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4 January 2022

Putative Anticancer Compounds from Plant-Derived Endophytic Fungi: A Review

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Department of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
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Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA 19140, USA
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Department of Pharmacy, University of Asia Pacific, Dhaka 1215, Bangladesh
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Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
Molecules2022, 27(1), 296;https://doi.org/10.3390/molecules27010296
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Abstract

Endophytic fungi are microorganisms that exist almost ubiquitously inside the various tissues of living plants where they act as an important reservoir of diverse bioactive compounds. Recently, endophytic fungi have drawn tremendous attention from researchers; their isolation, culture, purification, and characterization have revealed the presence of around 200 important and diverse compounds including anticancer agents, antibiotics, antifungals, antivirals, immunosuppressants, and antimycotics. Many of these anticancer compounds, such as paclitaxel, camptothecin, vinblastine, vincristine, podophyllotoxin, and their derivatives, are currently being used clinically for the treatment of various cancers (e.g., ovarian, breast, prostate, lung cancers, and leukemias). By increasing the yield of specific compounds with genetic engineering and other biotechnologies, endophytic fungi could be a promising, prolific source of anticancer drugs. In the future, compounds derived from endophytic fungi could increase treatment availability and cost effectiveness. This comprehensive review includes the putative anticancer compounds from plant-derived endophytic fungi discovered from 1990 to 2020 with their source endophytic fungi and host plants as well as their antitumor activity against various cell lines.

1. Introduction

In 1866, de Bary introduced the term “endophyte” [1]. An endophyte may be a fungal or bacterial microorganism that colonizes various interior parts of plants causing no apparent pathogenic effects on its host plants. The endophytes, most commonly endophytic fungi, are believed to help plants adapt to abiotic factors (high temperature and salinity, drought, metal toxicity, and harmful effects of light) as well as biotic factors (herbivores, insects, nematodes, and pathogens). This is mainly achieved by the secondary bioactive metabolites produced by the endophytic fungi. In their symbiotic relation, the endophytes are fed and protected by the host plant, and in return, these microorganisms produce bioactive secondary metabolites, enhancing the growth of the host plant and protecting the plant from pathogens and herbivores [2]. Therefore, endophytic fungal metabolites can also be exploited as drugs for the treatment of various types of human diseases, including cancer [3].
This group of microorganisms has drawn tremendous attention from researchers since the isolation, culture, purification, and characterization of this fascinating group of microorganisms revealed the presence of hundreds of important and diverse chemical classes of compounds. The interest of scientists in endophytes is also growing as they are a good reservoir of bioactive metabolites [4,5]. Until now, many cytotoxic agents including paclitaxel (also known as Taxol) [6] have been isolated from endophytes. Secondary metabolites with cytotoxic properties have the potential to be explored as anticancer drugs.
Recent studies revealed that naphthoquinone derivatives fusarubins including anhydrofusarubin and fusarubin (FUS) produced by endophytic fungi Cladosporium species [7] and Fusarium species [8] showed promising cytotoxicity against cancer cells. Although FUS was reported earlier to have antibacterial activity, its cytotoxic activity was reported recently. Very recently, for the first time, we have revealed the molecular mechanism of cytotoxic action of fusarubin isolated from a Cladosporium species inhabiting the leaves of Rauwolfia serpentina. We have reported that fusarubin and anhydrofusarubin inhibit proliferation and increase apoptosis in leukemia and other hematological tumor cells lines in different manners through the p21/p53-mediated pathway [9]. Our findings urge us to write this review on endophytic fungal metabolites as a fascinating group of bioactives or putative anticancer compounds. Many of these putative anticancer compounds have very promising cytotoxicity against a broad spectrum of cancer cell lines; some compounds are already used as treatments for different cancer types such as breast, bladder, colorectal, esophageal, lung, ovarian, prostate, melanoma, testicular, leukemia, and lymphoma.

