± 3.2 mm), NFF (12.8 ± 4.2 mm) HepG2

Breast cell BT220, lung cell HL251, leukemia cell HLK 210 SF-268

MDA-MB435 (3.3 mm), HCT-8 (14.7 mm), SF295 (5.0 mm), HL-60 (1.6 mm) HeLa, K-562

Steroids

Depsidone

Test cancer cell lines (IC50)

Chemical nature Type of test

References

Huang et al. (2011b)

Liu et al. (2011)

MTT assay

Cytotoxicity bioassays

(continued )

Gao et al. (2011)

Kumaran et al. (2011)

Cytotoxicity bioassays

In vitro apoptotic method of assay

Wang & Tang (2011c)

Ge et al. (2011)

MTT assay

ns

Lin et al. (2011)

Davis et al. (2010)

MTT assay

SRB assay

Wu et al. (2010)

Kumaran et al. (2010)

In vitro apoptotic method of assay CCK-8 assay

Abdou et al. (2010)

Borges Coutinho Gallo et al. (2010)

Cytotoxicity assays

MTT assay

L. Chen et al.

Dongzhai Harbor in Hainan, P. R. China

South China Sea in Guangxi Province, P. R. China

ns

Sichuan province, Southwest China ns

Xiamen University, Fujian, P. R. China Sanya district, Hainan province, China

Pestalactams B

Taxol

Kangwondo forest region of South Korea

Australia

Botryorhodine A and B

(22 E,24R)-8,14-epoxyergosta-4,22-diene-3,6dione

Crude extract/isolated metabolite

Cairo, Egypt

Andes

Locality of host plants

Table 1. Endophytic fungi producing metabolites with anticancer activity.

456 Crit Rev Microbiol, 2016; 42(3): 454–473

Ilex canariensis Ilex canariensis

Inner tissue of Laurencia sp. Leaves of Xylocarpus granatum

Living photosynthetic tissue of the moss Ceratodon purpureus

Stem of a beech

Camellia sinensis (Theaceae)

Tabebuia pentaphylla (Bignoniaceae) Aegiceras corniculatum

Cytospora sp. Cytospora sp.

Penicillium chrysogenum QEN-24S XG8D

Smardaea sp. AZ0432

Paraconiothyrium sp. MY-42

Pestalotiopsis fici

Pestalotiopsis pauciseta VM1 Alternaria sp. ZJ9-6B

Diterpenes

Sphaeropsidins A,

Beauvericin

Alkaloids

Quinones

Alterporriol K,

Zhanjiang Mangrove, Guangdong province, P.R. China

Alterporriol L

Diterpenes

Epoxycyclohexanediol

Taxol

Pestalofones G, Pestalofones H, Pestalodiols C

19-(2-acetamido-2deoxy-a-D-glucopyranosyloxy) isopimara7,15-dien-3b-ol, 19-(a-D-glucopyranosyloxy) isopimara7,15-dien-3-one Pestalofones F,

Diterpenes

Peroxides

Merulin C

Sphaeropsidins D

Polyketides

Penicitides A

Cytospolides Q Cytospolides P

Lactones Lactones

Peroxides

Talaperoxides B,

Talaperoxides D

Chemical nature

Crude extract/isolated metabolite

India

Hangzhou, China

Southwestern Research Station in the eastern Chiricahua Mountains of southeastern Arizona, USA Mt. Gassan, Yamagata, Japan

Weizhou Island of southern China sea Samutsakorn Province, Thailand

Gomera, Spain Gomera, Spain

Dongzhaigang Mangrove National Nature Reserve in Hainan Island, China

Locality of host plants

MDA-MB-435 (26.97 mm), MCF-7 (29.11 mm) MDA-MB-435 (13.11 mm), MCF-7 (20.04 mm)

HeLa (14.4 mm), MCF-7 (11.9 mm) – – HeLa (16.7 mm), MCF-7 (57.5 mm) ns

HL60 (9.8 mm)

HL60 (6.7 mm)

MDA-MB-231 (3.0 ± 0.05 mm) MDA-MB-231 (5.0 mm)

HUVEC (0.9 mm)

MCF-7 (1.33 mm), MDA-MB-435 (2.78 mm), HepG2 (1.29 mm), HeLa (1.73 mm), PC-3 (0.89 mm) MCF-7 (1.92 mm), MDA-MB-435 (0.91 mm), HepG2 (0.90 mm), HeLa (1.31 mm), PC-3 (0.70 mm) A-549 (10.55 mm) A-549 (2.05 mm), QGY (15.82 mm), U973 (28.26 mm) HepG2 (32 mm)

Test cancer cell lines (IC50)

(continued )

Wang et al. (2011a)

Huang et al. (2011a)

MTT assay

MTT assay

Vennila et al. (2012)

Liu et al. (2011)

Shiono et al. (2011)

Wang et al. (2011b)

Chokpaiboon et al. (2011)

Gao et al. (2010)

Lu et al. (2011) Lu et al. (2011)

Li et al. (2011)

References

ns

MTT assay

ns

Tube formation assay, proliferation assay, chemotactic migration Assay Resazurin-based colorometric (alamarBlue) assay. Cell migration inhibition assay

MTT assay

MTT assay MTT assay

Cytotoxicity bioassays

Type of test

Endophytic fungi with antitumor activities

Fusarium oxysporum

Healthy leaves of Sonneratia apetala

Host plant(s) (family), plant part or tissue

Talaromyces flavus

Endophytic fungal strain

DOI: 10.3109/1040841X.2014.959892

457

Rhizophora mucronata (Rhizophoraceae), Avicenna officialis (Acanthaceae), Avicenna marina (Acanthaceae), leaves Hibiscus tiliaceus

Hibiscus tiliaceus

Leaves of Avicennia sp.

