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Review

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

by
Md. Hridoy
1,2,
Md. Zobayer Hossain Gorapi
3,
Sadia Noor
3,4,
Nargis Sultana Chowdhury
5,
Md. Mustafizur Rahman
6,
Isabella Muscari
7,
Francesco Masia
7,
Sabrina Adorisio
8,
Domenico V. Delfino
8,* and
Md. Abdul Mazid
1,4,*
1
Department of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
2
Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA 19140, USA
3
Department of Pharmacy, University of Asia Pacific, Dhaka 1215, Bangladesh
4
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka 1000, Bangladesh
5
Department of Pharmacy, Manarat International University, Dhaka 1343, Bangladesh
6
Pharmacy Discipline, Khulna University, Khulna 9208, Bangladesh
7
Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
8
Department of Medicine and Surgery, Foligno Nursing School and Section of Pharmacology, University of Perugia, Piazzale Severi, S. Andrea delle Fratte, 06129 Perugia, Italy
*
Authors to whom correspondence should be addressed.
Molecules 2022, 27(1), 296; https://doi.org/10.3390/molecules27010296
Submission received: 22 November 2021 / Revised: 22 December 2021 / Accepted: 28 December 2021 / Published: 4 January 2022
Browse Figures
Versions Notes

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).
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).
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].

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.

Informed Consent 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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Molecules 27 00296 g001 550
Figure 1. Discovery of anticancer agents from endophytic fungi over time.
Figure 1. Discovery of anticancer agents from endophytic fungi over time.
Molecules 27 00296 g001
Molecules 27 00296 g002 550
Figure 2. Relative abundance of anticancer agents from endophytic fungi.
Figure 2. Relative abundance of anticancer agents from endophytic fungi.
Molecules 27 00296 g002
Molecules 27 00296 g003a 550Molecules 27 00296 g003b 550
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).
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).
Molecules 27 00296 g003aMolecules 27 00296 g003b
Molecules 27 00296 g004 550
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.
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.
Molecules 27 00296 g004
Table
Table 1. Different cell lines against which endophytic fungal derived metabolites showed cytotoxicity.
Table 1. Different cell lines against which endophytic fungal derived metabolites showed cytotoxicity.
Cell LinesCell Lines
A2780SOvarian tumor cell lineInt-407Human intestine cancer
A2058Human melanomaJurkatT cell leukemia
A549Lung carcinoma epithelialKBHuman nasopharyngeal epidermoid tumor
A431Skin carcinomaK562Human leukemia cells
ACHNRenal cellsL5178YMouse lymphoma cells
AsPC-1Human pancreatic cancer cellsMIA Pa Ca-2Pancreatic carcinoma
B16F10Skin carcinomaMiaPaka-2Pancreatic cancer
BCHuman breast cancer cell lineMDA-MB-231Breast cancer cell line
BC-1Breast cancerMDA-MB-435Human breast cancer cell line
BEL-7402Human hepatocellular carcinoma/human hepatoma cell lineMFCGastric cancer cells in mice
BEL-7404Human hepatocellular carcinoma/human hepatoma cell lineMCF-7Breast cancer cell line
BGC-823Gastric carcinomaMOLT-4Lymphoblastic leukemia
BT-220Breast cancer cell lineMRC-5Fibroblast-like fetal lung cells
BT474Human breast cancerMV4-11Human FLT3-ITD mutant AML cell line
CHOChinese hamster ovaryNCI-H187Human small-cell lung cancer
DU145Human prostate carcinomaNCI-H460Non-small-cell lung cancer
EACEhrlich ascites carcinomaNECColorectal neuroendocrine cell carcinoma
H116Human colon adenocarcinomaOVCAR-5Human ovarian cancer
HeLaCervical cancerPANC-1Human pancreatic carcinoma
HEp-2Human liver cancerP388Murine leukemia cells
HepG2Human hepatocellular liver carcinomaPC-3Prostate cancer
Hep3BHuman hepatoma cell linePC-3 MMetastatic prostate cancer
HM02Human gastric carcinomaRAW264.7Mouse macrophage cell
HL-60Human promyelocytic leukemia cell lineSF-268CNS glioma
HL251Human lung cancerSW480Human colon cancer cells
HL-7702Normal hepatocyte SW-620Colon tumor cell line
HLK 210Human leukemia SW1116Human colon cancer cell line
HCT-8Human colorectal adenocarcinomaSW1990Human pancreatic cancer cells
HCT-116Colon tumor cell lineT24Bladder carcinoma
H22Hepatic cancer cells in miceT47DBreast cancer
H1975Non-small-cell lung cancer cells/human lung adenocarcinomaTHP-1Human monocytic cell line
H522-T1Non-small cell lung cancerWI-38Normal human fibroblast cells
HT-29Human colon cancer lineU2OSHuman osteosarcoma cells
Table
Table 2. Anticancer compounds from plant-derived endophytic fungi.
Table 2. Anticancer compounds from plant-derived endophytic fungi.
CompoundsChemical ClassFungal EndophytesHost Medicinal PlantActivity Against Cell LinesIC50 ValuesRef.
Leucinostatin APeptideAcremonium spp.Taxus baccata twigBT-202 nM (LD50)[14]
Allantopyrone Aα-PyroneAllantophomopsis l. KS-97 A549 cells, HL-60˃32, 0.32 µM[15]
Alternariol, Altenusin, Alternariol 5-O-sulfate, Alternariol 5-O-methyl ether, DesmethylaltenusinPolyketideAlternaria sppPolygonum senegalense leavesL5178Y˂1 × 10−6, 1 × 10−5, 1 × 10−5, 1 × 10−5, 1 × 10−5 g/mL[16]
LapacholNaphtho-quinoneAlternaria spp.Tabebuia argentea leafDU145, HepG2, Hep3B & MCF-7
(β-Lapachone)		3.5, 3.5, 3.5 & 5 µM[17,18,19,20,21,22]
Resveratrodehydes A & BStilbenoid (Resveratrol dervatives) Alternaria spp. R6Myoporum bontioides rootMDA-MB-435,
HCT-116		˂10 µM[23]
Alterporriol K, Alterporriol LQuinonesAlternaria spp. ZJ9-6BAegiceras corniculatumMDA-MB-435,
MCF-7		26.97, 29.11 & 13.11, 20.04 µM[24]
Alternariol-10-methyl etherPolyketideAlternaria a.Capsicum annumHL-60, A549, PC-3, HeLa, A431,
MiaPaka-2 and T47D		85, ˃100, ˃100, ˃100, 95, ˃100 and ˃100 µM[25]
Camptothecine (CPT),
9-methoxy CPT, 10-hydroxy CPT		AlkaloidsAlternaria a.Miquelia dentata fruit and seed regionsHCT-116,
SW-480,
MCF-7		6.59, 7.2, 10.24 µg/mL (crude fungal ethyl acetate extract)[26]
Chrysin (5,7-dihydroxy flavone)FlavoneAlternaria a. (KT380662)Passiflora incarnata leavesMCF-734.066 µg/mL[27]
Alternariol 9-methyl etherDibenzopyranoneAlternaria a.Camellia sinensis branchesU2OS28.3 µM[28]
LapacholNaphtho-quinoneAlternaria a.Tabebuia argentea bark, leaf and stemDU145, HepG2, Hep3B & MCF-7
(β-Lapachone)		3.5, 3.5, 3.5 & 5 µM[17,18,19,20,21,22]
(6aR,6bS,7S)-3, 6a, 7,10-tetrahydroxy- 4,9-dioxo-4, 6a, 6b, 7, 8,9-hexahydroperylenePerylenesAlternaria t.Erythrophleum fordii barkHCT-81.78 µM[29]
1. Flavasperone,
2. Rubrofusarin B
3. Fonsecinone D		NaphthopyronesAspergillus sp.Limonia acidissima seeds1. Hep 3B and U87 MG
2. SW1116
3. SMMC-7721 and A549		1. Between 19.92 and 47.98 µM
2. 4.5 µg/mL
3. ˃10 µg/mL		[30]
Brefeldin ALactoneAspergillus c.Torreya grandis barkHL-60, KB, Hela, MCF-7 and Spc-A-11.0–10.0 ng/mL[31]
9-Deacetoxy fumigaclavine CAlkaloidsAspergillus f.Cynodon dactylon
stem		K5623.11 µM[32]
1. Fumitremorgin D,
2. 4,8,10,14-tetramethyl-6-acetoxy-14-[16-acetoxy-19-(20,21- dimethyl)-18-ene]-phenanthrene-1-ene-3,7-dione
3. 12,13-dihydroxy-fumitremorgin C
4. Verruculogen		AlkaloidsAspergillus f.Diphylleia sinensis mainly roots, rhizomesHepG21. 47.5 µM
2. 139.9 µM
3. 4.5 µM
4. 9.8 µM		[33]
2,14-Dihydrox-7-drimen-12,11-olideSesquiterpenesAspergillus g.Ipomoea batatas plantHep-G2, MCF-761, 41.7 µg/mL[34]
Nigerapyrones B, D & E
Asnipyrones A		PyronesAspergillus n.
