Pharmacologically active substances

Antitumor agents

Each year, about 12.7 million new cases of cancer are reported worldwide in addition to resulted 7.6 million deaths. Current clinical treatments, which include chemotherapy, hormonal therapy, and immunotherapy, are usually associated with high toxicity. Other treatments such as radiotherapy and local surgeries may not be highly efficient due to poor accessibility to hunor site as targeting minor cells is complicated. Other undesirable side effects such as non-specific cytotoxicity to normal cells increase the urgent demand for novel antitumor drugs, which improve cancer patient survival rate (El Sayed et al. 2016).

Natural products extracted from microorganisms have yielded effective drags as they are capable of binding to three-dimensional biological receptors and complex proteins. Indeed, most bioactive compounds and then functional activities presented in this section are summarized in Table 2. Thus, they have also provided better insights into mechanisms of action. According to an in vitro study using MTT method, trichomide cyclodepsipeptides derived from marine fungus Trichothecium roseum has resulted in cytotoxic effects on different human cancer cell lines: SW480, human colon cancer; HL-60, human myeloid leukemia; and MCF-7, breast cancer; with IC50 values of 0.149, 0.107, and 0.079 pM, respectively (Zhou et al. 2018).

Endophytic fungi are also recognized as sources of pharmacologically important bioactive compounds. Recently, extracted compounds from seaweed

Table 2. Summary of recently isolated bioactive compounds and then' pharmacological activities.

Bioactive compound

Microorganism/

producer

Source

Biological

activities

Reference

Trichomide

cyclodepsipeptides

Ihchothecium

roseum

Marine

Anti-cancer

(Zhou et al. 2018)

3-nitropropanoic acid, hexadecanoic acid, aud octadecanoic acid

Talaromyces

puipureogemis

Seaweed

(Kumari et al. 2018)

Breviones I

Penicillium sp. TJ403-1

Coral

(Yang et al. 2018)

Lipopeptaibol emericellipsin A

Emericellopsis

alkalma

Alkalophilic soil

(Rogozhiu et al. 2018)

Fimgal

immunomodulatory protem (FIP)

Nectria

haematococca

(Xie et al. 2018)

Lobophonn К

Streptomyces sp. M-207

Lophelia pertusa coral collected from Adles Canyon depths

Anti-cancer

(Braiia et al. 2017)

Actmomycms V, D, andX0>

Streptomyces sp. ZZ338

Marine

(Zhang et al. 2016)

Antbraquinone

derivative

Streptomyces sp. ZZ406

(Chen et al. 2018a)

Diheptyl phtlialate, maculosin, albocyclme M-2, and dotnacontane

Streptomyces sparsus strain VSM-30

Deep sea marine samples of Bay of Bengal

Antioxidant

(Managamun et al. 2017)

Clntosanase (CS038)

Bacillus mycoides TKU038

Taiwan soils

Anti-

mfiammatory

(Lians et al. 2016)

Streptochlorm

Streptomyces sp. 04DH110

Marine

(Shun et al. 2015)

Antmiycm-type

depsipeptide

Streptomyces somaliensis SCSIO ZH66

Deep sea

(Li et al. 2017)

Actinofuranones E-975 and E-492

Streptomyces

gramineus

Leprogium

trichophorum

lichen

(Ma et al. 2018)

Cumilann-type

polyketides

Penicillium sp. SF-5859

Marine

(Ha et al. 2017)

Mutolide

Lepidosphaeria sp. PM0651419

Horse dung samples collected from Rajkot, India

(Shah et al. 2015)

Table 2 contd. ...

... Table 2 contd.