Roots of Podophyllum hexandrum Bark of Erythrophleum fordii Oliver (Leguminosae)

Hypocrea lixii

Eurotium rubrum

Eurotium rubrum

Penicillium sp. ZH16

Fusarium solani

Leaves of Garcinia hombroniana Leaves of Ginkgo biloba

Inner leaf tissues of the plant Sonneratia caseolaris (Sonneratiaceae) Curcuma wenyujin

Bionectria ochroleuca

Diterpenes

Taxol Taxol

Polyketides

Peptide

ns

H22 (3.125 mg/ml), MFC (6.25 mg/ml) KB (138.1 mm), Vero (136.6 mm) MCF-7, A549, T98G

MTT assay

HeLa (12.6 mg/ml), HepG2 (31.7 mg/ml), U-251 (5.4 mg/ml) L5178Y Benzophenones

Tricycloalternarene Diterpenes

Chaetoglobosin X

Zhejiang Province, Wenzhou, China Songkhla Province, Thailand Konkuk University campus

MTT assay

HCT-8 (1.78 mm)

Perylenes

In vitro apoptotic method of assay ns

Cytotoxic assays

Cytotoxicity bioassays

MTT assay

ns

Lignans

MTT assay

(continued )

Mirjalili et al. (2012)

Kumaran et al. (2012)

Sommart et al. (2012)

Wang et al. (2012)

Ebrahim et al. (2012)

Luo et al. (2012)

Fang et al. (2012)

Nadeem et al. (2012)

Huang et al. (2012)

Yan et al. (2012)

Yan et al. (2012)

MTT assay

MTT assay

Bhimba et al. (2012)

Ding et al. (2012)

References

MTT assay

MTT assay

Type of test

KB (5 mg/ml), KBV200 (10 mg/ml) ns

SMMC-7721 (30 mg/ml), HepG2 (20 mg/ml), NCI-H460 (22 mg/ml) MCF-7 (20 mg/ml), SW1990 (20 mg/ml), SMMC-7721 (20 mg/ ml), Hela (30 mg/ml) SW1990 (25 mg/ml)

PC-3 (49.5 ± 3.8 mm), PANC-1 (47.2 ± 2.9 mm), A549 (10.4 ± 1.6 mm) HeLa (5.72 mm) HeLa (27.4 mm) Hep2, MCF7

Test cancer cell lines (IC50)

Coumarins

Quinones

Alkaloids



Cytochalasan

Chemical nature

Guignarenones A

Verticillin D

(6aR,6bS,7S)-3, 6a, 7, 10-tetrahydroxy- 4, 9-dioxo-4, 6a, 6b, 7, 8, 9-hexahydroperylene Pestalrone B

9-Dehydroxyeurotinone, emodin 5-Methyl-8-(3-methylbut2-enyl) furanocoumarin Podophyllotoxin

Alkaloid E-7

12-demethyl-12-oxoeurotechinulin B, Variecolorin G,

Aspochalasins D, Aspochalasins J Ethyl acetate extract

Crude extract/isolated metabolite

Hainan Island of the Dongzhai Mangrove Forest

Nanning, Guangxi Province, China

Dong Sai, Hainan of the South China Sea coast Dist. Bageshwar, Uttarakhand, India Nanning, Guangxi Province, People’s Republic of China

Hainan Island, China

Hainan Island, China

India

ns

Jiaoban Mountain, Taiwan Province, China

Locality of host plants

L. Chen et al.

Chaetomium globosum L18 Guignardia bidwellii PSU-G11 Phoma betae

Stems of Camellia sasanqua

Pestalotiopsis karstenii

Alternaria tenuissima

Panax notoginseng

Bark of Cinnamomum kanehirae

Host plant(s) (family), plant part or tissue

Trichoderma gamsii

Endophytic fungal strain

Table 1. Continued

458 Crit Rev Microbiol, 2016; 42(3): 454–473

Stem of Ceratonia siliqua (Fabaceae) Fresh barks of Ginkgo biloba

Penicillium citrinum

Stems of Ulmus macrocarpa

Branches of Camellia sinensis (Theaceae)

Huperzia serrata

Microsphaeropsis arundinis

Pestalotiopsis fici

Ceriporia lacerate

Colletotrichum sp., Chaetomium globosum Mycoleptodiscus sp. F0194

Healthy, mature leaf of Desmotes incomparabilis (Rutaceae)

Fruit and seed regions of Miquelia dentata (Icacinaceae)

Fomitopsis sp., Alternaria alternate and Phomposis sp.

Stemphylium globuliferum Hypocrea lixii

Inner bark of Taxus baccata Leaves of Rhizomphora annamalayana Mentha pulegium (Lamiaceae), stem Cajanus cajan (Fabaceae), roots, stems and leaves

Host plant(s) (family), plant part or tissue

Stemphylium sedicola SBU-16 Fusarium oxysporum

Endophytic fungal strain

Pan-An County, Zhejiang Province, PR China

Dongling Mountain, Beijing, People’s Republic of China Hangzhou, People’s Republic of China

Coiba National Park, Veraguas, Panama

Ceriponols K

MTT assay MTT assay

HeLa (173.2 ± 1.5 mm), HepG2 (32.3 ± 0.4 mm), SGC 7901 (77.5 ± 0.8 mm) HeLa (47.8 ± 1.6 mm), HepG2 (35.8 ± Sesquiterpenes

MTT assay HeLa (48.2 mm), HT29 (33.9 mm)

H460 (0.66 mm), A2058 (0.78 mm), H522-T1 (0.63 mm), PC-3 (0.6 mm), IMR-90 (0.41 mm) T24 (35.4 mm), A549 (81.6 mm)

Colorimetric assay with sulforhodamine B (SRB) CellTiter-Glo luminescent cell viability assay (Promega)

Alkyne

Coumarins

Arundinone B Siccayne [2-(3-Methyl-3buten-1-ynyl) Hydroquinone] Ceriponols F,

Alkaloids

A549, HT29, HCT116

Colletotriolide, Dothiorelone C Cytosporone Mycoleptodiscin B

Lactones

Linyi, Shandong Province, China

MTT assay

L5178Y (6.1 mm)

Alkaloids

9-methoxy CPT (9-MeOCPT) 10-hydroxy CPT (10-OHCPT) Citriquinochroman

Morocco

Chromatin condensation analysis

HCT-116 (7 mg/ml), SW-480 (8.5 mg/ml), MCF-7 (8 mg/ml) –

Alkaloids

Camptothecine



MTT assay

A549, PC-3, HT-29, HepG2

Flavonoids

Cajanol (5-hydroxy-3-(4hydroxy-2-methoxyphenyl)-7-methoxychroman-4-one)

Arboretum of the Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Harbin, China Western Ghats, India

Flow cytometry

ns

Type of test

K562, A549

ns

Test cancer cell lines (IC50)

Quinones

Diterpenes

Chemical nature

Altersolanol A

Taxol

Crude extract/isolated metabolite

Beni-Mellal, Morocco

Karaj, Alborz Province of Iran Vellar estuary, Thailand

Locality of host plants

(continued )

Ying et al. (2013)

Liu et al. (2013)

Luo et al. (2013)

Ortega et al. (2013)