MA-132		Avicennia marina plantHepG2, MCF-7, A549, SW1990, MDA-MB-23186, 105, 43, 38, 48 µM[35]
Rubrofusarin BNaphtho-γ-pyronesAspergillus n.Cynodon dactylonSW11164.5 µg/mL[36]
LapacholNaphtho-quinoneAspergillus n.Tabebuia argentea leavesDU145, HepG2, Hep3B & MCF-7
(β-Lapachone)		3.5, 3.5, 3.5 & 5 µM[17,18,19,20,21,22]
1. Sequoiatones A & B
2. Sequoiamonascin A & B		PolyketideAspergillus p.Sequoia sempervirens inner bark1. BC
2. MCF7, NCI-H460, SF-268		1. 4 to 10 µM
2. 19 × 10−4, 4 × 10−4, 15 × 10−4 M		[37,38]
Butyrolactone I and Butyrolactone VButenolideAspergillus t.—F7Hyptis suaveolensMDA-MB-231 and MCF-734.4, 17.4 & 22.1, 31.9 µM[39]
Terrein Aspergillus t. JAS-2Achyranthus asperaA-549121.9 µg/mL[40]
1. Violaceoid A,
2. Violaceoid C, Violaceoid D,
3. Violaceoid F		HydroquinonesAspergillus v.Wild Moss (Bryophyta unidentified species)1. HeLa, MCF-7, Jurkat, MOLT-4, HCT116, RAW264.7
2. Jurkat, MOLT-4
3. HCT116, RAW264.7		1. 24.6, 14.8, 3.1, 3.0, 5.8, 5.6 µM (LD50)
2. 8.2, 5.9 & 8.3, 6.2 µM (LD50)
3. 6.4, 6.5 µM (LD50)		[41]
TaxolTerpeneBartalinia r.Aegle marmelos
leaves		BT 220, H116,
Int 407, HL 251 and HLK 210		-[42]
Depsidone 1DepsidonePleosporales (BCC 8616)unidentified plant leaf of the Hala-Bala forest originKB, BC6.5, 4.1 µg/mL[43]
1. Diepoxin δ,
Palmarumycin C8
2. Diepoxins κ & ζ		Spirobis-naphthalenesBerkleasmium spp.Dioscorea zingiberensis1. HCT-8, Bel-7402, BGC-823, A 549, A2780
2. Bel-7402 and A 549		1. 1.7, 3.3, 3.3, 3.2, 5.8 & 4.2, 2.5, 2.6, 1.6, 1.3
µM
2. 6.4, 8.7 & 5.1, 8.8 µM		[44]
Verticillin DPeptideBionectria o.Sonneratia caseolaris Inner leaf tissuesL5178Y<0.1 µg/mL (EC50)[45]
Ophiobolin ASesterterpenoidBipolaris s.UnidentifiedMDA-MB-2310.4–4.3 µM[46]
1. Stemphyperylenol
2. Altenuene		1. Polyketide
2. Mycotoxin		Botryosphaeria d. KJ-1Melia azedarach stem barkHCT1163.13 µM[47]
Botryorhodine A and BDepsidoneBotryosphaeria r.Bidens pilosa stemHeLa, K-56296.97, 36.41 & 0.84, 0.003 µM (CC50)[48]
Cercosporene FGuanacastane DiterpenesCercospora spp.Fallopia japonica leavesHeLa, A549, MCF-7, HCT116 and T2419.3, 29.7, 46.1, 21.3 & 8.16 µM[49]
Ceriponol F, Ceriponol G, Ceriponol KSesquiterpenesCeriporia l.Huperzia serrataHeLa, HepG2, SGC7901173.2, 32.3, 77.5; 185.1, ˃500.0, ˃500.0 & 47.8, 35.8, 60.2 µM[50]
Cochliodinol, IsocochliodinolQuinonesChaetomium spp.Salvia
officinalis Stem		L5178Y7.0, 71.5 µg/mL (EC50)[51]
Chaetocochin CDiketopiperazineChaetomium spp.Cymbidium goeringii rootSW-4800.63 µM[52]
Chaetocochin GIndole diketo-piperazinesChaetomium spp. 88194Cymbidium goeringiiMCF-78.3 mg/mL[53]
ChaetominineAlkaloidsChaetomium spp. IFB-E015Adenophora
axilliflora leaves		K562, SW111621.0, 28.0 nM[54]
RadicicolLactoneChaetomium c.Ephedra fasciculate stemMCF-70.03 µM[55]
Chaetoglobosin XAlkaloidsChaetomium g. L18Curcuma wenyujinH22, MFC3.125, 6.25 µg/mL[56]
Chaetoglobosin C, E, F & U,
Penochalasin A		AlkaloidsChaetomium g. IFB-E019Imperata cylindrica stemKB cell line34.0, 40.0, 48.0 & 16.0, 48.0 µM[57]
Globosumone A & BEsterChaetomium g.Ephedra fasciculataNCI-H460, MCF-7, SF-268, MIA Pa Ca-2, WI-38 6.50, 21.30, 8.80, 10.60, 13.00 & 24.80, 21.90, 29.10, 30.20, 14.20 µM[58]
Chaetoglobosins A, Fex, Fa & 20-dihydrochaetoglobosinAlkaloids (cytochalasan mycotoxins)Chaetomium g.Ginkgo biloba leavesHCT1163.15, 4.43, 5.85, 8.44 µM[59]
Anhydrofusarubin and
methyl ether of Fusarubin		Naphtho-quinonesCladosporium spp.Rauwolfia serpentina leavesK-5623.97 & 3.58 µg/mL[7]
TaxolDiterpeneCladosporium c.Taxus media inner barkMCF-7, BT220, H116, INT-407, HL251, HLK2100.005 to 5 µM[60,61]
TaxolDiterpeneCladosporium o.Aegle marmelos, Coccinia indica and Moringa oleiferaHCT 15, T47D3.5, 2.5 µM[62,63]
TaxolDiterpeneColletotrichum c.Capsicum annuum fruitMCF-7, HL 251, HLK 210, BEL74020.005 to 5 µM[64,65]
Tyrosol C#Colletotrichum g.Pandanus amaryllifolius
leaves		A549, HT29, HCT116-[66]
Deacetylcytochalasin C and Zygosporin DCytochalasinsCordyceps t.unidentified95-D3.67 & 4.04 µM[67]
1. Cytospolide P,
2. Cytospolide Q		LactonesCytospora spp.Ilex canariensis1. A-549, QGY, U973
2. A-549		1. 2.05, 15.82, 28.26 µg/mL
2. 10.55 µg/mL		[68]
Xylarolide#Diaporthe t. GG3F6.Glycyrrhiza glabra rhizomesT47D7 µM[69]
TaxolDiterpenesDidymostilbe spp.Taxus chinensis var. mairei old inner barkMCF-7, HL 251, HLK 210, BEL74020.005 to 5 µM[64,65]
CamptothecinAlkaloidsEntrophospora i.Nothapodytes foetida inner barkA-549, HEP-2, OVCAR-5-[11]
1. Eutypellin A,
2. ent-4(15)-eudesmen-11-ol-1-one		1. γ-Lactone