Bioactive compound

Microorganism/

producer

Source

Biological

activities

Reference

Lipoteichoic acid

Streptomyces hygroscopicus NRRL 2387T

Immunomodulatory

(Cot et al 2011)

ASK2

Streptomyces sp. ASK2

Rluzosphere soil of a medicmal plant

(Lalitha et al. 2017)

Nocapyrone H Nocardiopsins A and В

Nocardiopsis sp. KMF-001 Nocardiopsis sp. CMB-M0232

Manne

(Bennur et al. 2016)

Polysaccharides,

L919/A and L919/B

Lactobacillus casei strain LOCK 0919

Fecal sample from a healthy 5-year-old boy

(Gorska et al. 2016)

Streptopeptolin

Streptomyces olivochromogenes NBRC 3561

Chymotrypsm

mhibitor

(Kodani et al. 2018)

Anthraquinoue

derivative

Streptomyces sp. ZZ406

Anemone

Haliplanella

lineata

Glioma

glycolytic

enzymes

mhibitor

(Chen et al. 2018a)

Aspergifurauone

Aspergillus sp. 16-5B

Sonneratia apetala leaves

a-glucosidase

mhibitor

(Liu et al. 2015)

Lasiodiplodms

Trichodenna sp. 307

Clerodendrwn inerme stem bark

a-glucosidase

mhibitor

(Zhang et al. 2017)

Sorokiniol

Bipolaris sorokiniana LK12

Rhazya stricta

Acetyl

cholmestrase

mhibitor

(All et al. 2016)

Talaromyces purpureogenus fungus such as 3-nitropropanoic acid, liexadecanoic acid, and octadecanoic acid were proven to be cytotoxic. MCF-7 and HeLa (cervical cancer) cells were the most affected by the ethyl acetate extract treatment, yielding respective IC50 values of 110 ± 3 and 101 ± 1.4 pg/inL. It was observed that induced cell membrane damage and mitochondrial depolarization has resulted in apoptosis in HeLa cells. However, the extract did not affect normal, НЕК 293T. human embryonic kidney cell line (Kumari et al. 2018).

Similar findings were publicized by a study on breviones I, a new breviane spiroditerpenoid extracted from coral-derived fungus Penicillium sp. TJ403-1. It exhibited significant inhibitory activities against HL-60 (acute leukemia), HEP3B (hepatic cancer), and A-549 (lung cancer) cell lines with IC50 values of 4.92 ± 0.65, 5.50 ± 0.67, and 8.60 ± 1.36 pM, respectively (Yang et al. 2018). In another regard. Lipopeptaibol emericellipsin A peptide from alkalophilic, and soil fungus Emericellopsis alkaline exhibited a selective cytotoxic activity against HeLa and HepG2 cancer cell lines (EC50 < 0.5 and 2.8 pM, respectively), making it about 40 times less toxic to normal cells when compared with doxorubicin as a positive control. The mode of action of this short peptaibol is presumably associated with its effects on cell membranes (Rogozhin et al. 2018).

Isolated phleichrome from a phytopathogenic fungus, Cladosporium Phlei, was assessed as photosensitizers for photodynamic therapy (PDT). This new fungal peiylenequinone displayed a good in vitro, photodynamic antitumor activity. MCF-7, HeLa, and SW480 cell lines had their lowest viability, at 10, 25, and 50 ng/mL treatment, respectively. However, all cell lines were more sensitive to phleichrome under illuminated conditions than under dark conditions. Discovering new photosensitizers is crucial as the currently used ones have several complications such as pain experienced during irradiation, skin sensitivity, and limited treatment depth (So et al. 2018).

Interestingly, fungal immunomodulatory protein, FIP, from Nectria haematococca was proven to negatively regulate PI3K_ Akt signaling in lung adenocarcinoma cells, which induced cell cycle arrest, autopliagy, and apoptosis. The Gl/S and G2/M cell cycle arrest resulted from suppressed Akt phosphorylation, which contributed to the dowmegulation of CDK2, CDK4, cyclin B1 and cycliu Dl, as well as the upregulation of p21 and p27 expression. In addition, autopliagy and A549 apoptosis were promoted by decreasing mTOR phosphorylation along with increasing Bax/Bcl-2 and c-PARP expression ratio, respectively (Xie et al. 2018).

