Effect of anti-cancerous compounds on cancer cells extracted from edible mushrooms: A review

Mushrooms have been an invaluable ingredient in terms of food and medicine to humanity since time immemorial. Mushrooms have been shown to be possessing properties such as anti-tumor, antiproliferative, antioxidant, immunomodulatory, anti-diabetic. Traditional Czech republic medicine involved using Piptoporus betulinus in curing colorectal cancer; similarly, fruiting bodies of Inonotus obliquus were employed in Folk medicine in eastern Europe since the 16 th century. The oriental practice of utilizing mushrooms has witnessed an overwhelming attentiveness from the global research fraternity in exploring its wonder substances. Cancer is one of the key problems faced by researchers in finding an efficient medicine without inducing severe health complications. Mushrooms contain a plethora of bioactive compounds involved in tumor inhibition, such as hispolon, lentinan, gannoderic acid, illudin-s, and many more. The current article briefly describes various edible mushrooms with anti-tumorigenic compounds and their effect on the cancer cells of various means. effect on anti-cancer drugs with minimal health complications in cancer chemotherapy.


Introduction
Mushroom has been considered gourmet cuisine across the planet since ancient times for its distinctive taste and flavor. In some traditions, mushroom consumption is linked to disease treatment, prevention, and surviving longevity. Among 14,000 mushroom species, 50 to 200 species have medicinal properties. Despite their long-term use in oriental medicine, their effects in promoting health are proven by contemporary based studies only. Few studies suggest that Agaricus, Polyozellus, Coprinus, Amauroderma, Grifola, Pleurotus, Phellinus, Lentinula, and Ganoderma helps in enhancing inflammatory responses and immune system (Figueiredo & Régis, 2017) (Patel & Goyal, 2012). Boletus edulis, commonly known as Penny Bun, is among the species of edible mushrooms used to observe anti-tumor activity in the middle of the 20 th century. Cancers are the leading cause of death worldwide, next to cardiovascular diseases, and the existing treatment methods are associated with various side effects. Conventional therapies 5 | P a g e compound, has neutralized chemotherapy and antineoplastic activities (Patel & Goyal, 2012).
Other compounds include maitake D-fraction (a proteoglycan derivative), polysaccharide peptides like PSP, PSK, triterpenoids, triterpenes. In vitro, in vivo, and clinical trials have shown the binding property of lectins to the membrane carbohydrates of mutant cells, thereby decreasing tumor growth. Lectins from the species such as A.bisporus and G.frondosa expressed anti-proliferative and anti-tumorigenic potential (Figueiredo & Régis, 2017). (S. T. Chang & Miles, 1989) In vitro experiments showed that 90 µg/ml of A.bisporus lectin extract could become potent antiproliferative agents.  (Yu et al., 2009). Agaritine, a hydrazine-derivative obtained from a hot-water extract of A.blazei Murrill shown promising effects on human leukemic monocyte lymphoma cells.
Agaritine induced annexin V expression, DNA fragmentation, and cytochrome c release.
Cells after treatment with agaritine shown an increase in their caspase 3,8 and 9 activities; thereby, apoptosis is induced easily in tumor cells. Extracts of A.blazei showing antileukemic effects were studied using tritiated thymidine cancer assays in vitro. The potent extracts were further investigated in human promyelocytic leukemia cells (Akiyama et al., 2011).
Studies including ELISA and DNA fragmentation assays showed that the fraction played a key role in inducing apoptosis of NB-4 cells (C.-F. Kim et al., 2009

Genus Phellinus
The genus Phellinus belongs to the family of Hymenochaetaceae. One of the important species in the genus Phellinus exhibiting anti-tumorigenic compounds is Phellinus linteus.
P.linteus extract possesses a substance called β-glycan (1→3), which has shown to be a potent immunomodulator with anti-metastasizing and antimutagenic properties (Baker et al., 2008). The extract plays a vital role in cancer prevention by inducing glutathione Stransferase and NAD(P)H: quinone oxidoreductase activities. Hispolon, a polyphenolic compound isolated from P.linteus, has played a vital role in inducing apoptosis in bladder and breast cancer cells

Genus Pleurotus
Pleurotus ostreatus extract rich in aqueous polysaccharide compound called pleura and evaluated for its proapoptotic and antiproliferative effects on HT-29 colon cancer cells (Lavi et al., 2006). Another novel water-soluble polysaccharide (POPS-1) was extracted from P. ostreatus fruiting bodies by Sepharose CL-6B gel filtration chromatography and DEAE-cellulose ion-exchange chromatography. Assays such as cytotoxicity assays

Flammulina velutipes
Flammulina velutipes belongs to the family of Physalacriaceae, which is commonly known as velvet shank, velvet foot, winter mushroom, seafood mushroom, and many more. were significantly inhibited. Further, the extract also played a vital role in inducing rapid apoptosis on various cancer types (Gu & Leonard, 2006).