2. Anticancer Activity of Endophytic Fungi

Endophytic fungi have been a known source of anticancer agents since the discovery of the valuable drug Taxol (also known as paclitaxel, a diterpenoid) isolated for the first time from an endophytic fungus Taxomyces andreanae obtained from the Pacific Yew bark (Taxus brevifolia) [6]. Since then, other anticancer drugs have been isolated from endophytic fungi, and among these 9-methoxycamptothecin and 10-hydroxycamptothecin from Fusarium solani [10], camptothecin from Entrophospora infrequens [11]; the anticancer lead compounds podophyllotoxin from Phialocephala fortinii [12] and deoxypodophyllotoxin from Aspergillus fumigatus [13] fueled further research on endophytic fungi to discover many other important known and novel anticancer compounds. According to this review, until now, more than 100 different fungal species have been identified to produce more than two hundred putative anticancer compounds (Figure 1 and Figure 2) reported to possess antiproliferative and/or cytotoxic properties against more than 60 different cell lines (Table 1, Table 2 and Table 3). Figure 1 indicates that endophytic fungal-derived anticancer agents gained attention from scientists over the past three decades. Meanwhile, Figure 2 represents the abundance of different chemical classes and diversity of fungal metabolites. The anticancer compounds isolated from endophytic fungi are effective against diverse cell lines that could be helpful in combating any particular type of cancer (Table 1).
Figure 1. Discovery of anticancer agents from endophytic fungi over time.
Figure 2. Relative abundance of anticancer agents from endophytic fungi.
Table 1. Different cell lines against which endophytic fungal derived metabolites showed cytotoxicity.
Table 2. Anticancer compounds from plant-derived endophytic fungi.
Table 3. Recently (2018–2020) reported potential cytotoxic metabolites isolated from medicinal-plant-associated endophytic fungi.
The genera of endophytic fungi containing two or more putative anticancer-agent-producing species are Acremonium, Alternaria, Aspergillus, Ceriporia, Chaetomium, Colletotrichum, Cytospora, Emericella, Eurotium, Eutypella, Fusarium, Guignardia, Hypocrea, Penicillium, Pestalotiopsis, Phomposis, Periconia, Stemphylium, Talaromyces, Thielavia, and Xylaria [4,221]. These endophytic fungi offer an alternative source of bioactive compounds. We may be able to increase their yield of specific anticancer compounds by employing biotechnology and genetic engineering [221].

2.1. Anti-Cancer Agents in Clinical Use Shared by Plants and Endophytic Fungi

Plants are prolific sources of anticancer agents. In the area of cancer, of the 175 approved small molecules over the years from the 1940s to 2014, 75% (131) are other than synthetic and 49% (85) are either natural products or their derivatives [222]. Very recently, it was reported that among the approved 321 anticancer molecules from all sources during the period of 1946 to 2019, 35 (10.9%) were unaltered natural products and 65 (20.2%) were natural product derivatives compared to 53 (16.5%) completely synthetic drug molecules. Some of these agents obtained from plants are also found in their corresponding endophytic fungi. The following are some examples of plant/endophytic fungi-derived cancer effective agents [1,6] (Figure 3a,b).
Figure 3. Anticancer compounds of different chemical classes from endophytic fungi-alkaloidal compounds and their derivatives: (a) (1–8), benzo[j]fluoranthene (9), Chromone (10), coumarin (11), depsidones (12, 13), depsideptide (14), ergochromes (15, 16), ester (17), lactones (18–22), lignans (23–24), peptide (25), polykedites (26); (b) polyketides (27–32), quinones (33–39), spirobisnaphthalenes (40–42), terpenes (43–54), xanthones (55), naphthoquinones (56, 57).
Paclitaxel (Taxol®) is used in combination with other anti-cancer drugs in ovarian, breast, non-small cell lung cancer (NSCLC), and Kaposi sarcoma. An active paclitaxel analogue, docetaxel is used in breast and non-small cell lung cancer (NSCLC) treatment [223]. Even though camptothecin exerted severe bladder toxicity in its clinical trial in the 1970s and therefore, was dropped, its two water-soluble derivatives, topotecan and irinotecan, have been shown to be more effective anti-cancer agents and are being utilized for these purposes [223]. Topotecan (Hycamtin®) was the first CPT derivative that was orally available and has been approved for cervical (when used in combination with cisplatin), ovarian, and non-small cell lung cancer treatment. Irinotecan (Camptosar®) has been approved for colorectal cancer treatment. These agents show cytotoxicity on account of their ability to inhibit a fundamental enzyme, topoisomerase-I, involved in the winding and unwinding process of DNA during replication or protein synthesis [1,223]. The vinca alkaloids, vinblastine and vincristine, and their semi-synthetic analogs, vinorelbine and vindesine, are primarily used in combination with other chemotherapeutic drugs in the treatment of advanced testicular cancer, breast cancer, Kaposi’s sarcoma, lung cancer, leukemias, and lymphomas [223]. Etoposide and teniposide are clinically effective semi-synthetic derivatives of a podophyllotoxin isomer, epipodophyllotoxin, which are used in bronchial cancers, lymphomas, and testicular cancer treatments [223].