Bungihan et al. (2013)

El-Neketi et al. (2013)

Shweta et al. (2013)

Zhao et al. (2013)

Teiten et al. (2013)

Elavarasi et al. (2012)

References

DOI: 10.3109/1040841X.2014.959892

Endophytic fungi with antitumor activities 459

Rajendran et al. (2013) ns

Fresh healthy plant of Avicennia marina

Fresh healthy leaves of Plectranthus amboinicus

Aspergillus niger MA-132

Pestalotiopsis microspora EF01

University Herbal Garden, Tamil Nadu, India

Healthy plant of Ipomoea batatas Aspergillus glaucus

Nigerasterols B

Taxol

Diterpenes

Liu et al. (2013) SRB and MTT assay

HL60 (0.3 ± 0.01 mm), A549 (1.82 ± 0.01 mm) HL60 (1.5 ± 0.01 mm), A549 (5.41 ± 0.02 mm) ns Steroids Nigerasterols A,

Asker et al. (2013) MTT assay Hep-G2 (61 mg/ml), MCF-7 (41.7 mg/ml) Sesquiterpenes 2,14-Dihydrox-7-drimen12,11-olide

MTT assay Huperzia serrata Ceriporia lacerate

Pan-An County, Zhejiang Province, PR China Herbarium of Agriculture Research Center (ARC), Cairo Hainan, China

Sesquiterpenes

1.2 mm), SGC 7901 (60.2 ± 2.0 mm) HeLa Ceriponol G

Type of test Chemical nature Host plant(s) (family), plant part or tissue

Locality of host plants

Crude extract/isolated metabolite

Test cancer cell lines (IC50)

Crit Rev Microbiol, 2016; 42(3): 454–473

Endophytic fungal strain

Table 1. Continued

Ying et al. (2013)

L. Chen et al.

References

460

Pestalotiopsis versicolor has been grown on various solid cultures of cellulosic substances and its production of cellulase has been studied (Maharachchikumbura et al., 2011). Pestalotiopsis microspora From the references investigated between 1990 and 2013, the largest number of publications has been on Pestalotiopsis microspore. The strain of this endophyte can produce taxol and other chemicals with antitumor activity, which has great value for further development. Pestalotiopsis microspora isolated from Taxus sp. from the foothills of Himalayas produces taxol (Strobel et al., 1996a). These researchers demonstrated that P. microspora inhabits the inner bark of the tree without causing any symptoms, however, physiological or environmental factors trigger the fungus to become pathogenic and at the same time the fungus produces antifungal exudates of pestaloside to compete with other fungi. Other species of Pestalotiopsis The information obtained from references harvested between 2010 and 2013 is as follows: in 2010, the stems of Australian plants Melaleuca quinquenervia (family Myrtaceae) were examined for its fungal content. Several different microfungal strains were purified and taxonomically identified, including one Pestalotiopsis sp. (BRIP 39872). Pestalactams A and B were tested against two different strains of the malaria parasite Plasmodium falciparum (3D7 and Dd2), and the mammalian cell lines, MCF-7 and NFF, and showed modest in vitro activity in all assays (Davis et al., 2010). In 2011, four isoprenylated epoxyderivatives Pestalofones F–H and pestalodiols C were isolated from endophytic fungi Pestalotiopsis fici. The fungi were extracted from the plant Camellia sinensis (Theaceae) in Guangzhou, China. Cytotoxicity test revealed that four compounds showed cytotoxicity against HeLa and MCF-7 cells (Liu et al, 2011b). In the same year, taxol was derived from an endophytic fungus, Pestalotiopsis pauciseta Sacc. VM1, and it was isolated from a medicinal plant Tabebuia pentaphylla Hemsl. Based on estimation and evaluation of series of enzymic and non-enzymic antioxidants (i.e. related to tumors), the results showed that the fungal taxol was found to be effective against 7,12-dimethyl benz(a)anthracene induced mammary tumors in Sprague– Dawley rats (Vennila et al., 2010). In 2012, Pestalrone B, an oxysporone derivative, from the endophytic plant fungus Pestalotiopsis karstenii was isolated from the stems of Camellia sasanqua. This compound exhibited significant activities against HeLa, HepG2 and U-251 with IC50 values of 12.6, 31.7 and 5.4 mg/mL, respectively (Luo et al., 2012). In 2013, Siccayne [2-(3-Methyl-3-buten-1-ynyl) hydro], a quinone was isolated from endophytic fungus Pestalotiopsis fici and showed cytotoxic activity against the human cancer cell lines, HeLa and HT29, with IC50 values of 48.2 and 33.9 mm, respectively (Liu et al., 2013). The genus Aspergilus Followed by the genus Pestalotiopsis, papers reporting Aspergilus accounted for the second highest reports and

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Figure 1. The chemical structures of secondary metabolites with antitumor activities isolated from endophytes between 2010 and 2013.

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Figure 1. Continued.

involved 11 strains and has the potential to be developed further. Aspergillus is one of the oldest genera of fungi and received its name from Micheli in 1729. This is the name used for a genus of moulds that reproduce only by asexual means, these species are common and widespread. They are among the most successful groups of moulds with important roles in natural ecosystems and play an important role in economic terms. By the time, Thom and Church published the first major

monograph on the genus in 1926, Aspergillus had become one of the well known and most studied mould groups. From the references collected between 2010 and 2013, four strains of endophytic fungi with antitumor activity were isolated. In 2011, three a-pyrone derivatives nigerapyrones B, D, E and one known congener, asnipyrone A, was isolated from marine-derived fungi Aspergillus niger MA-132, which showed weak cytotoxicity against some of the tested tumor cell lines of MCF-7, HepG2, Du145, NCI-

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Figure 1. Continued.

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Figure 1. Continued.

H460 and MDA-MB-231 (Liu et al., 2011a). In the same year, one known monomeric naphtho-g-pyrones, TMC 256 A1 from the mangrove endophytic fungus Aspergillus tubingensis (GX1-5E) displayed inhibitory activities against tumor cell lines of MCF-7, MDA-MB-435, Hep3B, Huh7, SNB19 and U87 MG (Huang et al., 2011b). In 2013, nigerasterols A and B were isolated from Aspergillus niger MA-132, an endophytic fungus from mangrove plant Avicennia marina. Both of these two compounds exhibited potent activities against tumor cell line HL60 and A549 (Liu et al., 2013). In the same year, 2,14-dihydrox-7-drimen-12,11-olide was isolated from

an endophytic fungus Aspergillus glaucus, which was collected from the leaves of Ipomoea batatas. In vitro anti-tumor assay showed that the active compound displayed moderate cytotoxic effect against Hep-G2 cell, and strongly affected the growth of MCF-7 cells (Asker et al., 2013). Aspergilli grow abundantly as saprophytes on decaying vegetation and is found in large numbers in moldy hay, organic compost piles, leaf litter and similar environments. Most species are adapted for the degradation of complex plant polymers, but they can also use diverse substrates such as dung, human tissues and antique parchment (Polacheck et al.,

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Figure 2. Taxonomy of endophytes isolated between 1990 and 2013.