2. Sesquiterpene		Eutypella sp. BCC 13199Etlingera littoralisNCI-H187, MCF7, KB, Vero cells1. 12, 84, 38, 88 µM
2. 11, 20, 32, 32 µM		[70]
Camptothecine (CPT),
9-methoxy CPT, 10-hydroxy CPT		AlkaloidsFomitopsis spp.Miquelia dentata fruit and seed regionsHCT-116,
SW-480,
MCF-7		5.63, 23.5, 10.32 µg/mL (crude fungal ethyl acetate extract)[26]
BeauvericinDepsipeptideFusarium o.Cinnamomum kanehirae barkPC-3, PANC-1, A54949.5, 47.2, 10.4 µM[71]
TaxolDiterpenesFusarium o.Rhizomphora annamalayana leavesBT220, HL251,
HLK 210		0.005 to 5 µM[72,73]
VincristineAlkaloidsFusarium o.Catharanthus roseus inner barkHeLa, MCF7, A549, U251, A431 & HEK2934.2, 4.5, 5.5, 5.5, 5.8 µg/mL [74,75]
BeauvericinDepsipeptideFusarium o.Cinnamomum kanehirae barkPC-3, PANC-1, A54949.5, 47.2, 10.4 µM[71]
BeauvercinDepsipeptideFusarium o.Ephedra fasciculata rootNCI-H460, MIA Pa Ca-2, MCF-7, SF-268, PC-3 M, MDA-MB-231, MRC-5, Hep-G21.41, 1.66, 1.81, 2.29, 3.0, 5.0, 4.7–5.0, 8.8–22.2 µM[76,77]
BeauvercinDepsipeptideFusarium o. EPH2RAACylindropuntia echinocarpus
stem		NCI-H460, MIA Pa Ca-2, MCF-7, SF-268, PC-3 M, MDA-MB-2311.41, 1.66, 1.81, 2.29, 3.0, 5.0 µM[77]
BikaverinPolyketideFusarium o.
CECIS		Cylindropuntia echinocarpus
stem		NCI-H460, MIA Pa Ca-2, MCF-7, SF-268, EAC, leukemia L 5178, sarcoma 371.41, 1.66, 1.81, 2.29, 0.5, 1.4, 4.2 µg/mL (ED50)[77,78]
Camptothecin (CPT) and 9-methoxy CPTAlkaloidsFusarium s.
(MTCC 9667 and MTCC 9668)		Apodytes
dimidiata		HCT-116,
SW-480,
MCF-7		7, 8.5, 8 &
7, 8.5, 8 µg/mL		[10,26]
PodophyllotoxinLignansFusarium s.Podophyllum hexandrum roots#-[79]
Camptothecine (CPT),
9-methoxy CPT, 10-hydroxy CPT		AlkaloidsFusarium s.Camptotheca acuminata inner barkOVCAR-5, HCT-116
SW-480, MCF-7		7, 8.5, 8 &
7, 8.5, 8 µg/mL		[26,80]
Gliocladicillins A & BEpipolythiodi-oxopiperazinesGliocladium spp. XZC04-CC-302Cordyceps sinensis bark.HeLa, HepG2,
MCF-7		0.50, 0.50,0.20 µg/mL (GI50)[81]
Guignarenone ATricyclo-alternareneGuignardia b. PSU-G11Garcinia hombroniana leavesKB, Vero0.38, 2.24 µM[82]
Guignardones Q & SMeroterpenoidsGuignardia m. A348Smilax glabra
leaves		MCF-783.7 & 92.1 µM[83]
Cajanol (5-hydroxy-3-(4- hydroxy-2-methoxyphenyl)-7-methoxychroman-4-one)FlavonoidsHypocrea l.Cajanus cajan roots, stems and leaves1. A549
2. PC-3, HT-29,
HepG2		1. 20.5 µg/mL after 72 h treatment, 24.6 µg/mL after 48 h; and 32.8 µg/mL after 24 h
2. 29.8, 21.4, 33.6 µg/mL (Fungal crude extract)		[84]
Daldinone C & DBenzo[j]fluorantheneHypoxylon t. IFB-18Artemisia annua surface-sterilized fresh stemsSW111649.5 & 41.0 µM[85]
1. * Brefeldin A, trichothecolone,
7α-hydroxy-scirpene
2. 8-deoxy-trichothecin,
7α-hydroxytrichodermol		* Lactone, Sesquiterpenes (trichothecenes)KLAR 5 (Hypocreales)Knema laurina
healthy twig		1. KB, BC-1, NCI-H187
2. BC-1, NCI-H187		1. 0.18, 0.04, 0.1; 12.90, 10.06, 11.31 & ˃75.10, 2.37, 1.73 µM
2. ˃62.81, 0.88, 1.48 & 8.47, 21.53, 27.76 µM		[86]
TaxolDiterpenesLasiodiplodia t.Morinda citrifolia leaves1. MCF-7
2. BT220, H116, INT-407, HL251, HLK210		1. 300 µg/mL
2. 0.005–5.00 µM		[60,87]
LasiodiplodinMacrolideLasiodiplodia t. (MUB-65)Myracrodruon urundeuva
branches		HCT-11611.2 µg/mL[88]
VincristineAlkaloidsMycelia s. 97CY (3)Catharanthus roseus leavesHeLa, MCF7, U251, A549, A431 & HEK2934.2, 4.5, 5.5, 5.5, 5.8 µg/mL[74,89]
Spiromamakone ASpirobis naphthaleneMycelia s.Knightia excelsa surface-sterilized leavesP3880.33 µM[90]
CercosporinQuinonesMycosphaerella spp.Psychotria horizontalisMCF74.68µM[91]
Arundinone BCoumarinsMicrosphaeropsis a.Ulmus macrocarpa stemsT24, A54935.4, 81.6 µM[92]
Mycoleptodiscin BAlkaloidsMycoleptodiscus spp. F0194Desmotes incomparabilis healthy mature leavesH460, A2058,
H522-T1, PC-3,
IMR-90		0.66, 0.78, 0.63, 0.60, 0.41 µM[93]
Myrotheciumone ALactoneMyrothecium r.Ajuga decumbensHepG2, SMMC-7721, A549, MCF-7 cells, QSG-7701, HL-77025.36, 6.56, 5.88, 7.56, 16.30, 20.69 µM[94]
Dihydromyrothecine CTrichothecene MacrolideMyrothecium r. IFB-E012Artemisia annuaKB44.48 µM[95]
CamptothecinAlkaloidsNeurospora c.Nothapodytes foetida seedA-549, HEP-2, OVCAR-5-[11,96]
(2R*,4R*)-3,4-dihydro- 4-methoxy-2-methyl-2H-1-benzopyran-5-olPyransNodulisporium spp.Aquilaria sinensis stemSF-268-[97]
Brefeldin ALactonePaecilomyces spp.1. Torreya grandis
2. Taxus mairei
bark		HL-60, KB, Hela, MCF-7 and Spc-A-110.0, 9.0, 1.8, 2.0 & 1.0 ng/mL[31]
(22E,24R)-8,14-epoxyergosta-4,22-diene-3,6- dioneSteroidsPapulaspora i.Smallanthus sonchifolius roots & leavesMDA-MB435, HCT-8, SF295, HL-603.3, 14.7, 5.0, 1.6 µM[98]
1. 19-(α-d-glucopyranosyloxy) isopimara-7,15-dien-3β-ol,