2.2. Putative Anticancer Compounds from Endophytic Fungi

2.2.1. Alkaloids and Nitrogen-Containing Heterocycles

Camptothecin (CPT) (1), a pentacyclic quinoline alkaloid, was, at first, isolated from the Camptotheca acuminata (happy tree) woods showing antileukemic and anti-cancer effects in animals [1]. It exerts its cytotoxicity by inhibition and dissociation of the DNA-topoisomerase-I complex during DNA replication [224,225]. However, recently, CPT has been isolated from some endophytic fungi, Entrophospora i., residing in these plants. Since Entrophospora i. also lives inside the inner bark of Nothapodytes foetida [11], in 2008, CPT was isolated from a Nothapodytes foetida seed endophyte, Neurospora c., and both authentic and fungal CPT exhibited comparable cytotoxic effects in human cancer cell lines HEP-2 (liver cancer), A549 (lung cancer), and OVCAR-5 (ovarian cancer) [96]. In 2009, CPT along with its two derivatives, 9-methoxycamptothecin and 10-hydroxycamptothecin, were isolated from a Camptotheca acuminata inner bark endophyte, Fusarium s. (Figure 3a). These derivatives are more water soluble and more potent inhibitors of the topoisomerase-I enzyme [80] (Table 2).
Cytochalasins (2a–2d) are fungal metabolites that inhibit cell division by means of inhibiting actin filament polymerization [226]. Four cytochalasins (cytochalasin 1, 2, 3, and E) have been isolated from an endophytic fungus, Rhinocladiella spp. from the Tripterygium wilfordii dead tree limbs and were tested against HCT-116 (colon tumor cell line), A2780S (ovarian tumor cell line), and SW-620 (colon tumor cell line) showing cytotoxic activities [136].
The vinca alkaloid (3a, 3b), vincristine (leurocristine), was isolated from Catharanthus roseus [227]. This alkaloid has also been isolated from some fungal endophytes of Catharanthus roseus such as Fusarium o. (inner bark), Mycelia s. 97CY(3) (Leaves), and Talaromyces r. CrP20 (Leaves) [74,75,89]. Vincristine irreversibly binds to the spindle proteins and microtubules during the S-phase of cell cycle hampering mitotic spindle formation and therefore arresting tumor cell division in the metaphase [1].
Chaetominine (4) was isolated from an endophyte, Chaetomium sp. IFB-E015 from the healthy leaves of Adenophora axilliflora, and it was cytotoxic against K562 (human leukemia cells) and SW1116 (human colon cancer cells) [54].
Cytochalasan-based alkaloids (5a–5c, 6), namely chaetoglobosin C, E, F, U, and penochalasin A (6), were obtained from the endophyte Chaetomium g. IFB-E019 residing inside the Imperata cylindrica healthy stem. Chaetoglobosin U was cytotoxically active against the KB cell line (human nasopharyngeal epidermoid tumor) with an IC50 value of 16.0 µM, whereas chaetoglobosin C (IC50 34.0 µM), E (IC50 40.0 µM), F (IC50 52.0 µM), and penochalasin A (IC50 48.0 µM) were moderately active against the KB cell line [57]. Endophytic fungus Chaetomium g. L18 from the plant Curcuma wenyujin produces chaetoglobosin X that exerted cytotoxic activity against H22 (hepatic cancer cells in mice) and MFC (gastric cancer cells in mice) cell lines [56] (Table 2).

2.2.2. Benzo[j]fluoranthenes

Daldinone C (9a) and D (9b) were discovered from an Artemisia Artemisia annua endophyte, Hypoxylon t. IFB-18, where both agents exerted strong cytotoxic action against the human colorectal cancer SW1116 cell line at IC50 values of 49.5 and 41.0 μM, respectively [85] (Table 2, Figure 3a).

2.2.3. Chromones

A novel chromone, Pestalotiopsone F (10), was isolated from an endophytic fungus Pestalotiopsis spp. associated with a mangrove plant Rhizophora mucronata. Pestalotiopsone F showed moderate cytotoxicity to L5178Y (murine cancer cell line) at an EC50 value of 8.93 μg/mL [110]. Pestaloficiol I, J, K, and L are new isoprenylated chromone derivatives discovered from a Camellia sinensis endophyte, Pestalotiopsis f., that displayed cytotoxicity against HeLa (Cervical cancer) and MCF-7 (Breast cancer) cell lines [115] (Table 2).

2.2.4. Coumarins

Arundinone B (11) was isolated from an endophyte Microsphaeropsis a. associated with Ulmus macrocarpa. The compound showed cytotoxicity to T24 (Bladder carcinoma) and A549 (Lung carcinoma epithelial) cell lines [92] (Table 2).

2.2.5. Depsidones

Botryorhodines A (12a) and B (12b), two depsidones, were isolated from the endophytic fungus Botryosphaeria r. associated with Bidens pilosa. These compounds exhibited weak antitumor activity against the HeLa cell line at a concentration of 96.97 and 36.41 μM, respectivel [48]. Depsidone 1 was discovered from a fungus of the Pleosporales order (BCC 8616) isolated from an unidentified plant leaf of the Hala-Bala forest origin. Depsidone 1 displayed weak cytotoxicity to KB and BC cell lines with IC50 values 6.5 and 4.1μg/mL, respectively [43] (Table 2).