Figure 3. The diversity of species of the genera of endophytes isolated between 1990 and 2013 (x axis: species numbers of the genera; y axis: the type of the genera).

1989). Several species contaminate grains and other foods with toxic metabolites that are a threat to human health and animals. Certain Aspergillus species can also infect humans directly causing both localized and systemic infections, especially in immunocompromised individuals. Aspergillus apores are common components of aerosols where they drift on air currents, when the spores come in contact with a solid or liquid surface, they are deposited and if conditions of moisture are right, they can germinate (Kanaani

et al., 2008). Fungi, like animals, are heterotrophic and while animals eat their food and then digest it, fungi do the opposite in that they digest their food and then ‘‘eat’’ it. They are most often found in terrestrial habitats and are commonly isolated from soil and associated plant litter, the decomposition process of which is important in driving natural cycling of chemical elements, particularly the carbon cycle where they contribute to replenishment of the supply of carbon dioxide and other inorganic compounds (Carroll & Wicklow, 1992).

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Maximum decomposition occurs when there is sufficient nitrogen, phosphorus and other essential inorganic nutrients. Aspergillus and other moulds play an important role in these consortia because they are adept at recycling starches, hemicelluloses, celluloses, pectins and other sugar polymers. Species within the genus Aspergillus have a large chemical repertoire. Commodity products produced in Aspergillus cell ‘‘factories’’ include citric, gluconic, itaconic and kojic acid. The use of Aspergillus niger in citric acid production dates back to Currie (1917); the history of the development of the fermentation process from stationary cultures to submerged fermentation has been reviewed by Bentley & Bennett (2008). Citric acid is one of the most widely used food ingredients and is commonly used in the pharmaceutical and cosmetic industries as an acidulant and a hardener. Aspergillus niger has also found use in the industrial production of gluconic acid, which is used as an additive in certain metal cleaning applications, as well as for the therapy for calcium and iron deficiencies. Several Aspergillus secondary metabolites also have major economic importance of which the statins and their derivatives are most profitable (Tobert, 2003). These cholesterol lowering drugs are now among the mostly widely used medicines. Other compounds with pharmacological activities include cholecystokinin and neurokinin antagonists, ion channel ligands, antifungal drugs and a host of other compounds. Taxol producing endophytes Taxol, a highly functionalized diterpenoid, is found in each of the world’s yew (Taxus) species (Suffness, 1995). It is used to treat a number of human tissue-proliferating diseases, however, its cost makes it unavailable to many people worldwide. Therefore, alternative resources are needed in view of uneconomic organic synthesis and low-production, its expensive chemical isolation coupled with mass destruction to the natural habitat (Strobel, 2003). Fortunately, taxolproducing endophyte Taxomyces andreanae has been isolated from the phloem (inner bark) of the Pacific yew, Taxus brevifolia (Stierle et al., 1993). Since then, several research groups have successively reported their findings on taxolproducing endophytes. The interesting thing about taxol production from Pestalotia heterocornis is that it was isolated from the soil collected in yew forest (Noh et al., 1999). Therefore, as a successful clinical drug, based on numerous publications about taxol use in the treatment of a number of human malignant diseases, the study on endophytic fungi producing taxol will always be significant and important in plant–microbe interaction (Vennila et al., 2012). The latest review on taxol production from endophytic fungi was published by Rajendran et al. (2013). The studies of taxol derived from endophytic fungi between 2010 and 2013 were investigated as follows: the characterization of the studies was the discovery of new source for producing taxol. The taxol derived from an endophytic fungus, Pestalotiopsis pauciseta Sacc. VM1 was isolated from a medicinal plant Tabebuia pentaphylla Hemsl. Based on estimation and evaluation of series of enzymic and non-enzymic antioxidants (i.e. related to tumors), the results showed that the fungal taxol was found to be effective against 7,12-dimethylbenz(a)anthracene induced mammary tumors in Sprague–Dawley rats (Vennila

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et al., 2010). Fusarium culmorum SVJM072, producing taxol, was identified based on the morphology of the fungal culture, mechanism of spores production, characteristics of the spores and molecular characterization. The fungal Taxol showed strong activity against human cancer cell lines by MTT assay (Sonaimuthu et al., 2010). In 2011, an endophytic fungi Colletotrichum capsici, producing taxol, was isolated from the diseased fruits of Chili plant Capsicum annuum. The maximum amount of fungal taxol production was recorded as 687 mg/l, which was 13 740-fold higher than that previously reported for the fungus Taxomyces andreanae. Hence, the fungus C. capsici is an excellent candidate for an alternate source of taxol supply and can serve as a potential species for genetic engineering to enhance the production of taxol to a higher level (Kumaran et al., 2011). A new endophytic taxoland baccatin III-producing fungus was isolated from Taxus chinensis var. mairei. The fungus was identified as one of Didymostilbe sp. (designated as DF110) by its morphological characteristics (Wang & Tang, 2013). Interestingly, in 2012, an endophytic fungus producing taxol Fusarium oxysporum was isolated from Rhizomphora annamalayana and was identified by its morphology and spore characteristics (Elavarasi et al., 2012). In the same year, a new endophytic taxol-producing fungus of Stemphylium sedicola SBU-16 was collected from Taxus baccata (Mirjalili et al., 2012). In addition, an endophytic producing taxol fungus of Phoma betae was isolated from the leaves of Ginkgo biloba (Kumaran et al., 2012). In 2013, new endophytic producing taxol fungi were isolated from plants in succession, such as Pestalotiopsis microspora EF01, which was isolated from fresh healthy leaves of Plectranthus amboinicus (Rajendran et al., 2013).

