Natural Products/Bioactive Compounds as a Source of Anticancer Drugs

Simple Summary Cancer is considered as a large group of diseases involving abnormal cell growth, which results in an alarming rise in the mortality rate at the worldwide level. Presently, the main point of interest in pharmaceutical research is the development of the novel and efficient anticancer drugs based on natural sources. In this regard, plants, and some microbial species, due to their composition, ecology, phytochemical, and ethnopharmacological properties, play a significant role. Accordingly, a series of plant-derived bioactive compounds are in the clinical development phase against cancer. The present review highlights the significance of several medicinal plants, plant extracts, and their bioactive compounds for their potential anticancer activities. The presented results can be useful for researchers in developing novel anticancer drugs, public health specialists, and for the public in general. Abstract Cancer is one of the major deadly diseases globally. The alarming rise in the mortality rate due to this disease attracks attention towards discovering potent anticancer agents to overcome its mortality rate. The discovery of novel and effective anticancer agents from natural sources has been the main point of interest in pharmaceutical research because of attractive natural therapeutic agents with an immense chemical diversity in species of animals, plants, and microorganisms. More than 60% of contemporary anticancer drugs, in one form or another, have originated from natural sources. Plants and microbial species are chosen based on their composition, ecology, phytochemical, and ethnopharmacological properties. Plants and their derivatives have played a significant role in producing effective anticancer agents. Some plant derivatives include vincristine, vinblastine, irinotecan, topotecan, etoposide, podophyllotoxin, and paclitaxel. Based on their particular activity, a number of other plant-derived bioactive compounds are in the clinical development phase against cancer, such as gimatecan, elomotecan, etc. Additionally, the conjugation of natural compounds with anti-cancerous drugs, or some polymeric carriers particularly targeted to epitopes on the site of interest to tumors, can generate effective targeted treatment therapies. Cognizance from such pharmaceutical research studies would yield alternative drug development strategies through natural sources which could be economical, more reliable, and safe to use.