2.2.6. Depsipeptides

Beauvericin (14), a depsipeptide, was isolated from two fungi, Fusarium o. EPH2RAA and Fusarium o., associated with the plants Cylindropuntia echinocarpus and Ephedra fasciculate, respectively. Beauvericin displayed cytotoxicity to NCI-H460 (human non-small cell lung cancer), MIA Pa Ca-2 (human pancreatic carcinoma), MCF-7 (human breast cancer), and SF-268 (human CNS cancer) cell lines with IC50 values of 1.41, 1.66, 1.81, and 2.29 μM, respectively, showing selective cytotoxicity toward MIA PaCa-2 and NCI-H460 (Table 2). Beauvericin also inhibited the metastasis of MDA-MB-231 (Breast cancer) and PC-3M (metastatic prostate cancer) cells at concentrations ranging between 3.0–4.0 and 2.0–2.5 µM, respectively [77]. According to other studies, beauvericin displayed cytotoxicity against A549 (Lung carcinoma epithelial), PC-3 (Prostate cancer), and PANC-1 (human pancreatic carcinoma) cell lines with IC50 values of 10.4 ± 1.6, 49.5 ± 3.8, and 47.2 ± 2.9 μM, respectively [71]. Additionally, in 2006, Ivanova et al. demonstrated the cytotoxicity of beauvericin against Hep-G2 (hepatocellular carcinoma) and MRC-5 (fibroblast-like fetal lung cell line) cells as well [76].

2.2.7. Ergochromes

Phomopsis l., an endophytic fungus of Dicerandra frutescens, produced three compounds dicerandrols A, B, and C (15a–15c), structurally related to the ergochromes and secalonic acids as they also have the same tricyclic C15 system with a similar arrangement of substituents. These compounds displayed modest antitumor activities toward A549 (lung adenocarcinoma epithelial cell line) and HCT-116 (colon tumor cell line) cell lines [132] (Table 2).
Secalonic acid D (16), isolated from mangrove plant endophytic fungus no. ZSU44, displayed potent cytotoxicity against HL60 (the human promyelocytic leukemia cell line) and K562 (human leukemia cells) cells with IC50 values of 0.38 and 0.43 μM, respectively. It caused apoptosis in those cell lines and cell cycle arrest in the G(1) phase as well [158].

2.2.8. Esters

Globosumones A (17a) and B (17b), isolated from the endophyte Chaetomium g. associated with Ephedra fasciculate, were shown to have cytotoxicity to MCF-7 (breast cancer), MIA PaCa-2 (pancreatic carcinoma), NCI-H460 (non-small cell lung cancer), SF-268 (CNS glioma), and WI-38 (normal human fibroblast cells) cell lines [58].

2.2.9. Lactones

The lactone compound Brefeldin A (18) was obtained from two endophytic fungi, Aspergillus c. and Paecilomyces spp., isolated from the plants Taxus mairei and Torreya grandis. Brefeldin A exhibited antitumor activities to Hela, HL-60, KB, MCF-7, and Spc-A-1 with IC50 values of 1.8, 10.0, 9.0, 2.0, and 1.0 ng/mL [31]. Brefeldin A was also obtained from the endophyte Acremonium spp. isolated from the healthy Knema laurina twig. It showed cytotoxicity to BC-1 (breast cancer), KB (epidermoid cancer of the mouth), and NCIH187 (human small-cell lung cancer), with IC50 values of 0.04, 0.18, and 0.11 μM, respectively [86] (Table 2).
Radicicol (19) was obtained from Chaetomium c. associated with Ephedra fasciculate and it is a HSP90 (heat shock protein) inhibitor, which is frequently expressed highly in cancer cells. It also showed cytotoxicity to the MCF-7 (breast cancer) cell line at an IC50 value 0.03 μM [55].
Photinides A–F (20a–20f) were obtained from the endophyte Pestalotiopsis p. associated with Roystonea regia, and all of these γ-lactones at 10 μg/mL exerted cytotoxicity against the MDA-MB-231 (breast cancer) cell line with inhibitory rates of 24.4, 24.2, 23.1, 24.4, and 24.6%, respectively [123] (Table 2).
Eutypellin A (21), isolated from the endophyte Eutypella spp. BCC 13199 associated with Etlingera littoralis, showed cytotoxicity to KB, MCF-7NCI-H187 (human small-cell lung cancer cells), and nonmalignant Vero cells with IC50 values of 38, 84, 12, and 88 μM, respectively [70].

2.2.10. Lignans

Podophyllotoxin (22), a precursor to the topoisomerase-I-inhibiting anticancer drugs teniposide (23), etoposide (24), and etoposide phosphate, were isolated from the endophyte Phialocephala f. associated with Podophyllum peltatum [12]. This was also obtained from the endophyte Trametes h. associated with Podophyllum hexandrum and from the endophyte Fusarium s. associated with Podophyllum hexandrum [1,79,148] (Table 2).

2.2.11. Peptides

Leucinostatin A was isolated from the endophyte Acremonium spp. associated with Taxus baccata and was shown to be effective against BT-20 (breast cancer) cell line with an LD50 value of 2 nM [14]. It inhibits the growth of prostate cancer cells through the suppression of IGF-I (Insulin-Like Growth Factor-I) expression in PrSC (prostate stromal cells) [228] (Table 2).