Secondary metabolites with antitumor effects of endophytic fungi in medicinal plants Alkaloids and nitrogen-containing heterocycles Plant-derived alkaloids exhibit a wide range of biological activities including toxic, medicinal and recreational. Many plant alkaloids have been studied as potential anticancer agents (Kharwar et al., 2011) and until 2010, at least dozens of alkaloids were isolated from endophytic fungi. The antitumor mechanism of some alkaloids compounds have been uncovered and of some have been explored as commercial drugs for use in clinical application for targeting tumors such as Camptothecin 2 (CPT), Vincristine 5. In recent years, several new alkaloids with antitumor activity have been isolated from endophytic fungi. Beauvercin (1), isolated from Fusarium oxysporum, showed cytotoxicity against PC-3, PANC-1 and A549 with IC50 value of 49.5 ± 3.8, 47.2 ± 2.9 and 10.4 ± 1.6 mm, respectively (Wang et al., 2011a,b). One dioxopiperazine alkaloid, 12-demethyl-12-oxo-eurotechinulin B (2) and two alkaloid compounds variecolorin G (3), alkaloid E-7 (4) (Wang et al., 2007) were isolated from an endophytic fungus of Eurotium rubrum from the inner tissue of Hibiscus tiliaceus. The three compounds displayed cytotoxic activities against SMMC-7721, HepG2 and NCI-H460, MCF-7, NCI-H460, SMMC-7721 and HeLa cell lines, respectively (Yan et al., 2012).

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Camptothecine (Campothecin, CPT), a quinoline alkaloid, is a potent inhibitor of eukaryotic topoisomerase I. Three endophytic fungi, Fomitopsis sp., Alternaria alternate and Phomposis sp. were isolated from fruit and seed regions of Miquelia dentata (Icacinaceae). They produce CPT (5), 9-methoxy CPT (9-MeO-CPT) (6) and 10-hydroxy CPT (10-OH-CPT) (7), respectively. Methanolic and ethyl acetate extracts of these fungal species are cytotoxic to colon and breast cancer cell lines (Shweta et al., 2013). Three novel azaphilone alkaloids, chaetomugilides A–C (8–10), together with chaetoviridin E (11) and one related compound was isolated from an endophytic fungus of Chaetomium globosum TY1 isolated from Ginkgo biloba. Chaetomugilides A showed significant cytotoxicity against HepG2 with IC50 values of 1.7 lM, chaetomugilides B, C and chaetoviridin E and one related compound showed moderate cytotoxicity with IC50 values ranging from 19.8 to 53.4 lM (Li et al., 2013). One novel alkaloid, mycoleptodiscin B (12), was isolated from endophytic fungus Mycoleptodiscus sp. which was isolated from Desmotes incomparabilis. Mycoleptodiscin B was active in inhibiting the growth of cancer cell lines with IC50 values in the range 0.600.78 mm (Ortega et al., 2013). Citriquinochroman (13) was isolated from the endophytic fungus Penicillium citrinum grown on rice and white bean media. It features a new skeleton, consisting of quinolactacide and (3S)-6-hydroxy-8-methoxy-3,5-dimethylisochroman linked by a CC bond. The fungus Penicillium citrinum was collected from a fresh stem of the Moroccan plant Ceratonia siliqua. The Citriquinochroman showed cytotoxicity against the murine lymphoma L5178Y cell line with an IC50 value of 6.1 mm (El-Neketi et al., 2013) Pestalactams A and B (14,15), isolated from the endophytic fungus Pestalotiopsis sp., were tested against the mammalian cell lines, MCF-7 and NFF, and showed modest in vitro activity in all assays (Davis et al., 2010). Two cytochalasans analogues, aspochalasins D (16) and J (17) were isolated from the culture of Trichoderma gamsii, which was obtained from the traditional Chinese medicinal plant Panax notoginseng. The two compounds displayed inhibitory activity against the HeLa cells with an IC50 value of 5.72 and 27.4 mm, respectively (Ding et al., 2012). Coumarins A new furanocoumarin, 5-methyl-8-(3-methylbut-2-enyl) furanocoumarin (18), was isolated from the mangrove endophytic fungus, Penicillium sp. ZH16. The compound exhibited cytotoxicity against KB and KBV200 cells in vitro with IC50 values 5 and 10mgml1, respectively (Huang et al., 2012). A polyoxygenated benzofuran-3(2H)-one dimer, arundinone B (19), was isolated from the extract of a plant endophytic fungus, Microsphaeropsis arundinis. Arundinone B, showing cytotoxicity against T24 and A549 cells (Luo et al., 2013). Lactones Cytospolide P (20) is a nonanolide isolated from Cytospora sp., an endophytic fungus from Ilex canariensis. In an in vitro

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cytotoxicity assay toward the tumor cell lines of A549, HCT116, QGY, A375 and U973, the -lactone 17 demonstrated a potent growth inhibitory activity toward the cell line A-549, while nonanolide 16 (Cytospolides P) with (2S) configuration showed the strongest activity against cell lines A-549, QGY and U973. A cell cycle analysis indicated that compound Cytospolides P can significantly mediate G1 arrest in A549 tumor cells, confirming the important role of the C-2 methyl in the growth inhibition toward the tumor line (Lu et al., 2011). A new macrolide, colletotriolide (21), was isolated from the endophytic fungus Colletotrichum sp. isolated from Pandanus amaryllifolius. Dothiorelone C (22) and cytosporone (23) were isolated from the fungus Chaetomium globosum. The two fungi were isolated from the leaves of Pandanus amaryllifolius. The colletotriolide, dothiorelone C and cytosporone were inactive against the A549, HT29 and HCT116 cell lines (Bungihan et al., 2013). Seven new azalomycin F analogs, 25-malonyl demalonylazalomycin F5a monoester (24), 23-valine demalonylazalomycin F5a ester (25), 23-(6-methyl)heptanoic acid demalonylazalomycins F3a ester (26), F4a ester (27) and F5a ester (28), 23-(9-methyl) decanoic acid demalonylazalomycin F4a ester (29) and 23-(10-methyl) undecanoic acid demalony lazalomycin F4a ester (30) were isolated from endophytic fungus Streptomyces sp. 211726. Biological assays indicate that these seven compounds display broadspectrum antimicrobial and anti HCT-116 activities in vitro with IC50 values of 1.81–5.00 mg/ml (Yuan et al., 2013). Peptides Verticillin D (31), depsipeptides pullularin A (32), C (33) was isolated from endophytic fungus Bionectria ochroleuca and it was separated from the inner leaf tissues of the plant Sonneratia caseolaris (Sonneratiaceae). Cytotoxic activities test revealed the Verticillin D showed pronounced cytotoxic activities against the tested cell line L5178Y. Antiproliferative properties were also prevalent among the cyclic depsipeptides pullularin A, C and chloro-derivative of pullularin E (34) with EC50 values ranging between 0.1 and 6.7 mg/ml (Ebrahim et al., 2012). Beauvericin (1) is a depsipeptide isolated from mangrove endophytic fungus Aspergillus terreus (No. GX7-3B) and was separated from a branch of Bruguiera gymnoihiza (Deng et al., 2013). It has also previously been isolated from several other fungi (Kharwar et al., 2011). The compound exhibited moderate cytotoxic activities against MCF-7, A549, HeLa and KB cell lines with IC50 values 2.02 (MCF-7), 0.82 (A549), 1.14 (HeLa) and 1.10 mm (KB). Peroxides Two norsesquiterpene peroxides, talaperoxides B (35) and D (36) were isolated from an endophytic fungus, Talaromyces flavus which was collected from mangrove plant Sonneratia apetala. The evaluation of cytotoxic activities in vitro against human cancer cell lines revealed that the two compounds showed cytotoxicity against the five human cancer cell lines (MCF-7, MDA-MB-435, HepG2, HeLa and PC-3) with IC50 values between 0.70 and 2.78 mg/ml (Li et al., 2011).

