**5. Antitumor**

Tumoral cells are submitted to high levels of ROS and RNS, manifesting uncontrolled proliferation, death evasion, angiogenesis, invasiveness and metastasis, causing loss of cellular function due to changes in the DNA [66].

The action of ROS and RNS may trigger different factors that stimulate angiogenic processes such as the vascular endothelial growth factor inducing proliferation, migration and tubule formation [67], as well as the induction of epithelial-mesenchymal transition by upregulation of transforming growth factor β [68].

In this regard, antioxidants serve as chemopreventive agents on healthy tissue while increasing the damage on cancerous cells; this phenomenon has been studied on secondary metabolites of plant origin such as soy isoflavone, and polyphenols such as resveratrol and hydroxychalcones [69].

Among microbial compounds that presented a correlation between antitumor and antioxidant activity were in extracts of *Streptomyces malaysiense* with compounds identified as pyrrolizidines and deferoxamine, exhibiting antioxidant as well as antitumor activities. Deferoxamine, which is listed in the World Health Organization's List of Essential Medicines, presents antioxidant activity by chelating iron and antitumoral activities [70].

Another interesting example of antitumoral compounds is an already known compound that is widely used for breast cancer stage III and IV treatment, which is doxorubicin [71], isolated from a mutant strain of *Streptomyces peuceticus*. Doxorubicin works as a DNA intercalating agent by inhibiting the activity of topoisomerase II in DNA replication [72].

Since the 1950s there has been an increase in the interest of studying marine microbial sources for drug discovery in the area of anticancer drugs such as tetracenoquinocin and 5-iminoarianciamicina, extracted from *Streptomyces* sp. in 2010, which were effective against human cervical carcinoma HeLa cells and myelogenous leukemia LH-60 [73].

A similar case is the research reported by [74], where they isolated 32 strains from lagoon sediment in Lagos. The strains were identified mostly as *Streptomyces* and *Micromonospora.* Nine isolates from *Streptomyces* genus presented cytotoxic activity against human acute myelocytic and promyelocytic leukemia, cervical carcinoma, human gastric, breast adenocarcinoma cell lines varying their effectiveness at a concentration below 1 mg/mL. The compounds present in the extracts were identified as kigamicin and staurosporine analogues.

Other kind of compounds found in *Streptomyces* strains are pyrrolopyrazines (found on *Streptomyces colonosanans*), which presented anticancer activity against human colon cancer cell lines [75].

Diketopiperazines from *Streptomyces nigra* (isolated from a mangrove soil) were effective against several human cancer-derived cell lines, while with normal cell lines they were inactive at a concentration range of 50–100 μg/mL. Other compound found on *Streptomyces nigra* was β-carboline, which is a compound widely found in plants with anticancer activity against a variety of cancer cell lines that act inhibitis DNA topoisomerase as well as intercalates in the DNA strands, changing the DNA structure; and tamoxifen [76] which is commonly used to control breast cancer after chemo and radiotherapy have been applied to the patient.

Another actinobacteria with discovered antitumor activity is *Rhodococcus*, where [77] a *Rhodococcus* strain was isolated from a contaminated soil. The extract exhibited cytotoxic activity against HepG2 and Hela cell line with an IC50 of 33 and 73 μg/mL respectively.

Another class of compounds that exhibit antitumor properties are polysaccharides, which inhibit cell growth and induce apoptosis as well as exert a synergistic effect with other chemotherapeutical agents such as doxorubicin [78], such as that reported on resveratrol [79, 80]. Examples of these kind of compounds are exopolysaccharides (EPs) produced by *Bacillus mycoides* composed of a sugar mixture containing galactose, mannose, glucose and glucuronic acid; such EPs exhibited antitumor activity by observing morphological abnormalities in HepG2 and Caco-2 cancer cell lines with an IC50 of 138 and 159 μg/mL respectively, while on normal cells the IC50 was 245 μg/mL [81]. A similar activity was observed with *Bacillus licheniformis* EP constituted by glucose, galactose, fructose, mannose and galacturonic acid on MCF cancer cell lines with an IC50 value of 840 μg/mL [82].

It can be observed from both *Bacillus* species that changes in the polysaccharide composition may influence the antitumor activity; as observed by [83] in three EPs of *Streptococcus thermophilus*, two of them were mainly composed by mannose, while the other contained mainly glucose with a protein moiety. The latter exhibited a higher antitumor activity on HepG2 cells with an IC50 of 313.75 μg/mL, while for the other two compounds the antitumor activity was below 50%.

Some *Trichoderma* species are also able to synthesize EP constituted by mannose, glucose, galacturonic acid and glucuronic acid with a mannan core, where the antitumor activity was more effective on HeLa cells than on MCF-7 cells by arresting G2/M phase and inducing apoptosis [84].

Fungal endophytes are another kind of microorganisms that could be used as alternative sources of bioactive compounds found in plants. Such as taxol (a chemotherapeutic), pestalactams and penicestorids. Taxol was discovered initially on *Taxus brevifolia*, and it presents a similar activity as doxorubicin [85]. Another example, camphotecin, found commonly on *Campotheca acuminata*, was also found on *Fusarium solani.* Camphotecin from *Fusarium solani* was proved to induce apoptosis on Vero cells at a concentration of 30 μg/mL for 24 h with a maximum apoptosis of 15% [86].

Endophytic fungi are also able to produce EP with antitumor activity. An example is *Bionectria ochroleuca* whose activity was proved to be effective against liver, gastric and colon cancer cell lines in a concentration range from 100 to 450 μg/mL without exhibiting toxicity in healthy cells [87].

Fungal co-cultivation techniques have also been used in the obtention of antitumor compounds. For example, *Isaria felina* with *Aspergillus sulphureus* was used for obtaining oxirapentyn L, which exhibited antitumor activity at IC50 greater than 100 μg/mL [88].