2.2.12. Polyketides

Two novel oblongolides, Y (26a) and Z (26b) (Figure 3a), are produced by the endophyte Phomopsis spp. BCC 9789 housed in Musa acuminate (a wild banana). Oblongolide Y exhibited cytotoxicity against BC (human breast cancer) cell line (IC50 48 μM) and Oblongolide Z showed cytotoxicity against BC (human breast cancer), KB (human oral epidermoid cancer), NCI-H187 (small-cell lung cancer), and nonmalignant (Vero) cell lines with IC50 values of 26 μM, 37 μM, 32 μM, and 60 μM, respectively [130] (Table 2).
Five tricyclic lactone polyketides, alternariol (27a), alternariol 5-O-sulfate (27b), alternariol 5-O-methyl ether (27c), altenusin (28a), and desmethylaltenusin (28b) (Figure 3b), were isolated from the endophyte Alternaria spp. housed in the leaves of Polygonum senegalense. All these compounds manifested significant cytotoxicity against L5178Y (mouse lymphoma cells) with EC50 values of 1.7, 4.5, 7.8, 6.8, and 6.2 μg/mL, respectively [16]. According to another study conducted by Devari et al. in 2014, alternariol 5-O-methyl ether showed antiproliferative activity against HL-60 (human promyelocytic leukemia), A549 (lung cancer), PC-3 (prostate cancer), HeLa (cervical cancer), A431 (skin carcinoma), MiaPaka-2 (pancreatic cancer), and T47D (breast cancer) cell lines. Among all these cell lines, HL-60 (human promyelocytic leukemia) cells were most sensitive (IC50 85 μM) to alternariol 5-O-methyl ether [25].
Two novel polyketides, leptosphaerone C (29) and penicillenone (30), are produced by an endophytic fungus Penicillium spp. JP-1, isolated from Aegiceras corniculatum. Leptosphaerone C showed cytotoxicity to A549 (lung carcinoma epithelial) with an IC50 value of 1.45 μM, and penicillenone exhibited activity against P388 (leukemia cells) with an IC50 value of 1.38 μM [103].
Bikaverin (31) was isolated from an endophytic fungus Fusarium o. strain CECIS associated with Cylindropuntia echinocarpa [77]. It exerted cytotoxic activities against cancer cell lines, MIA PaCa-2 (pancreatic carcinoma), NCI-H460 (non-small cell lung cancer), MCF-7 (human breast cancer), and SF-268 (human CNS cancer) with IC50 values of 0.26, 0.43, 0.42, and 0.38 μM, respectively, showing selective cytotoxicity toward MIA PaCa-2 and NCI-H460. Bikaverin was also proven to be cytotoxic against EAC (Erlich ascites carcinoma), leukemia L5178, and sarcoma 37 cell lines affecting precursor utilization of nucleic acid and protein synthesis [78].
Sequoiatone A (32a) and B (32b), two novel polyketides (Figure 3b), were isolated from a Sequoia sempervirens bark endophyte, Aspergillus p. These polyketide compounds were tested against 60 diverse human tumor cell lines, and among them, breast cancer cell lines showed the greatest sensitivity [37] (Table 2).

2.2.13. Quinones

Torreyanic acid (33) (Figure 3b), a dimeric quinine, was isolated from an endophyte of Torreya taxifolia, Pestalotiopsis m. It causes cytotoxicity by apoptosis against A549 (lung carcinoma epithelial) and NEC (human colorectal neuroendocrine cell carcinoma) cell lines with IC50 values of 3.5 μg/mL and 45 μg/mL, respectively [119] (Table 2).
Four endophytes, Alternaria spp., Alternaria a., Aspergillus n., and Penicillium spp., associated with Tabebuia argentea, produced the antitumor and anti-metastatic agent lapachol (34) [17,20,21,22]. It acts by interfering with the bioactivities of the topoisomerase enzymes, which are crucial for DNA replication [22]. β-Lapachone showed activity on DU145 (human prostate carcinoma) and MCF-7 (breast cancer cell line) cell lines [20,22]. Additionally, its antitumor and anti-metastatic activities were evident in HepG2 (human hepatocellular liver carcinoma) and Hep3B (human hepatoma cell line) cell lines [19]. Notably, Aspergillus n. can be used to produce lapachol in a large scale within a short time [18].
Two bianthraquinone derivatives, Alterporriol K (35a) and L (35b), are produced by the endophytic fungus Alternaria spp. ZJ9-6B associated with the mangrove Aegiceras corniculatum. Alterporriol K and L exerted moderate cytotoxicity against MDA-MB-435 and MCF-7 (breast cancer cell line) cell lines with IC50 values between 13.1 and 29.1 μM [24].
Cercosporin (36) was isolated from the endophytic fungus Mycosphaerella spp., associated with Psychotria horizontalis, and exhibited cytotoxicity against MCF-7 [91].
Another endophytic fungus, isolated from the Salvia officinalis stem, was Chaetomium spp., which produced the cytotoxically active agents, cochliodinol (37) and isocochliodinol (38) (Figure 3b). These compounds were tested against the L5178Y (mouse lymphoma cells) cell line where cochliodinol showed higher cytotoxicity (EC50 7.0 µg/mL) than isocochliodinol (EC50 71.5 µg/mL) [51] (Table 2).
Azaanthraquinones, 7-desmethylscorpinone (39), and 7-desmethyl-6-methylbostrycoidin (40) (Figure 3b) isolated form Fusarium s. showed cytotoxic activity against four human tumor cell lines, MDA MB 231, MIA PaCa2, HeLa, and NCI H1975 [229].