Other isolatedhaloalkaliphilic bacteria from Algerian Sahara desert soils were also screened for genes coding for antitumor compounds. It was found that isolate M5A, which was identified as Actinopolyspora sp., was positive for tryptophan dimer gene primers, showing 76% homology to the strain AR1455 gene cluster. The tryptophan dimerization enzymes were shown to biosynthesize structurally diverse tryptophan dimmers that in turn possess an antitumoral activity. Streptomyces sp. strain Ig6, on the other hand, showed a mixed PCR product that included a high intensity band for Glul/Glu2 primers, corresponding to dNDP-glucose 4,6-dehydratase genes. These were previously used to search for anti-cancer biomolecules such as elloramycin, novobiocin, and ravidomycin (Selama et al. 2014). Furthermore, hydroxy marilone C, a secondary metabolite extracted from Streptomyces badius, was also shown effective against two tumor cell lines (MCF-7 and A-549). The calculated IC50 for the cell line A-549 was 443 pg/ml, indicating low anti-tumor affinity, while the other cell line MCF-7 demonstrated an IC50 of 147.9 pg/ml (El Sayed et al. 2016).

Lobophorin К is another anti-cancer metabolite that is isolated from marine Streptomyces sp. M-207, endophytic to cold-water coral Lophelia pertusa collected from Aviles Canyon depths. This new natural bioactive compound displayed cytotoxic activities against human pancreatic carcinoma (MiaPaca-2) and human breast adenocarcinoma (MCF-7) cell lines, with IC50 values of 34.0 ± 85.1 and 23.0 ± 8.9 pM respectively (Braiia et al. 2017). Moreover, recently extracted secondary metabolites from Streptomyces sp. strain MUM265 contributed to 34.57±4.99% reductions in cell viability of Caco-2 colon cancer cells at 400 pg/mL extract concentration. However, ED50, the dose that is required to induce 50% cell viability reduction, was not achieved even at this highest concentration tested. Treatment with MUM265 strain extract caused abnormal rounding, cell shrinkage with reduced cytoplasm mass, and detachment of Caco-2 cells. It also induced potential depolarization of mitochondrial membrane, as well as DNA fragmentation and accumulation of subG, cells in cell cycle after 24 hours, suggesting potential apoptosis effects (Tan et al.

2019).

Other forms of cancer such as gliconra were also affected by marine Streptomyces sp. ZZ338 metabolites. The proliferation of rat glioma C6 cells as well as human glioma U251 and SHG44 cells were inhibited with IC50 values ranging from 0.42 to 1.80 rrM for actinomycirr V, 1.01 to 10.06 nM for actinomycin D, and 3.26 to 25.18 rrM for actinomycin Xop. In contrast, the control Doxorubicin, on the other hand, had ICJ0 values ranging from 0.70 to 9.61 pM (Zhang et al. 2016). An authraquinone derivative from Streptomyces sp. ZZ406 also demonstrated potent inhibition activity against the proliferation of hitman glioma SHG44, U251. and U87MG cells with IC50 values ranging from 4.7 to 8.1 pM, compared to 1.9-9.6 pM of control Doxorubicin. In addition to having a high selectivity index (CCJ0/IC50, > 12.3 to 21.3), this compound also showed good stability in human liver microsomes (Chen et al. 2018).

Antioxidant agents

Antioxidants play an essential role in scavenging and inhibiting fr ee radicals such as reactive oxygen species (ROS), whose increased levels result in oxidative stress and eventually induces damage to human cells by attacking DNA, proteins, and membrane lipids. ROS that include superoxide, hydroxyl, and peroxyl radicals can lead to severe health complications such as diabetes mellitus, neurodegenerative and inflammatory' diseases, and even cancer. They have also been linked to deterioration of food products via lipid oxidation, which causes loss of essential fatty acids and fat-soluble vitamins. Although a number of synthetic antioxidants were used by pharmaceutical and food industries, they have been associated with potential health risks including carcinogenesis and liver damage (Tan et al. 2018). For this reason, modem research is now targeting naturally occurring antioxidative agents from microorganisms and plants that can serve as protective safe therapeutics. Nocardiopsis and Streptomyces species are two of the actinomycetes which gained enormous attention hr pharmaceutical biotechnology, as recent studies focused on then antioxidant system responses under various oxidative stress conditions (Janardhan et al. 2014, Tan et al. 2018).