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One chamigrane endoperoxide merulin C (37) was isolated from a Thai mangrove-derived fungus and it exhibited potent antiangiogenic activity mainly by suppression of endothelial cell proliferation and migration in a dose-dependent manner, and its effect is mediated by reduction in the phosphorylation of Erk1/2 (Chokpaiboon et al., 2011). Polyketides The first natural S-containing benzophenone dimer guignasulfide (38) was isolated from an endophytic fungus Guignardia sp. IFB-E028, which resides in healthy leaves of Hopea hainanensis. The compound displayed cytotoxic activity against the human liver cancer cell line HepG2 (IC50 value: 5.2 ± 0.4 mm; Wang et al., 2010). One polyketide derivatives penicitide A (39) has been isolated from Penicillium chrysogenum QEN-24S, an endophytic fungus separated from an unidentified marine red algal species of the genus Laurencia. It exhibited moderate cytotoxic activity against the human hepatocellular liver carcinoma cell line (Gao et al., 2011). Chaetoglobosins belongs to the cytochalasin family and has an affinity for Actin filaments. The basic structure derives from a C18 polyketide, linked to an amino-acid. Chaetoglobosin X (40) was isolated from an endophytic fungus, Chaetomium globosum from the medicinal plant Curcuma wenyujin. The compound exhibited strong cytotoxic activity against H22 and MFC cancer cell lines (Wang et al., 2012).

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by one- and two-dimensional NMR spectroscopy, MS data analysis and circular dichroism measurements. In bioassays, alterporriol K and L exhibited moderate cytotoxic activity towards MDA-MB-435 and MCF-7 cells with IC50 values ranging from 13.1 to 29.1 mm (Huang et al., 2011a). One new anthraquinone derivative, 9-dehydroxyeurotinone (49) and one anthraquinone compound emodin (50) was isolated from an endophytic fungus of Eurotium rubrum from the inner tissue of Hibiscus tiliaceus. The two compounds displayed cytotoxic activities against SW1990 and Du145 cell lines respectively (Yan et al., 2012). Altersolanol A (51), a natural product from the endophytic fungus Stemphylium globuliferum, shows cytotoxic activity against human chronic myeloid K562 leukemia and A549 lung cancer cells. It was isolated from the medicinal plant Mentha pulegium (Lamiaceae), Altersolanol A induces cell death by apoptosis through the cleavage of caspase-3 and -9 and through the decrease of anti-apoptotic protein expression (Teiten et al., 2013). Steroids

A new benzopyran, (2R*,4R*)-3,4-dihydro-4-methoxy-2methyl-2H-1-benzopyran-5-ol (41) was isolated from the culture of Nodulisporium sp. A4, an endophytic fungus from the stem of Aquilaria sinensis. The compound exhibited weak cytoxicity (ca. 57.9% inhibition rate) against the SF-268 cell line at the concentration of 100 mg/ml, compared with the positive control, cisplatin (Wu et al., 2010). The isolated compounds of pyrones or its derivatives were mainly from the endophytic genus Aspergillus. Three a-pyrone derivatives nigerapyrones B (42), D (43), E (44) and one known congener, asnipyrone A (45), were isolated from Aspergillus niger MA-132, an endophytic fungus obtained from the fresh tissue of the marine mangrove plant Avicennia marina. The four compounds showed weak cytotoxicity against some of the tested tumor cell lines (MCF-7, HepG2, Du145, NCI-H460 and MDA-MB-231 cell lines; Liu et al., 2011a). One known monomeric naphtho-g-pyrones, TMC 256 A1 (46) from the mangrove endophytic fungus Aspergillus tubingensis (GX1-5E) displayed inhibitory activities against tumor cell lines of MCF-7, MDA-MB-435, Hep3B, Huh7, SNB19 and U87 MG with IC50 values between 19.92 and 47.98 mm in the in vitro cytotoxicity assays (Huang et al., 2011b).

Penicisteroids A (52) and B, two new polyoxygenated steroids, were obtained from the culture extract of Penicillium chrysogenum QEN-24S, an endophytic fungus isolated from an unidentified marine red algal species of the genus Laurencia. Penicisteroid A displayed potent antifungal and cytotoxic activity in the preliminary bioassays (Gao et al., 2011). Two new 6,8(14),22-hexadehydro-5a,9a-epidioxy-3,15dihydroxy sterols, nigerasterols A (53) and B (54) were isolated from Aspergillus niger MA-132, an endophytic fungus from mangrove plant Avicennia marina. Nigerasterol B displayed potent activity against the tumor cell line HL60 with an IC50 value of 1.50 mm, nigerasterol A displayed stronger activity with an IC50 value of 0.30 mm. Both of two compounds exhibited potent activities against A549 cell line with IC50 values of 1.82 and 5.41 mm, respectively (Liu et al., 2013). In the same year, 3b,5a-dihydroxy-(22E,24R)ergosta-7,22-dien-6-one (55) a phytoecdysteroids was isolated from mangrove endophytic fungus Aspergillus terreus (No. GX7-3B), and it was separated from a branch of Bruguiera gymnoihiza. The compound exhibited strong cytotoxic activities against MCF-7, A549, HeLa and KB cell lines with IC50 values 4.98 (MCF-7), 1.95 (A549), 0.68 (HeLa) and 1.50 mm (KB; Deng et al., 2013). (22E,24R)-8,14-epoxyergosta-4,22-diene-3,6-dione (56) was isolated from Papulaspora immerse and it was separated from roots and leaves of Smallanthus sonchifolius (Asteraceae). The compound showed the highest cytotoxic activity against the human tumor cell lines MDA-MB435 (melanoma), HCT-8(colon), SF295 (glioblastoma) and HL-60 (promyelocytic leukemia), with IC50 values of 3.3, 14.7, 5.0 and 1.6 mm, respectively (Borges Coutinho Gallo et al., 2010).