2.2.14. Spirobisnaphthalenes

Mycelia s., an endophytic fungus isolated from the leaves of Knightia excelsa, was shown to produce Spiromamakone A (41) (Figure 3b) that exhibited cytotoxicity to P388 (murine leukemia cell line) at an IC50 value 0.33 μM [90] (Table 2).
A novel spirobisnaphthalene, spiropreussione A (42), was isolated from the endophyte Preussia spp. associated with Aquilaria sinensis. It displayed cytotoxicity to A2780 (human ovarian carcinoma) and BEL-7404 (human liver carcinoma) cell lines with IC50 values of 2.4 and 3.0 μM, respectively [135].
Diepoxin δ (43), palmarumycin C8 (44), and diepoxins κ and ζ were isolated from the endophytic fungus Berkleasmium spp. associated with Dioscorea zingiberensis. Diepoxin δ and palmarumycin C8 displayed pronounced cytotoxicity to A-549, A-2780, Bel-7402, BGC-823, and HCT-8 cell lines with IC50 values between 1.28 and 5.83 μM, while diepoxins κ and ζ selectively inhibited A-549 and Bel-7402 cells’ growth showing moderate to weak cytotoxicity [44] (Table 2).

2.2.15. Terpenes (Diterpenes, Sesquiterpenes, Triterpenes)

Several terpenes of plant and fungal origin have been established as potential anticancer drugs (Figure 3b, structures 45–54). Among these, paclitaxel (Taxol) (45) was isolated from Taxus brevifolia (Pacific yew tree) [230,231]. However, due to less availability of the pacific yew tree and insignificant yield of this metabolite, scientist have set up other approaches, including tissue culture, chemical synthesis, and semi-synthesis [230,232]. However, this diterpenoid was also reported to be produced by an endophytic fungus, Taxomyces a., isolated from the Taxus brevifolia [6]. Following this report, a number of paclitaxel producing other endophytes were reported. Some of them are Bartalinia r. from the leaves of Aegle marmelos [42] and Pestalotiopsis n. and Pestalotiopsis v. from the plant Taxus cuspidate [73]. This metabolite has been found to induce apoptosis when screened against INT-407, BT220, H116, HL251, and HLK210 cell lines [42] (Table 2).
A fusicoccane diterpene, periconicin B (46), was isolated from a Xylopia aromatica endophyte, Periconia a. It exerted potent cytotoxicity against HeLa (cervical cancer) and CHO (Chinese hamster ovary) cell lines [109].
Four sesquiterpens, trichothecolone (47), 7α-hydroxy-scirpene (48), 8-deoxy-trichothecin (49), and 7α-hydroxytrichodermol (50), were isolated from an endophyte, KLAR 5, housed in the healthy twig of Knema laurina. Compounds 47 and 48 were moderately active against BC-1 (human breast cancer cells), KB (Human nasopharyngeal epidermoid tumor), and NCI-H187 (human small-cell lung cancer cells), whereas compounds 49 and 50 showed selective cytotoxic activity against BC-1 and NCI-H187 [86].
Ent-4(15)-eudesmen-11-ol-1-one (51), an eudesmane sesquiterpene, isolated from an Etlingera littoralis endophyte, Eutypella spp. BCC 13199, showed weak cytotoxicity against KB, MCF7, NCI-H187, and Vero cells with IC50 values of 32, 20, 11, and 32 μM, respectively [70].
Two sesquiterpenes, Merulin A (52a) and Merulin C (52b), are produced by a Xylocarpus granatum endophytic fungi, XG8D, where both of them showed significant cytotoxic activity against SW620 (colon cancer) and BT474 (breast cancer) cell lines with IC50 values of 4.84 and 4.11 μg/mL for SW620 and 4.98 and 1.57 μg/mL for BT474, respectively [151].
Three novel eremophilane-type sesquiterpenes (Figure 3b), eremophilanolides 1, 2, and 3 (53a–53c), were isolated from the endophytic fungi Xylaria spp. BCC 21097 of the Licuala spinose plant and were moderately cytotoxic against KB, MCF-7, and NCI-H187 cell lines [152].
Tauranin (54) is produced by a Platycladus orientalis endophyte, Phyllosticta s., exhibiting cytotoxicity against MCF-7 (breast cancer), MIA Pa Ca-2 (pancreatic carcinoma), NCI-H460 (non-small cell lung cancer), PC-3 M (metastatic prostate cancer), and SF-268 (CNS cancer- glioma) cell lines with IC50 values of 1.5, 2.8, 4.3, 3.5, and 1.8 μM, respectively [133] (Table 2).