2. 19-(2-acetamido-2- deoxy-α-d glucopyranosyloxy) isopimara- 7,15-dien-3β-ol,
3. 19-(α-d-glucopyranosyloxy) isopimara-7,15-dien-3-one		DiterpenesParaconiothyrium spp. MY-42Fagus stemHL601. 11.2 µM,
2. 6.7 µM,
3. 9.8 µM		[99]
Brasilamides EBisabolane SesquiterpenoidsParaconiothyrium b. (M3-3341)Acer truncatum branchesMCF-7 and MGC8.4 & 14.7 µM[100]
5-Methyl-8-(3-methylbut-2-enyl) furanocoumarinCoumarinsPenicillium spp. ZH16Avicennia sp. leavesKB, KBV2005, 10 µg/mL[101]
1. Penicillenol A1,
2. Penicillenol B1		Polyketides (tetramic acids derivatives)Penicillium spp. GQ-7Aegiceras corniculatum
inner bark		1. A-549, BEL-7402, P388, HL-60
2. HL-60		1. 23.8, 13.03, 8.85, 0.76 µM
2. 3.20 µM		[102]
1. Leptosphaerone C
2. Penicillenone		PolyketidesPenicillium spp. JP-1Aegiceras corniculatum
inner bark		1. A549
2. P388		1. 1.45 µM
2. 1.38 µM		[103]
PenifupyroneFuniconePenicillium spp. HSZ-43Tripterygium wilfordii leavesKB4.7 µM[104]
LapacholNaphtho-quinonePenicillium spp.Tabebuia argentia leavesDU145, HepG2, Hep3B & MCF-7
(β-Lapachone)		-[17,18,19,20,21,22]
Arisugacin B, Arisugacin FMeroterpenoidsPenicillium spp. SXH-65Tamarix chinensis leavesHela, HL-60 and K56259.9, 24.2, 36.2 & 44.4, 45.9, 46.6 µM[105]
1. TMC-264,
2. PR-toxin		1. Heptaketide
2. Mycotoxin		Penicillium ch.
HLit-ROR2		Hertiera littoralis root1,2 >> HuCCA-1, HepG2, A549,
MOLT-3, HeLa T47D, MDAMB231, MRC-5,
2. >> HL-60		1,2. 5.62, 3.27, 8.01, 1.36, 4.49, 1.08, 2.81, 12.64 & 0.81, 3.41, 3.59, 0.09, 1.22, 1.00, 2.19, 3.66 µM
2. 0.06 µM		[106]
CitriquinochromanAlkaloidsPenicillium ci.Ceratonia siliqua stemL5178Y6.1 µM[107]
1. (+)-(3S,6S,7 R,8S)- periconone A,
2. (−)-(1R, 4R, 6S, 7S)-2-caren-4,8-olide		TriterpenesPericonia spp.Annona muricata leavesHCT-8, Bel-7402, BGC-823, A549, A2780, MCF-7˃10−5 M[108]
Periconicin BDiterpenePericonia a.Xylopia aromatica
leaves		HeLa and CHO8.0 µM[109]
Pestalotiopsone FChromonePestalotiopsis spp.Rhizophora mucronate leavesL5178Y8.93 µg/mL (EC50)[110]
Pestalactam A, Pestalactam BAlkaloidsPestalotiopsis spp.Melaleuca quinquenervia stemMCF-7, NFF64.4, 20.2 & 58.5, 12.8 µM[111]
1. (4S,6S)-6-[(1S,2R)-1, 2-dihydroxybutyl]-4-hydroxy-4-methoxytetrahydro-2H-pyran-2-one,
2. (6S,2E)-6-hydroxy-3-methoxy-5-oxodec-2-enoic acid, 3. LL-P880γ 4. LL-P880α
5. Ergosta-5,7,22-trien-3b-ol		Monoterpenoids
(1,2)		Pestalotiopsis spp. DO14Dendrobium officinale1–4 >> HL-60
1, 2, 4 and 5 >> LOVO		1–4. 15.24, 30.09, 64.87, 30.75 µM
1,2,4,5. 50.97, 41.91, 68.88 & 65.20 µM		[112]
Siccayne [2-(3-Methyl-3-buten-1-ynyl) Hydroquinone]AlkynePestalotiopsis f.Camellia sinensis branchesHeLa, HT2948.2, 33.9 µM[113]
1. Pestalofone F, G & H,
Pestalodiol C,
2. Pestaloficiol I, J, K & L		1. Epoxycyclo-
hexanediol
2. Isoprenylated chromone		Pestalotiopsis f.Camellia sinensis branchesHeLa, MCF-71. 14.4, 36.4, 36.4, 16.7 & 11.9, 33.6, 33.6, 57.5 µM
2. ˃136.1, 21.2, 99.3, 8.7 & 136.1, ˃153.8, ˃132.5, 17.4 µM		[114,115]
Pestalrone BBenzophenonesPestalotiopsis k.Camellia sasanqua stemsHeLa, HepG2, U-25112.6, 31.7, 5.4 µg/mL[116]
TaxolDiterpenePestalotiopsis m. EF01Plectranthus amboinicus healthy leavesHep G2, MCF-7, BT220, HL2510.5 µM[117,118]
Torreyanic acidQuinonesPestalotiopsis m.Torreya taxifoliaNEC, A5493.5, 45 µg/mL[119]
TaxolDiterpenePestalotiopsis m.Taxus wallichianaBT220, H116, INT-407, HL251, HLK210,
MCF-7		0.005–0.5 µM[60,120]
TaxolDiterpenesPestalotiopsis p. VM1Tabebuia pentaphyllaMCF-7 breast cancer cell line350 µg/mL[121]
Photinides A–F,
Photipyrone B		γ-LactonesPestalotiopsis p.Roystonea regiaMDA-MB-23110 µg/mL (IC25)[122,123]
TaxolDiterpenesPestalotiopsis t.Terminalia arjuna leavesBT220, H116, INT-407, HL251, HLK210,
MCF-7		-[60,121]
TaxolDiterpenesPestalotiopsis v., Pestalotiopsis n.Taxus cuspidate leaves and inner barkBT220, HL251, HLK 210-[73]
PodophyllotoxinLignanPhialocephala f.Podophyllum peltatumTopoisomerase I-[12]
Phialomustin A–DAzaphilonePhialophora m.Crocus sativusT47D10, 1, 7, 9.2 µM[124]
1. 4-hydroxymellein
2. 4,8-dihydroxy-6-methoxy-3-methyl-3,4-dihydro-1H-isochromen-1-one		1. Polyketide
2. Benzopyran		Phoma spp.Cinnamomum mollissimumP3881. 94.6 (%)
2. 48.8 (%)		[125]
TaxolDiterpenesPhoma b.Ginkgo biloba leavesMCF-7, A549, T98G-[117]
Camptothecine (CPT)
9-methoxy CPT (9-MeO-CPT),
10-hydroxy CPT (10-OH-CPT)		AlkaloidsPhomposis spp.Miquelia dentata fruit and seed regionsHCT-116,
SW-480,
MCF-7		-[26]
1. 2-(7′-hydroxyoxooctyl)-3-hydroxy-5-methoxybenzene-acetic acid ethyl ester
2. 3-O-(6-O-a-L-arabinopyranosyl)- β-d-glucopyranosyl-1,4-dimethoxyxanthone		1. Polyketide