Introduction
Cancer is the anomalous growth of cells in the body; it is the leading cause of death and is also known as the biggest public health burden [1]. Cancer cells can also attack and damage the body's normal cells [2]. Millions of people have died due to four common types of cancers every year, including breast, lung, prostate, and rectum/colon cancer with an unknown etiology. The present tenet indicates a conspicuous difference between cancer chemotherapy and chemoprevention. Cancer chemotherapy is the control of the developed disease, while cancer chemoprevention is the phenomenon of a carcinogenesis intervention by blocking the agents of the induction of the neoplastic process or averting the processing of transformed cells to the malignant phenotype using suppressing agents. Cancer chemoprevention may also implicate the reversal of the progression of cancer cells [3].
The investigation of anticancer agents through natural sources dates back to about 1550 BC. However, the scientific exploration of this research is very recent and originated in the 1950s with the generation of majorly found plant-derived anticancer agents, including vinca alkaloid analogs, camptothecin derivatives, podophyllotoxin derivatives, and taxol semi-synthetic analogs which are clinically helpful anticancer therapeutic drugs ( Figure 1) [4,5]. Over 180,000 microbial-derived anticancer agents, 16,000 marine-derived organisms, and 114,000 plant-derived compounds were screened by the US National Cancer Institute (NCI) for their anti-cancerous activity from the 1960s to the 1980s [6]. Plant-based drug development also provided a platform for synthesizing efficient and safe anti-tumor drugs through the complete cognizance of a synergistic relation between numerous components of anti-tumor herbs [7,8]. According to the WHOs estimation, approximately 80% of African and Asian countries rely on traditional medicines for fundamental health care. A neoteric study shows that approximately more than 60% of patients use herbs or vitamins as cancer therapy [9,10]. Herbal remedies are among the most favored form of traditional medicine and are tremendously profit-making at the international commercial level. By the 2050s, the worldwide herbal medicine market is expected to hit USD 5 trillion [11]. Natural products provide a sustainable source with a considerable efficacy to treat and overcome several disorders and fatal diseases, including cancer. In the last time period, the role of the bioactive compound and natural products, as a source of anticancer drugs, has been marked within a collaborative, integrated, and multidisciplinary approach. Plants have long been known for having medicinal effects since aeon [12][13][14][15][16]. More than 50% of modern clinical drugs are of a natural source origin and have the capability to treat cancer cells [17]. A neoteric study shows that approximately more than 60% of patients use herbs or vitamins as cancer therapy. The ability of natural sources as anticancer agents were identified in the 1950s by the US National Cancer Institute and contributed to finding new naturally existing anti-tumor agents [18]. Plant-based drug development needs a specific production strategy with optimized environmental conditions and nutrient availability. In 1998, Sohn et al. estimated that an extraction from 10,000 kg of the bark of yew trees is required to produce 1 kg of taxol. The production of 25 kg of taxol required 38,000 yew trees for the treatment of 12,000 cancer patients [19]. The plant collection for finding anticancer agents ended in 1982, but in 1986, the generation of new screening strategies led to the amelioration of plants and the collection of other organisms mainly focused on the sub-tropical and tropical zones of the world. Hartwell listed more than 3000 plants in his review against cancer treatment [20]. Various anti-cancerous drugs are available to treat cancer, but they also exhibit toxic effects that limit their use [18,21]. Because of the severe side effects of radiotherapy and chemotherapy and the high mortality rate, recent research revolves around the need to design appropriate chemotherapy for cancer treatment without side effects [21,22]. Biodiversity has been determined to be a significant source of remarkable anticancer agents until now [23][24][25][26][27][28].
A significant investigation is devoted to finding more effective treatments with minimum undesirable toxic effects. However, many anti-tumor agents exhibit a restricted Natural products provide a sustainable source with a considerable efficacy to treat and overcome several disorders and fatal diseases, including cancer. In the last time period, the role of the bioactive compound and natural products, as a source of anticancer drugs, has been marked within a collaborative, integrated, and multidisciplinary approach. Plants have long been known for having medicinal effects since aeon [12][13][14][15][16]. More than 50% of modern clinical drugs are of a natural source origin and have the capability to treat cancer cells [17]. A neoteric study shows that approximately more than 60% of patients use herbs or vitamins as cancer therapy. The ability of natural sources as anticancer agents were identified in the 1950s by the US National Cancer Institute and contributed to finding new naturally existing anti-tumor agents [18]. Plant-based drug development needs a specific production strategy with optimized environmental conditions and nutrient availability. In 1998, Sohn et al. estimated that an extraction from 10,000 kg of the bark of yew trees is required to produce 1 kg of taxol. The production of 25 kg of taxol required 38,000 yew trees for the treatment of 12,000 cancer patients [19]. The plant collection for finding anticancer agents ended in 1982, but in 1986, the generation of new screening strategies led to the amelioration of plants and the collection of other organisms mainly focused on the subtropical and tropical zones of the world. Hartwell listed more than 3000 plants in his review against cancer treatment [20]. Various anti-cancerous drugs are available to treat cancer, but they also exhibit toxic effects that limit their use [18,21]. Because of the severe side effects of radiotherapy and chemotherapy and the high mortality rate, recent research revolves around the need to design appropriate chemotherapy for cancer treatment without side effects [21,22]. Biodiversity has been determined to be a significant source of remarkable anticancer agents until now [23][24][25][26][27][28].
A significant investigation is devoted to finding more effective treatments with minimum undesirable toxic effects. However, many anti-tumor agents exhibit a restricted therapeutic window due to a lack of specificity of against cancer cells [29,30]. The ultimate objective of a cancer treatment is the generation of safe and effective drugs that can particularly kill malignant cancer cells or make them benign cancer cells without killing normal cells [31]. This review aims to highlight the significance of several medicinal plants, plant extracts, and their bioactive compounds with potential anticancer activities to facilitate the researchers to develop novel anticancer drugs providing some considerable benefits, such as highly selective and significant anticancer activity, less to no toxicity, low side effects, being economic and eco-friendly, as well as providing a cancer preventing role via an increasing immunity [32][33][34].

Methodology
A descriptive review was conducted in order to evaluate the anticancer potential of several natural plants and their bioactive compounds. The articles documented on anticancer, chemopreventive, and cytotoxic effects with experimental investigations (such as in vitro, in vivo, and clinical trials) were critically evaluated. The bibliographic material was collected using the Google Scholar, ScienceDirect, Web of Science, and PubMed databases. Several search terms such as "natural plants", "medicinal plants", "bioactive compounds", "phytoconstituents", "phytochemicals", "plant extracts", "anticancer agents", "plant-derived therapeutics", "cytoxicity analysis", "antiproliferative", and "apoptotic effects" were used to collect literature in a variety of combination forms. The generated articles were screened in order to fulfill the desired selection criteria by evaluating their titles and further abstract summaries. The irrelevant articles, like those with any other language except English, or articles with insignificant outcomes, aiming to evaluate natural plant products or their bioactive compounds as effective anticancer agents treating different types of cancers, were excluded from the selected data. Moreover, all of the selected publications were exclusively read to gather effective literature based on their potential anticancer effects indicated by experimental investigations.