Grifola frondosa
Grifola frondosa, commonly known as Maitake or dancing mushrooms, is an important mushroom species in showing anti-cancer effects. The extract of G.frondosa is abundant in β-glucan and was found to be working synergistically along with cisplatin, besides increasing its efficacy (Masuda et al., 2009) Data from annexin V-PI assay and flow cytometric analysis showed that GFPPS1b arrested the G2/M phase of SGC-7901 cells (Cui et al., 2007).

Calvatia utriformis
Handkea utriformis or Calvatia utriformis, which belongs to the Lycoperdaceae family, commonly called puffball mushroom, has potent anti-oncogenic properties. A ubiquitinlike peptide extracted from the fruiting bodies of C.utriformis had shown excessive antiproliferative effect against breast cancer cells. (Ng et al., 2003) identified and purified a novel protein called calcaelin from Calvatia caelata, a potent ribosome inactivator with anti-mitogenic and translation-inhibiting activities. A reduction in the viability of the breast cancer cells when treated with calcaelin (Patel & Goyal, 2012).

Genus Clitocybe
The

Boletus badius
Boletus badius or Xerocomus badius is a mushroom species extensively produced using submerged fermentation, consists of an anti-tumor agent called Theanine (γ-glutamyl ethyl amide) (J. . L-theanine is an analog of L-glutamate, and L-glutamine can work efficiently in combination with other anti-cancerous drugs such as cisplatin, doxorubicin, anthracyclines, irinotecan (Patel & Goyal, 2012). With the demonstration of fewer experiments, L-theanine has modulated effect on anti-cancer drugs with minimal health complications in cancer chemotherapy.

Coprinus comatus
Coprinus comatus, commonly known as shaggy ink cap mushroom, belongs to the family of Agaricomycetideae was tested for its anti-oncogenic properties. The ethyl acetate extract targeted the IαBα phosphorylation when the mushroom extract of IC50 value 32 μg/mL was administered. The effect of ethyl acetate was compared simultaneously with the effect of a known NF-κB pathway inhibitor, curcumin. Besides, the ethyl acetate extract slowed down the IKK complex activity by 90% compared to the untreated sample. The results demonstrated that the extract could effectively treat malignant estrogen-independent breast cancer (Asatiani et al., 2011). (Zaidman et al., 2008) elucidated the effect of ethyl acetate and ethanol extract on prostate cancer cell growth (LNCaP). The extract was found to inhibit the cell viability of dihydrotestosterone-induced tumor growth, thereby arresting the G1 phase. These pieces of evidence suggested the possible mechanism of action could be via androgen receptor or non-androgen receptor-mediated.
Schizophyllum commune belongs to the family of Schizophyllaceae, and it is commonly known as split-gill mushroom. It consists of a water-soluble, non-ionic homopolysaccharide called Schizophyllan with linear chain including β-Ɒ-(1-6)glucopyranosyl groups and β-Ɒ-(1-3)-glucopyranosyl groups. Schizophyllan is a potent antineoplastic and immunomodulatory agent and has grabbed the pharmaceutical industry's attention recently (Kumari et al., 2008). C.militaris extract elevated the levels of IL-18 transcription by enhancing the activity of the P1 promoter region in mice liver and brain, thereby stimulating the INF-γ secretion in leukemic mouse monocyte cell line (C. S. Kim et al., 2008). NCI-H406 cell-transplanted nude mice were administered aqueous extract for 4 weeks. There was a significant reduction in tumor size, and the extract prolonged the lifespan of mice, indicating the anticancer effects of C.militaris in nude mice (Park et al., 2009). Cordycepin, an adenosine nucleoside derivative from C.militaris, effectively inhibited the growth of human leukemic cells in a dose-dependent manner by stimulating apoptosis. The stimulation was associated with activation of caspases, mitochondrial dysfunction, cleavage of polymerase protein, and production of reactive oxygen species. Cordycepin initiates apoptosis through a signaling cascade pathway along with ROS-mediated caspase pathway (Jeong et al., 2011).

Conclusion and Future perspectives
Mushrooms are a few things set to create a revolution in their usage, research, and therapeutic agent for various cancers. Mycologists across the globe firmly trust that mushrooms could be a breakthrough in curing various forms of cancers. Over the past 50 years, the interest in focusing on medicinal mushrooms increased exponentially. Many areas of the mushrooms as a useful source for producing beneficial products are neglected.
One such area is their oncogenic properties. 80% of fungal species have not been analyzed for their anti-tumor and antibiotic activity. Primarily, a tumor has many vulnerable spots and can be focused at various levels, viz., regulation of apoptosis, angiogenesis, tumorspecific proliferation signaling, metastasis, and modulation of the immune system. The eccentricity of the mushroom is a mass producer of various kinds of compounds and can be potentially used for cancer treatment either in a synergistic way or in combination with existing cancer drugs minimizing the harmful side effects. So, mushrooms can be the next biggest thing in oncology with their ubiquity in nature and abundance in producing a plethora of bioactive compounds. The use of mushroom extract as a sole therapeutic agent is also a key area to focus on and research.