2. Xanthone O-glycoside		Phomopsis spp.
ZSU-H76		Excoecaria agallocha stemHEp-2 and HepG232–64 µg/mL (MIC)[126,127]
1. Phomopsidone A
2. Diaporthelactone,
7-hydroxy-4,6-dimethyl-3H-isobenzofuran-1-one and
7-methoxy-4,6-dimethyl-3H-isobenzofuran-1-one		1. Depsidone
2. Isobenzo-furanones		Phomopsis spp. A123Kandelia candel
foliage		1. MDA-MB-435
2. Raji cell line		1. 63 µM
2. 27, 47 & 18 µM		[128]
Phomoxanthone A and BXanthonePhomopsis spp. BCC 1323Tectona grandisKB, BC-1, Vero0.99, 0.51, 1.4 & 4.1, 0.70, 1.8 µg/mL[129]
1. Oblongolide Y
2. Oblongolide Z		Polyketide
(hexaketide γ-lactone)		Phomopsis spp.
BCC 9789		Musa acuminata leaf1. BC
2. KB, BC, NCI-H187, Vero cells		1. 48 µM
2. 37, 26, 32, 60 µM		[130]
18-metoxycytochalasin J, Cytochalasins H and JCytochalasinsPhomopsis spp.Garcinia kola nutHeLa8.18, 35.69 & 3.66 µg/mL (LC50)[131]
Dicerandrol A, B & CErgochromesPhomopsis l.Dicerandra frutescens stemA549, HCT-1167, 1.8, 1.8 & 7, 1.8, 7 µg/mL (IC100)[132]
TauraninSesquiterpene QuinonePhyllosticta s.Platycladus orientalis
leaf tissue		NCI-H460, PC-3 M, MCF-7, SF-268, MIA Pa Ca-24.3, 3.5, 1.5, 1.8, 2.8 µM[133]
ErgoflavinErgochromePM0651480Mimusops elengiTNF-a, IL-6, ACHN, H460, Panc1, HCT116, and Calu11.9, 1.2, 1.2, 4, 2.4, 8, & 1.5 µM[134]
Spiropreussione ASpirobis naphthalenePreussia spp.Aquilaria sinensisA2780, BEL-74042.4, 3.0 µM[135]
Cytochalasin 1, 2, 3 and EAlkaloidsRhinocladiella spp.Tripterygium wilfordii dead tree limbsA2780S, HCT-116,
SW-620		3.91, 15.6, 3.91; 15.6, 62.5, 15.6; 3.91, -, 15.6 & ˂0.0153, 0.977, 0.244 µg/mL (IC100)[136]
1. Rhytidones B
2. Rhytidones C, MK3018,
Palmarumycin CR1		Spirobis
naphthalenes		Rhytidhysteron spp.Azima sarmentosa leaves1. CaSKi
2. MCF-7 and CaSki		1. 22.81
2. 17.30, 20.10, 14.47 & 24.44, 25.59, 21.95 µM		[137]
TMC-264HeptaketideRhizopycnis v. Nitaf22Nicotiana tabacumHCT-116, HepG2, BGC-823, NCIH1650, and A27804.2, 5.9, 7.8, 3.2, 3.6 µM[138]
Rhytidenone H & FSpirobisnaphthalenesRhytidhysteron r. AS21BAzima sarmentosaRamos and H19750.018, 0.252 & 0.048, 1.17 µM[139]
1. Secalonic acid A, Penicillixanthone A
2. Hypothemycin		1. Tetrahydro-xanthone
2. RAL		Setophoma t.Unidentified (leaf litter collected in a mangrove habitat)MDA-MB-435 and SW-6201. 0.16, 0.41 & 0.18, 0.21 µM
2. 0.58, 2.14 µM		[140]
Sphaeropsidin A, Sphaeropsidin DDiterpenesSmardaea spp. AZ0432Ceratodon purpureus living photosynthetic tissueMDA-MB-2311.4, 3.7 µM[141]
TaxolDiterpenesStemphylium s. SBU-16Taxus baccata inner barkMCF-7, A549, T98G-[117,142]
1. Altersolanol A,
2. Alterporriol G and H		QuinonesStemphylium g.Mentha pulegium stem1. K562, A549,
2. L5178Y		1. ˃1, ˃2 µM
2. 2.7 µg/mL (EC50)		[143,144]
1. 3-Dehydroxymethylbisde-thio-3,10a-bis(methylthio)-gliotoxin
2. Bisdethiobis(methylthio)-
Gliotoxin
3. Didehydrobisdethiobis
(methylthio)gliotoxin		AlkaloidsTalaromyces spp. LGT-2Tripterygium wilfordiB1686, 82 & 78% at 500 µg/mL[145]
Talaperoxide B, Talaperoxide DPeroxidesTalaromyces f.Sonneratia apetala healthy leavesMCF-7, MDA-MB-435, HepG2, HeLa, PC-31.33, 2.78, 1.29, 1.73, 0.89 & 1.92, 0.91, 0.90, 1.31, 0.70 µg/mL[146]
Vincristine and VinblastineAlkaloidsTalaromyces r. CrP20Catharanthus roseus leaf tissuesHeLa, MCF7, U251, A549, A431 4.2, 4.5, 5.5, 5.5, 5.8 µg/mL[74]
TaxolTerpenesTaxomyces a.Taxus brevifolia
inner bark		BT220, H116, INT-407, HL251, MCF-7HLK210-[6,60]
Hypericin, EmodinPolyketidesThielavia s.Hypericum perforatum stemTHP-1-[147]
PodophyllotoxinLignanTrametes h.Podophyllum hexandrumTopoisomerase I-[148]
Aspochalasin D, Aspochalasin JCytochalasanTrichoderma g.Panax notoginsengHeLa5.72, 27.4 µM[149]
Trichothecinol-AMycotoxinsTrichothecium spp.Phyllanthus amarusMDA-MBA-231, B16F10500 µM (LC25), 500 µM (LC50)[150]
Merulin A
Merulin C		SesquiterpenesXG8D
(a basidiomycete, not better identified)		Xylocarpus granatum plantBT474, SW6204.98, ˃10 & 4.84, ˃10 µg/mL[151]
Eremophilanolide 1,2 & 3SesquiterpenesXylaria spp. BCC 21097Licuala spinosaKB, MCF-7, NCI-H187, Vero cells3.8–21 µM[152]
1. 2-Chloro-5-methoxy-3-methylcyclohexa-2,5-diene-1,4-dione
2. Xylariaquinone A		BenzoquinoneXylaria spp.Sandoricum koetjapeVero cells1.35, ˃184 µM[153]
1. Cytochalasin D
2. Cytochalasin C and Q		CytochalasinsXylaria spp. NC1214Hypnum sp.1,2 >> NCI-H460, PC-3M, SF-268, MDA-MB-231;
1. >> MCF-7,		D: 1.03, 0.22, 0.43, 1.01 µM; C: 1.65, 1.06, 0.96, 1.72 µM; Q: 1.53, 1.51, 1.31, 1.32; 1.44 µM[154]
Cytochalasin EAlkaloidsXylaria spp. XC-16Toona sinensisbrine shrimp2.79 µM (LC50)[155]
1. Cytochalasin D
2. Ergosterol peroxide		1. Cytochalasins
2. Steroid		Xylaria cf. c. PK108Unidentified1. NCI-H187, KB, Vero cell
2. NCI-H187, Vero cell		1. 5.95, 3.25, 0.36 µg/mL
2. 5.81, 47.95 µg/mL		[156]
Xylariacin A
Xylariacin B
Xylariacin C		TriterpenesXylarialean spp. A45Annona squamosal
phloem		HepG248, 9.7, 46.7% at 20 µg/mL[157]
Secalonic acid DErgochromeZSU44 (not better identified)(unidentified) mangrove plantHL-60, K5620.38, 0.43 µM[158]
* Compounds with IC50 values less than 10 μM are reported.