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Alterporriol K (47) and L (48), anthraquinone compounds, were separated from extracts of the endophytic fungus Alternaria sp. ZJ9-6B which was isolated from the mangrove Aegiceras corniculatum. Their structures were elucidated

Two isopimarane diterpenes, 19-(2-acetamido-2-deoxy-a-Dglucopyranosyloxy)isopimara-7,15-dien-3b-ol (57) and 19(a-D-glucopyranosyloxy) isopimara-7, 15-dien-3-one (58), were isolated from the endophytic fungus Paraconiothyrium

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sp. MY-42 showed moderate cytotoxicities against the human promyelocytic leukemia cell line HL60 (Shiono et al., 2011). Two diterpenes, sphaeropsidins A (59) and D (60), were isolated from an endophytic fungal strain, Smardaea sp. AZ0432, occurring in living photosynthetic tissue of the moss Ceratodon purpureus. Together with one sphaeropsidins A derivative, 6-O-acetylsphaeropsidin A (61), the three compounds were evaluated for their potential anticancer activity using several cancer cell lines and cells derived from normal human primary fibroblasts. The results revealed that the three compounds showed significant cytotoxic activity. More importantly, sphaeropsidin A showed cell-type selectivity in the cytotoxicity assay and inhibited migration of metastatic breast adenocarcinoma (MDA-MB-231) cells at subcytotoxic concentrations (Wang et al., 2011a,b). Sesquiterpenes Three tremulane sesquiterpenes ceriponols F (62), G (63) and K (64) were isolated from the cultures of Ceriporia lacerate, a fungal endophyte residing in the stems of the medicinal plant Huperzia serrata. Ceriponols F and K exhibited moderate cytotoxicity against HeLa, HepG2 and SGC 7901 with IC50 values ranging from 32.3 ± 0.4 to 173.2 ± 1.5 lM, while ceriponol G showed slightly better cytotoxicity against a HeLa cell line (Ying et al., 2013). 2,14-Dihydrox-7-drimen-12,11-olide (65) was isolated from an endophytic fungus Aspergillus glaucus which was collected from the leaves of Ipomoea batatas. In vitro antitumor assay showed that the active compound has moderate cytotoxic effect against Hep-G2 cell IC50 value 61 mg/ml, and it strongly affects the growth of MCF-7 cells, IC50, 41.7 mg/ml (Asker et al., 2013). Triterpenes Xylariacins A–C (66–68), three new triterpenes, were isolated from the fermentation extract of an endophytic fungus Xylarialean sp. A45. Their structures were determined by spectroscopic analyses, 1D- and 2D-NMR and HR-ESI-QTOF mass spectrometry. The in vitro cytotoxic activities of Xylariacins A–C were tested against human tumor cell line HepG2, and these compounds showed modest cytotoxic activity (Lin et al., 2011). Two new terpenoids, (+)-(3S,6S,7R,8S)-periconone A (69) and ()- (1R,4R,6S,7S)-2-caren-4,8-olide (70), were isolated from an endophytic fungus Periconia sp. which was collected from the plant Annona muricata. In the in vitro assays, the two compounds showed low cytotoxic activities against six human tumor cell lines (HCT-8, Bel-7402, BGC-823, A549, A2780 and MCF-7) (Ge et al., 2011). Others Siccayne [2-(3-Methyl-3-buten-1-ynyl) hydro] (71) is an alkyne isolated from endophytic fungus Pestalotiopsis fici. The compound showed cytotoxic activity against the human cancer cell lines, HeLa and HT29, with IC50 values of 48.2 and 33.9 mm, respectively (Liu et al., 2013). (R)-5-Hydroxy-2-methylchroman-4-one (72), from an endophytic Cryptosporiopsis sp. which was isolated from Clidemia hirta, exhibited significant cytotoxic activity against

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the human leukemia cell line, HL-60 with an IC50 of 4 lg/ml. This compound induced G2 arrest of the HL-60 cell cycle significantly (Zilla et al., 2013). Botryorhodine A (73) and B (74) were isolated from Botryosphaeria rhodina which was from the stems of the medicinal plant Bidens pilosa (Asteraceae). The two compounds show moderate to weak cytotoxic activities against HeLa cell lines with a CC50 of 96.97 mm and 36.41 mm, respectively (Abdou et al., 2010). Four isoprenylated epoxyderivatives Pestalofones F–H (75–77) and pestalodiols C (78) were isolated from endophytic fungus Pestalotiopsis fici. Cytotoxicity test revealed the four compounds showed cytotoxicity against HeLa and MCF-7 cells (Liu et al., 2011b). Cajanol, 5-hydroxy-3-(4-hydroxy-2-methoxyphenyl)-7methoxychroman-4-one (79), is an iso-flavone from an endophytic fungus Hypocrea lixii which was isolated from Cajanus cajan. The compound possessed stronger cytotoxicity activity towards A549 cells in time- and dose-dependent manners (Zhao et al., 2013). Podophyllotoxin, the aryl tetralin lignin, is normally used as precursor of some anticancer drugs like etoposide, teniposide and etopophos phosphate. A new endophytic podophyllotoxin-producing fungus of Fusarium solani was isolated from roots of Podophyllum hexandrum (Nadeem et al., 2012). Pestalrone B (80), an oxysporone derivative, was from the endophytic plant fungus Pestalotiopsis karstenii and was isolated from stems of Camellia sasanqua. The compound exhibited significant activities against HeLa, HepG2 and U-251 with IC50 values of 12.6, 31.7 and 5.4 mg/ml, respectively (Luo et al., 2012). (6aR, 6bS, 7S)-3,6a,7,10-tetrahydroxy-4,9-dioxo-4,6a,6b, 7,8,9-hexahydroperylene (81) was isolated from the endophytic fungus Alternaria tenuissima, which was separated from the bark of Erythrophleum fordii. The compound showed selective cytotoxic activity on human colon cancer cell HCT-8 (IC50 ¼ 1.78 mmol/l) by MTT test in vitro (Fang et al., 2012). One new tricycloalternarene derivatives, guignarenone A (82) was isolated from the endophytic fungus Guignardia bidwellii PSU-G11. The compound displayed mild cytotoxic activity against oral cavity cancer and African green monkey kidney fibroblast (Vero) cell lines (Sommart et al., 2012).