2.2.16. Xanthones

Phomoxanthone A (55a) and B (55b) (Figure 3b), isolated from the endophyte Phomopsis spp. BCC 1323 associated with Tectona grandis, exerted significant cytotoxicity against KB, BC-1, and nonmalignant Vero cells with IC50 values of 0.99, 0.51, and 1.4 μg/mL, respectively, for phomoxanthone A and 4.1, 0.70, and 1.8 μg/mL, respectively, for phomoxanthone B [129] (Table 2).

2.3. Recently Reported Metabolites with Potential Cytotoxicity and the Case of Fusarubin

More than one hundred metabolites have been isolated and evaluated for putative anticancer activities in the years 2018 to 2020. Cytotoxic activities of these endophytic metabolites have been summarized in Table 3. Among the reported metabolites, penicolinate A isolated form Bionectria spp. [159] and pyrrocidine A isolated from Cylindrocarpon spp. [166] exhibited potent cytotoxicity against against the human ovarian cancer cell line A2780. Fusarithioamide B, a new type benzamide, isolated form Fusarium c., showed potent activity against several cell lines [160]. 3-(4-nitrophenyl)-5-phenyl isoxazole was reported to have a potent effect against HepG2 and SMCC-7721 cells [161], while spiciferone F was reported to have a strong effect against MCF7 [162]. Liu et al. isolated two metabolies, namely xylariphthalide A and cis-4-hydroxy-6-deoxytalone, and Sharma V. et al. isolated Xylarolide A from Diaporthe spp. [163,164]. All these metabolites showed activity towards cancer cells. Three naphthaquinones, anhydrofusarubin, fusarubin, and 3-deoxyfusarubin, and one aza-anthraquinone, bostrycoidin, have potentiality as bioactive compounds against cytotoxicity on vero cells. These metabolites were isolated from a Fusarium s. strain isolated from Casia alata. [8]. Monolinolein, bafilomycin d, and 3′-hydroxydaidzein displayed a strong effect against A549 cells. These metabolites were isolated from actinomycete strain YBQ59 residing in Cinnamomum cassia [167]. Colletotrichum g. A12 produced colletotricone A, which showed moderate activity against MCF-7, NCI-H460, HepG-2m and SF-268 tumor cell lines [168]. Mollicellin G, a depsidone, was reported as a moderately active cytotoxic metabolite towards HepG2 and Hela cells [169]. A metabolite of Pestalotiopsis spp., named demethylincisterol A3, showed potential cytotoxicity against human cancer cell lines Hela, A549, and HepG [170].
A new type of cytochalasin, named jammosporin A, isolated from endophytic fungi Rosellinia s.-c., exhibited cytotoxic potential towards MOLT-4 cells [165]. Prenylated diphenyl ethers, namely diorcinol N and analogues isolated from Arthrinium a. TE-3, showed moderate cytotoxicity against the human monocytic cell line (THP-1 cell line), with IC50 values of 40.2, 28.3, and 25.9 μM, respectively [233].
An indole diterpenoid, shearilicine, isolated form Penicillium spp. (strain ZO-R1-1) of Zingiber officinale, showed potent cytotoxicity towards L5178Y cells and A2780 cells [171]. Flavipin from Chaetomium g. displayed activity against A549, HT-29, and MCF-7 cells [172]. Emodin, an anthraquinone from Diaporthe l., significantly inhibited the growth of murine leukemia P-388 cells [219].
Recently reported metabolites, namely chloroisosulochrin from Pestalotiopsis t. (N635) [206], cytosporin W from Pseudopestalotiopsis t. [207], terezine E and 14-hydroxyterezine D from Mucor spp. [208], citrinin (CIT) and dicitrinin-A from Penicillium c. [209], allantopyrone E from Aspergillus v. [210], integracin A and B from Cytospora spp. [211], (±)-asperteretone F (3a/3b), and compound 6 (name not established in the paper) Aspergillus t. [212], sterigmatocystin, a xanthone, from Paecilamyces spp. TE-540 [213], mutolide [234] and pramanicin A from Aplosporella j. [216], myrothecines H and I from Paramyrothecium r. A697 [217], and colletotrichalactone A and colletotrichalactone Ca from Colletotrichum spp. JS-0361, exhibited promising activity against different cancer cells [218]. A summary of the putative cytotoxic effects of recently reported endophytic fungal metabolites are summarized in Table 3.
Fusarubin and anhydrofusarubin have been isolated from the endophytic fungi Cladosporium residing inside Rauwolfia leaves. These compounds inhibited the cell growth of different leukemia cell lines (OCI-AML3, HL-60, U937, and Jurkat) by arresting the cell cycle and augmenting apoptosis. Whereas fusarubin exerted an antiproliferative effect on OCI-AML3 cells by up-regulating p21 in a p53-dependent manner, apoptosis was induced only in a small sub-population of leukemic cells by inducing the production of the Fas ligand (Figure 4) [9].
Figure 4. Fusarubin (FUS) and FUS analogues with proposed mechanism of action. (A) Structures of FUS derivatives and (B) Proposed mechanism of action of FUS on OCI-AML3 cells.