Table
Table 3. Recently (2018–2020) reported potential cytotoxic metabolites isolated from medicinal-plant-associated endophytic fungi.
Table 3. Recently (2018–2020) reported potential cytotoxic metabolites isolated from medicinal-plant-associated endophytic fungi.
SlIsolated Metabolites *Fungus NameHost Medicinal PlantReported ActivityReferences
1Penicolinate ABionectria spp.Raphia taedigeraDisplayed potent cytotoxicity against cells with an IC50 value of 4.1 μM.[159]
2Fusarithioamide BFusarium c.Anvillea arcinia (Burm.f.) DC.Showed selective and potent effect towards BT-549, MCF-7, SKOV-3, and HCT-116 cell lines with IC50s 0.09, 0.21, 1.23, and 0.59 μM, respectively[160]
33-(4-nitrophenyl)-5-phenyl isoxazoleAspergillus n. spp. Exhibited potent cytotoxic effect on HepG2 and SMCC-7721 cells with the IC50 values were 0.347 and 0.380 mM, respectively[161]
4Spiciferone FPhoma b.Kalidium foliatum (Pall.) MoqExhibited strong biological effect against MCF7 with a half-maximal inhibitory concentration value at 7.73 ± 0.11 μM[162]
5Xylariphthalide ADiaporthe spp.Tylophora ouataDisplayed cytotoxic activity against human tumor cell lines BGC-823 cells with IC50 values of 1.5 μmol·L−¹[163]
6Cis-4-hydroxy-6-deoxytaloneDiaporthe spp.Tylophora ouataDisplayed cytotoxic activity against human tumor cell lines BGC-823 cells with IC50 8.6 μmol·L−¹[163]
7Xylarolide ADiaporthe spp.Datura inoxiaShowed promisingly inhibited growth of MIAPaCa-2 and PC-3 cells with an IC50 values of 20 14 µM[164]
8Jammosporin ARosellinia sanctae-crucianaAlbizia lebbeckExhibited promising cytotoxic potential against the human leukemia cancer cell line (MOLT-4)[165]
9Pyrrocidine A
(Pyridone alkaloid)		Cylindrocarpon spp.Sapium ellipticumShowed potent cytotoxicity against the human ovarian cancer cell line A2780 with an IC50 value of 1.7 μM[166]
10BostrycoidinFusarium s.Cassia alata Linn.
plant		Significant cytotoxicity against vero cell line[8]
11Anhydrofusarubin
121-MonolinoleinStreptomyces c. YBQ59Cinnamomum cassia
plant		Exhibited cytotoxicity against human lung adenocarcinoma EGFR-TKI-resistant A549 cells with IC50 values of 3.6 µM[167]
13Bafilomycin DShowed activity against EGFR-TKI-resistant A549 cells with IC50 values 6.7 µM
143′-HydroxydaidzeinShowed activity against EGFR-TKI-resistant A549 cells with IC50 values 7.8 µM
15Colletotricone AColletotrichum g. A12Aquilaria sinensisInhibited growth of MCF-7, NCI-H460, HepG-2, and SF-268 tumor cells with IC50 values ranging from 15.7 to 46.8 μM[168]
16Mollicellin GChaetomium spp. Eef-10Eucalyptus exsertaCytotoxic against two human cancer cell lines HepG2 and Hela withIC50 values of 19.64 and 13.97 µg/mL, respectively[169]
17Demethylincisterol A3Pestalotiopsis spp.Rhizophora mucronataShowed potent activity against the Hela, A549 and HepG, with IC50 values ranging from 0.17 to 14.16 nM[170]
18Shearilicine (1), Paspalinine-13-ene (2), 7-Hydroxypaxilline-13-ene (3), Shearinine O (6), Shearinine P (7), emindole SB (10), paspaline (18), 7-hydroxy-13-dehydroxypaxilline (19) *Penicillium spp. (strain ZO-R1-1)Zingiber officinale1 showed the most pronounced cytotoxicity against L5178Y (IC50 is 3.6 μM) whereas 2, 3, 6, 7 & 19 exhibited cytotoxicity with IC50 values ranging between 5.3 and 8.1 μM. 1, 6, 10 and 18 displayed pronounced cytotoxicity with IC50 values ranging between 5.3 and 8.7 μM against A2780[171]
19FlavipinChaetomium g.Couroupita guianensis Aubl. leavesExhibited cytotoxicity toward A549, HT-29, and MCF-7 cancer cells with an IC50 concentration of 9.89 µg/mL, 18 µg/mL, and 54 µg/mL, respectively[172]
20Bellidisin DPhoma b.Tricyrtis maculate leavesExhibited significant cytotoxicity against HL-60, A549, SMMC-7721, MCF-7, and SW480 cells with IC50 value ranged from 3.40 to 15.25 μM[173]
21Epicorazine AEpicoccum n.Salix sp.Displayed strong to moderate cytotoxic activities against L5178Y, Ramos, and Jurkat J16 cell lines with IC50s ranging from 1.3 to 28 mM[174]
22Cytochalasin EAspergillus spp.Pinellia ternata tubersExhibited significant cytotoxicity with an IC50 value of 7.8 μM[175]
23Asperchalasin A-F (seco-cytochalasins), Asperlactone G-H (asperlactones)All the compounds showed cytotoxicity against A-549 with IC50 values ranging from 23.3 to 70.2 μM