Optimization strategy of targeted endophytic fungi The screening and isolation of the endophytic fungi with antitumor activity is only the prophase of research. However, the economic production of the target antitumor chemicals is the key to the application of these findings. Currently, fermentation and optimization of the culture conditions are the main direction to increase the production. Solid-state fermentation (SSF) and pulse fed-batch methods are popular strategies for production of targeted antitumor chemicals from related endophytic fungi. Solid-state fermentation Fermentation processes may be divided into two systems: submerged fermentation (SmF), which is based on the microorganisms cultivation in a liquid medium containing

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nutrients, and SSF, which consists of the microbial growth and product formation on solid particles in the absence (or near absence) of water; however, substrate contains the sufficient moisture to allow the microorganism growth and metabolism (Pandey, 2003). It is found to be ideal when the organism is a fungus and the substrate is insoluble. Production of bioactive compounds by fermentation is an alternative that merits attention, since it is able to provide high-quality and high-activity extracts while precluding any toxicity associated to the organic solvents. In this process, bioactive compounds are obtained as secondary metabolites produced by microorganisms after the microbial growth is completed. Studies on liquid culture show that the production of these compounds is limited by the exhaustion of one key nutrient: carbon, nitrogen or phosphate source (BarriosGonza´lez et al., 2005). In recent years, SSF has received more interest from researchers since several studies have demonstrated that this process may lead to higher yields and productivities or better product characteristics than SmF. In addition, due to the utilization of low-cost agricultural and agroindustrial residues as substrates, capital and operating costs are lower compared to SmF. The low water volume in SSF also has a large impact on the economy of the process mainly due to smaller fermenter-size, reduced downstream processing, reduced stirring and lower sterilization costs (Ho¨lker & Lenz, 2005; Pandey, 2003; Raghavarao et al., 2003). The main drawback of this type of cultivation concerns the scaling-up of the process, largely due to heat transfer and culture homogeneity problems (Di Luccio et al., 2004; Mitchell et al., 2000). However, research attention has been directed towards the development of bioreactors that overcome these difficulties. Pulse fed-batch methods Solid-state fermentation (SSF) is not suitable for all endophytic fungi. For example, some filamentous fungi are sources of novel bioactive natural compounds (Schulz et al., 2002), but their exploitation has been hampered by inadequate supplies (Couto & Toca-Herrera, 2007). To harvest enough bioactive compounds for pharmaceutical research, optimization of cultivation of marine filamentous fungi is necessary (Bhadury et al., 2006). In 2011, 1403C (also called SZ-685C), a novel anthraquinone derivative was isolated from cultures of the marinederived mangrove endophytic filamentous fungus Halorosellinia sp. (No. 1403) was investigated to improve its yields. It is a potential Akt (protein kinase B, PKB) inhibitor and anti-cancer drug candidate (Xie et al., 2010), however, not enough 1403C is available for pre-clinical studies. In a study by Kang et al., the inhibitory effect of high glucose levels on 1403C biosynthesis was avoided, and 1403C yields were improved by using a low initial glucose level and pulse feedings of glucose during cultivation.

Conclusions and perspectives As a new source of producing the antitumor compounds and potential key lead compounds for exploring the antitumor drugs, the endophytic fungi play an essential role in challenging the increase in the number of deaths associated

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with cancers and lowering the huge expense of anticancer therapy. This review has highlighted the occurrences, distributions, classification and characteristics of endophytic fungi which can produce antitumor compounds. Due to the huge economic value, from 2010 to 2013, nearly 100 studies on the bioactive metabolites of endophytic fungi were reported, covering most countries and regions, especially countries with rich biodiversities such as China and India. These studies refer to extensive host plants including lichen, fern, gymnosperm and flowering plants and at least 30 novel compounds were separated. Interestingly, several novel compounds with antitumor activities were separated from the endophytic fungi derived from the marine microbe, which has also raised concern. In view of much limited knowledge and massive unknown species of ocean, exploring endophytic fungi from the ocean will be extremely promising. In addition, the studies of the important antitumor agent taxol have been highlighted not only on the isolation of more strains of endophytic fungi (8 new endophytic fungi were isolated during 2010–2013) which can produce taxol, but also the improvement of culture conditions and fermentation engineering for the active endophytic fungi. Unfortunately, much of work reported on the anti-tumor activities of endophytic fungi was confined to in vitro studies, in vivo animal studies and human intervential trials are needed to find potential antitumor chemicals. In the future, studies on the isolation and identification of new endophytic fungi strains which can produce antitumor compounds will be of great interest to the researchers. On the other hand, the cultivation of the endophytic fungi which can produce antitumor compounds, the improvement of the fermentation conditions, the continuously new findings of antitumor compounds and the study on the antitumor mechanism will provide a broadly promising chance for challenging the life crisis of cancer. Therefore, some fundamental questions in endophyte need to be addressed over the next several decades, such as:  How to set up a guide in the screening of endophytic fungi producing antitumor agents other than screening uncritically?  How to solve the degradation problem of desired metabolites production of endophytic fungi?  What is the intrinsic relationship between endophytic fungi and their host plant?  What is the biosynthetic pathways which produce bioactive secondary metabolites in endophytic fungi?  What are the possible mechanisms by which endophytic fungi are likely to exert anti-tumor activity? We believe that there are good prospects for obtaining new insights into drug discovery and clinical utility by the continued study of endophytes, which has the potential of playing a key front line role in the prevention and treatment of cancer.

Declaration of interest The authors declare that they have no conflict of interests. This article was supported by TCM Modernization

DOI: 10.3109/1040841X.2014.959892

Foundation of Science and Technology Commission of Shanghai (No. 14401902900 and No. 13401900102), the Young Scientist Special Project of the National High Technology Research and Development Program of China (No. 2014AA020508) and ‘‘Chen Guang’’ project supported by Shanghai Municipal Education Commission and Shanghai Education Development Foundation (13CG40).

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Endophytic fungi with antitumor activities: Their occurrence and anticancer compounds.

Plant endophytic fungi have been recognized as an important and novel resource of natural bioactive products, especially in anticancer application. Th...
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