For instance, the potential isolate GN2 from Indian mangrove soil that was identified as Nocardiopsis alba, contained high phenolic content in its extracted secondary metabolites. This is considered as a key element for antioxidative efficiency as the two variables are positively correlated. The total antioxidant capacity was investigated in in vitro, yielding 2.72 ± 0.4. 2.95 ± 1.18, 3.05 ± 0.98, and 1.62 ± 0.4 AA/g for four different fractions, compared to 10.63 ± 0.85 AA/g for ascorbic acid as standard. The radical scavenging effect of fractions F2, F3, and F4 was higher than 50% at concentration of 50 pg/mL and at lOOpg/mL for FI (Janardhan et al. 2014).

Other mangrove sites such as Kuala Selangor, Malaysia constitute a rich bioresource for Streptomyces bacteria. According to 16S rRNA phylogenetic analysis, isolated strain MUM292 showed gene sequence similarity of 99.54% with Streptomyces griseoruber NBRC12873. Its secondary metabolites have contributed to 35.98 ± 5.39% DPPH. 67.96±2.23% ABTS+ radicals, and 79.23 ± 0.70% 0,- scavenging activities, at a concentration of 4mg/mL. Moreover, MUM292 extract also exhibited a significant metal-chelating activity of 22.54±2.37% as it reduced complex formation between Fe2~ ion and ferrozine, in addition to 28.94 ± 2.70% inhibition of iron-induced lipid peroxidation, at the same concentration (Tan et al. 2018). Streptomyces sp. MUM265 is another strain which demonstrated strong antioxidant capacities. Based on 16S rRNA gene sequence similarity, it was found to be closely related with Streptomyces phaeoluteichromatogenes NRRL 5799 and Streptomyces misionensis NBRC13603 by 99.8%. Strain MUM265 exhibited significant scavenging activities of 42.33±3.99% for DPPH, 88.50±0.37% for ABTS" radicals, and 55.99± 1.03% for O," radicals, at 4mg/mL concentration. The ability of Streptomyces sp. MUM265 extract to chelate metals was also evaluated and the assay showed a 46.02±0.86% inhibition of ferrozme-Fe2- complex formation at 4mg/mL (Tan et al. 2019). The antioxidant potentials of Streptomyces strains are mainly attributed to the presence of cyclic dipeptides and phenolic compounds as bioactive agents as investigated using Pearson’s correlation analysis (Tan et al. 2018,2019).

Deep sea marine samples of Bay of Bengal are also a promising source for new bioactive compounds that remain widely unexplored. The ethyl acetate extract of isolated strain VSM-30, identified as Streptomyces sparsus, was subjected to chemotypic and GC-MS analysis. Findings revealed the presence of bioactive molecules known to possess antioxidant activities such as dilieptyl phthalate, maculosin, albocycliue M-2, and dotriacontane (Managamuri et al. 2017). Similarly, crude extract of isolated strain RD-5 from Gulf of Khambhat, which was the designated strain as Streptomyces variabilis, exhibited DPPH free radical scavenging and metal chelating activities of82.86 and 89%, respectively, at 5.0 mg/mL, compared to 64% H,0, scavenging activity at 0.05 mg/mL concentration. On the other hand, ascorbic acid used as standard control showed 74.5% H,0, scavenging activity and 86% DPPH free radical scavenging activity at 0.05 mg/mL concentration (Dholakiya et al. 2017).

 
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