3. Conclusions

Several hundred endophytic fugal metabolites have been isolated to have cytotoxic and antimicrobial effects. Many metabolites are currently available as drugs on the market. Given that plants host endophytes as part of a symbiotic relationship, some plant metabolites might have an endophytic fungal origin. In fact, increasing evidence indicates that some of these plant metabolites are also produced by fungi. Many of the isolated metabolites of endophytic fungi inhabitant medicinal plants have been proved to have cytotoxic effects in vitro. Several of these compounds have been investigated at the molecular level to elucidate the mechanism, since these metabolites are produced in very small quantities by endophytes of plant origin. Due to very insignificant yields and isolation difficulties, these secondary metabolites may not be available to carry out in vivo studies in animal models. Some laboratories applied synthetic approaches to produce natural product derivatives, and one group also tried to synthesize some of these compounds. Optimizing derivatization and synthetic approaches is critical to attain higher yields for animal studies. These approaches will be key for investigating and developing these putative anticancer compounds into treatments.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

Fungus NameAbbreviation
Allantophomopsis lycopodinaAllantophomopsis l.
Alternaria alternataAlternaria a.
Alternaria tenuissimaAlternaria t.
Aspergillus clavatusAspergillus c.
Aspergillus fumigatusAspergillus f.
Aspergillus glaucusAspergillus g.
Aspergillus nigerAspergillus n.
Aspergillus parasiticusAspergillus p.
Aspergillus terreusAspergillus t.
Aspergillus violaceofuscusAspergillus v.
Bartalinia robillardoidesBartalinia r.
Bionectria ochroleucaBionectria o.
Bipolaris setariaeBipolaris s.
Botryosphaeria dothideaBotryosphaeria d.
Botryosphaeria rhodinaBotryosphaeria r.
Ceriporia lacerateCeriporia l.
Chaetomium chiversiiChaetomium c.
Chaetomium globosumChaetomium g.
Cladosporium cladosporioidesCladosporium c.
Cladosporium oxysporumCladosporium o.
Colletotrichum capsiciColletotrichum c.
Colletotrichum gloeosporioidesColletotrichum g.
Cordyceps taiiCordyceps t.
Diaporthe terebinthifoliiDiaporthe t.
Entrophospora infrequensEntrophospora i.
Fusarium oxysporumFusarium o.
Fusarium solaniFusarium s.
Guignardia bidwelliiGuignardia b.
Guignardia mangiferaeGuignardia m.
Hypocrea lixiiHypocrea l.
Hypoxylon truncatumHypoxylon t.
Lasiodiplodia theobromaeLasiodiplodia t.
Mycelia steriliaMycelia s.
Microsphaeropsis arundinisMicrosphaeropsis a.
Myrothecium roridumMyrothecium r.
Neurospora crassaNeurospora c.
Papulaspora immersaPapulaspora i.
Paraconiothyrium brasilienseParaconiothyrium b.
Penicillium chermesinumPenicillium ch.
Penicillium citrinumPenicillium ci.
Periconia atropurpureaPericonia a.
Pestalotiopsis ficiPestalotiopsis f.
Pestalotiopsis karsteniiPestalotiopsis k.
Pestalotiopsis microsporaPestalotiopsis m.
Pestalotiopsis paucisetaPestalotiopsis pa.
Pestalotiopsis photiniaePestalotiopsis ph.
Pestalotiopsis terminaliaePestalotiopsis t.
Pestalotiopsis versicolorPestalotiopsis v.
Pestalotiopsis neglectaPestalotiopsis n.
Phialocephala fortiniiPhialocephala f.
Phialophora musteaPhialophora m.
Phoma betaePhoma b.
Phomopsis longicollaPhomopsis l.
Phyllosticta spinarumPhyllosticta s.
Rhizopycnis vagumRhizopycnis v.
Rhytidhysteron rufulumRhytidhysteron r.
Setophoma terrestrisSetophoma t.
Stemphylium sedicolaStemphylium s.
Stemphylium globuliferumStemphylium g.
Talaromyces flavusTalaromyces f.
Talaromyces radicusTalaromyces r.
Taxomyces andreanaeTaxomyces a.
Thielavia subthermophilaThielavia s.
Trametes hirsutaTrametes h.
Trichoderma gamsiiTrichoderma g.
Xylaria cf. cubensisXylaria cf. c.

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