24Demethylchaetocochin C, dethiotetra(methylthio)chetomin, chaetoperazine A, 4-formyl-N-(30-hydroxypyridin-20-yl) benzamideChaetomium g. 7951Panax notoginseng rootShowed cytotoxicity against MCF-7, MDA-MB-231, H460, and HCT-8 cell lines with IC50 values ranging from 4.5 to 65 μM[176]
25Chetoseminudin F (1), chaetocochin C (6), ergosterol (8), chetomin A (9), chetomin (12)Chaetomium spp. SYP-F7950Panax notoginseng
Stem		1 displayed more potent cytotoxic activity against MDA-MB-231 cells than paclitaxel with IC50 of 26.49 μM. 6, 8, 9 and 12 exhibited strong cytotoxicity with IC50 values ranging between 2.75 and 8.68 μM against A549 and MDA-MB-231[177]
26Ascomylactam A to C (1–3)Didymella spp. CYSK-4Pluchea indica healthy branch1 and 3 exhibited moderate cytotoxic activities against MDA-MB-231, MDA-MB-435, NCI-H460, PC-3 & HCT116 cell lines with IC50 values ranging between 4.2 and 7.8 μM. 2 showed cytotoxicity towards the MDA-MB-231 and HCT116 cells with IC50s of 6.6 and 4.5 μM, respectively[178]
27Pleosporalin FPleosporales spp. F46Mahonia fortuneiExhibited moderate cytotoxicity towards MDA-MB-231 cell line with an IC50 value of 22.4 ± 1.1 μM.[179]
2819,20-epoxycytochalasins C (1) and D (2), and 18-deoxy-19,20-epoxy-cytochalasin C (3)Nemania spp. UM10MTorreya taxifolia leaf1 and 3 displayed moderate toxicity against SK-MEL and BT-549 cell lines. 2 showed moderate toxicity against BT-549 and LLC-PK11 cell lines[180]
29Gartryprostatins A to C (1–3)Aspergillus spp. GZWMJZ-258Garcinia multiflora fruit 1–3 showed selective cytotoxicity against the cell line, MV4–11, with IC50 values of 7.2, 10.0, and 0.22 μM, respectively[181]
3019,20-epoxycytochalasin CXylaria cf. c.Solanum tuberosum stem tissues Displayed significant specific cytotoxic activity against HL-60 cells with an IC50 of 1.11 μM.[182]
31Sporulosaldein FParaphaeosphaeria spp. F03Paepalanthus planifolius leavesDisplayed weak cytotoxic activities against MCF-7 and LM3 cells, with IC50 values of 34.4 and 39.2 µM, respectively.[183]
32Trichodermic acidPenicillium o.Taxus media roots Displayed moderate cytotoxicity towards A549, LN229, MGC, LOVO, and MDA231 with IC50 values of 51.45, 23.43, 39.16, 46.97, and 42.85 μg/mL, respectively.[184]
33Stemphyperylenol (5), (17R)-4-hydroxy-17-methylincisterol (10)Alternaria a.Psidium littorale Raddi leaves 5 showed cytotoxicity against MCF-7 and HepG-4 cell lines (IC50 values of 4.2 ± 0.6 and 7.9 ± 0.9 μM, respectively); 10 exhibited cytotoxicity against HepG-4 cell line with an IC50 value of 9.73 ± 1.2 μM.[185]
34Aspergisocoumrins A & BAspergillus spp. HN15-5DAcanthus ilicifolius fresh leavesExhibited cytotoxicity against MDA-MB-435 cells (IC50 values of 5.08 ± 0.88 and 4.98 ± 0.74 μM, respectively)[186]
35Phomoxanthone A (1) and Penialidin A (2)Coniochaeta spp. F-8Ageratina adenophora1 showed a stronger cytotoxicity than 2[187]
36MacrophinPhoma m.Glycyrrhiza glabra LinnExhibited prominent cytotoxic activity against all the cancer-cell lines (MDA-MB-231, T47D, MCF-7, and MIAPaCa-2 with IC50 values of 14.8, 8.12, 13.0, and 0.9 μM, respectively).[188]
37Myrothecines D–G (1–4), 16-hydroxymytoxin B (5), and 14′-dehydrovertisporin (6)Myrothecium r., IFB-E008, IFB-E009, and IFB-E012 strainsTrachelospermum jasminoidesShowed cytotoxicity against K562 and SW1116 cells (IC50 values ranging between 56 nM and 16 μM).[189]
38GiluterrinAspergillus t. P63Axonopus leptostachyus rootsExhibited cytotoxicity against 786-0 and PC-3 cell lines (IC50 of 22.93 μM and 48.55 μM, respectively).[190]
392′-aminodechloromaldoxin (1) and 2′-aminodechlorogeodoxin (2)Pestalotiopsis f.Cinnamomum camphora branches 1 & 2 displayed moderate cytotoxicity against NCI-H460, SF-268, MCF-7 and PC-3cell lines (IC50 values of 18.63, 20.23, 23.53, 20.48 μM and 16.47, 17.57, 20.79, 19.43 μM, respectively).[191]
40Stachybochartins A, B, C, D and G. Stachybotrys c. PT2–12Pinellia ternataShowed cytotoxicity against MDA-MB-231 and U-2OS cells (IC50 values ranging between 4.5 to 21.7 μM).[192]
41(S)-3,6-dihydroxy-8-methoxy-3-methylisochroman-4-one (1a), 6-methoxy-3-methylisochromane-3,8-diol (2).Aspergillus f.Cordyceps sinensis fruiting body 1a & 2 exhibited moderate growth inhibition against MV4–11 (IC50 values of 38.39 μM and 30.00 μM, respectively).[193]
42FlavoglaucinAspergillus spp.
AV-2		Avicennia marina healthy leaves Exhibited most potent cytotoxicity against Caco-2 cells (IC50 of 2.87 μM)[194]
43Peniquinone A (1) & peniquinone B (2)Penicillium spp. L129Limonium s.1 showed cytotoxicity against the cell lines, MCF-7, U87, and PC3 (IC50 ranging between 9.01 and 14.59 µM); 2 exhibited relatively weak cytotoxicity against the same cells (IC50 ranging between 13.45 and 25.32 µM)[195]
44Pestalolide B (1), pestalotether F (4)Pestalotiopsis spp.Melaleuca alternifolia leaves 1 displayed remarkable inhibitory effect against the cell lines, HL60, U87MG, MDA-MB-231, and HEP-3B cells (IC50 ranging from 1.42 to 5.90 μM); 4 exhibited significant inhibitory potency against HL60 (IC50 5.05 μM)[196]
45Emeridone B (2), Emeridone D (4), Emeridone F (6)Emericella spp. TJ29Hypericum perforatum root2, 4, and 6 showed cytotoxicity against cell lines, SMMC-7721 & SW-480 (IC50 values ranging between 8.19 and 18.80 μM). Compound 4 also exhibited cytotoxicity against A-549 (IC50 of 11.33 μM)[197]
46Lithocarin B & C, Tenellone HDiaporthe l. A740Morinda officinalis twigsDisplayed weak inhibitory activities against SF-268, MCF-7, HepG-2, and A549 cell lines with IC50 values ranging between 30 and 100 μM[198]
47Cytosporaquinone A–D, leucomelone. Cytospora spp. CCTU A309Juglans (Walnut tree)All Showed significant cytotoxicity against the cell lines, L929 and KB-3-1 (IC50 values ranging from 2.4 to 26 μg/mL)[199]
48Ilanpyrone (1), methyl
Asterrate (4)		Annulohypoxylon i.Cinnamomum sp.1 showed moderate cytotoxicity against MCF-7 cells (IC50 is 4.79 µM). 4 displayed cytotoxicity towards MCF-7, NCI-H460, and SF-268 cells (IC50 values ranging between 5.46 to 8.56 μM)[200]
49Rhinomilisin A (1), Rhinomilisin G (7) and Gliocladic acid (15)Rhinocladiella s.Acrostichum aureum1, 7 & 15 exhibited cytotoxic activities against L5178Y (IC50 values of 5.0, 8.7, and 24.4 μM, respectively).[201]
50Koninginol B (2), 1R,3S,6S,7R,10S-7-isopropyl-4,10-dimethylbicyclo[4.4.0]dec-4-en-3,10-diol (15), 1R,3R,6S,7R,10S-7-isopropyl-4,10-dimethylbicyclo[4.4.0]dec-4-en-3,10-diol (16)Trichoderma k. A729Morinda officinalis branches2, 15, and 16 showed antiproliferative activities against A549 (IC50 values of 46.6, 31.3, and 22.2 μM, respectively)[202]
51Cytochalasin D1 (1) and C1 (2)Xylaria cf. cu.Solanum tuberosum stem tissues1 and 2 showed moderate cytotoxicity against HL-60 (IC50 value of 12.7 and 22.3 μM, respectively)[203]
52Bipolahydroquinone C (3), cochlioquinone I (4), cochlioquinones K-M (6–8)Bipolaris spp. L1–2Lycium barbarum fresh leaves3, 4, and 6–8 exhibited cytotoxic activities against NCIH226 and/or MDA-MB-231 (IC50 values ranging between 5.5 to 9.5 μM)[204]
53Botryosulfuranol ABotryosphaeria m. strain E224Bixa orellana fresh leavesExhibited cytotoxicity against HT-29, HepG2, Caco-2, HeLa, IEC6, and vero cells (IC50 values ranging between 8 to 23.5 μM)[205]
54ChloroisosulochrinPestalotiopsis t. (N635)Camellia sinensis (Theaceae)Exhibited moderate cytotoxicity towards the HeLa cell line with an IC50 value of 35.2 μM[206]
55Pestalotether DExerted cytotoxicity against HeLa and MCF-7 cell lines with IC50 values of 60.8 and 22.6 M, respectively
56Cytosporins W *Pseudopestalotiopsis t.Rhizophora racemosa
mangrove plants		Exhibited potent cytotoxicity towards mouse lymphoma cell line L5178Y with an IC50 value of 3.0 μM[207]
57Terezine E and 14-hydroxyterezine DMucor spp.Centaurea stoebeShowed potent activity against K-562 and HUVEC cell lines[208]
58Citrinin (CIT) and dicitrinin-APenicillium ci.Dichotomaria marginataShowed toxicity in A. saline, with LC50 (24 h) 1.71 μg/mL and 2.29 μg/mL, and LC50 (48 h) of 0.54 μg/mL and 0.54 μg/mL, respectively[209]
59Allantopyrone EAspergillus v.Avicennia marina mangroveShowed cytotoxic effect on HeLa cells with IC50 = 50.97 μM[210]
60Integracin A and BCytospora spp.Ceriops tagal (Chinese mangrove)Both compounds showed promising cytotoxicity towards HepG2 Cells with IC50 values of 5.98 ± 0.12 µM and 9.97 ± 0.06 µM, respectively[211]
61(±)-Asperteretone F (3a/3b)Aspergillus t.Hypericum perforatumPotent cytotoxic activities against human pancreatic cancer cells, including AsPC-1, SW1990 and PANC-1 cells, with IC50 values ranging from 1.2 to 15.6 μM[212]
62SterigmatocystinPaecilamyces spp. TE-540Nicotiana tabacum L.showed moderate to strong cytotoxicity towards A549, BT-549, HepG2, and MCF-7 cells with IC50 values ranging from 5.6 to 14.2 µM[213]
63Methyl 3-chloroasterric acidPleosporales spp. SK7.Kandelia candel leavesExhibited cytotoxicity against MDA-MB-435 cell with an IC50 of 25.96 ± 0.32 μM [214]
64Rhizoperemophilane NRhizopycnis v.Nicotiana tabacumExhibited selective cytotoxicity against NCI-H1650 and BGC823 tumor cells[215]
65Pramanicin AAplosporella j.Orychophragmus violaceus (L.) O. E. Schul exhibited strong cytotoxic activities against human lymphoma (Ramos) and leukemia (Jurkat J16) cells with IC50 values of 4.7 and 4.4 μM, respectively[216]
66Myrothecines H and IParamyrothecium r.Morinda officinalisBoth the compounds exhibited promising cytotoxicity against SF-268, NCI-H460, and HepG-2 tumor cell lines with the IC50 ranging from 0.0002–16.2 μM and induced apoptosis of HepG-2 cells[217]
67Colletotrichalactone A and colletotrichalactone CaColletotrichum spp. JS-0361Morus albaExhibited moderate-to-potent cytotoxic activities against MCF7 cells with IC50s of 35.06 and 25.20 µM, respectively[218]
68Emodin, (an anthraquinone)Diaporthe l.Artocarpus heterophyllusexhibited cytotoxicity against murine leukemia P-388 cells with an IC50 value of 0.41 μg/mL[219]
69Demethyli cisterol A3Aspergillus t. YP-2.Taxus yunnanensis barkShowed cytotoxicity against the A549 and HepG2 cell with IC50 values of 5.34 and 12.03 μM, respectively[220]
70Demethylincisterol A5Showed cytotoxicity against the A549 and HepG2 cell with IC50 values of 11.05 and 19.15 μM, respectively
* Compounds with IC50 values less than 10 μM are reported in bold.
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Hridoy, M.; Gorapi, M.Z.H.; Noor, S.; Chowdhury, N.S.; Rahman, M.M.; Muscari, I.; Masia, F.; Adorisio, S.; Delfino, D.V.; Mazid, M.A. Putative Anticancer Compounds from Plant-Derived Endophytic Fungi: A Review. Molecules 2022, 27, 296. https://doi.org/10.3390/molecules27010296

AMA Style

Hridoy M, Gorapi MZH, Noor S, Chowdhury NS, Rahman MM, Muscari I, Masia F, Adorisio S, Delfino DV, Mazid MA. Putative Anticancer Compounds from Plant-Derived Endophytic Fungi: A Review. Molecules. 2022; 27(1):296. https://doi.org/10.3390/molecules27010296

Chicago/Turabian Style

Hridoy, Md., Md. Zobayer Hossain Gorapi, Sadia Noor, Nargis Sultana Chowdhury, Md. Mustafizur Rahman, Isabella Muscari, Francesco Masia, Sabrina Adorisio, Domenico V. Delfino, and Md. Abdul Mazid. 2022. "Putative Anticancer Compounds from Plant-Derived Endophytic Fungi: A Review" Molecules 27, no. 1: 296. https://doi.org/10.3390/molecules27010296

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