Plant-Derived Bioactive Compounds as Anti-Cancerous Agents
Over the last decade, several researchers have investigated the ethnopharmacological and ethnomedicinal properties of numerous plant-derived bioactive compounds and, recently, their antimicrobial and antibiofilm activities [35]. Several in vitro and in vivo experimental investigations revealed the therapeutic significance of numerous phytochemicals (Table 1). Some photos of the most studied plants with a significant anticancer potential with their bioactive compounds are presented in Figure 1. The most common plant-derived anti-cancerous agents include vinca alkaloids and their derivatives, camptothecin and its derivatives, podophyllotoxin and its semi-synthetic analogs, and terpenes.

Vinca Alkaloids and Their Derivatives
The use of plants as anticancer agents was established with two alkaloids' isolation, vincristine, and vinblastine, using Catharanthus roseus and Madagascar periwinkle [93]. These drugs have been clinically used in oncology for about 50 years. They perform their function by blocking the polymerization phenomenon of tubulin molecules, averting the mitotic spindle formation, and resulting in apoptosis or metaphase arrest [94]. Several anticancer drugs, such as vincristine, vinblastine, vinorelbine, vinflunine, veratridine, and berbamine, are plant-derived natural alkaloids ( Figure 2).
A number of semi-synthetic analogs of these two alkaloid drugs have been produced. Vindestine was produced by the replacement of the C acetyl group with an amino group in vinblastine [95], primarily applied for the treatment of acute lymphocytic leukemia (ALL) and rarely prescribed for chronic myelocytic leukemia (CML), breast cancer, non-small cell lungs cancer (NSCLC), colorectal cancer, and renal cancer treatment. Vinorelbine (also known as navelbine) is another semi-synthetic analog of vinblastine synthesized by shortening one carbon from the indole ring linking the bridge to piperidine nitrogen, resulting in a water elimination from the piperidine ring, and was approved in 1989 in France for the treatment of NSCLC under the brand name Navelbine. Vinflunine, a dihydrofluoro semi-synthetic analog of vinorelbine, is used as the second line of treatment in metastatic urothelial cancer. It was approved in 2009 by the European medical agency [96,97]. Alike other semi-synthetic analogs of vinca alkaloids, vinflunine also attaches to tubulin molecules resulting in the inhibition of microtubule polymerization and the formation of tubulins para crystals [98][99][100][101].

Vinca Alkaloids and Their Derivatives
The use of plants as anticancer agents was established with two alkaloids' isolation, vincristine, and vinblastine, using Catharanthus roseus and Madagascar periwinkle [93]. These drugs have been clinically used in oncology for about 50 years. They perform their function by blocking the polymerization phenomenon of tubulin molecules, averting the mitotic spindle formation, and resulting in apoptosis or metaphase arrest [94]. Several anticancer drugs, such as vincristine, vinblastine, vinorelbine, vinflunine, veratridine, and berbamine, are plant-derived natural alkaloids ( Figure 2). A number of semi-synthetic analogs of these two alkaloid drugs have been produced. Vindestine was produced by the replacement of the C acetyl group with an amino group in vinblastine [95], primarily applied for the treatment of acute lymphocytic leukemia (ALL) and rarely prescribed for chronic myelocytic leukemia (CML), breast cancer, nonsmall cell lungs cancer (NSCLC), colorectal cancer, and renal cancer treatment. Vinorelbine (also known as navelbine) is another semi-synthetic analog of vinblastine synthesized by shortening one carbon from the indole ring linking the bridge to piperidine nitrogen, resulting in a water elimination from the piperidine ring, and was approved in treatment. The anticancer potential of NOS-NPs combined with DOX and alone was evaluated against 4T1 breast cancer cells (in vitro) and mice (in vivo). The NOS-NPs, in combination with DOX, significantly showed a 68.50% inhibition against the growth of breast cancer. The DOX and NOS-NPs alone exhibited a 32 to 55.10% inhibition, respectively [105].

Camptothecin and Its Derivatives
Camptotheca acuminata plant species are a source of the anticancer agent camptothecin (CPT), a quinoline alkaloid that acts by inhibiting the activity of topoisomerase-I, causing DNA damage and, ultimately, cell death [106]. Because of its severe toxicity and low aqueous solubility, it was terminated from clinical trials. Several CPT derivatives are developed and approved for clinical use to combat these limitations. Some of the CPT derivatives are irinotecan, belotecan, and topotecan, which actively inhibit DNA topoisomerase-I, an enzyme involved in DNA replication and transcription (Figure 3a,b,d) [107]. 9-aminocamptothecin (9-AC) is another CPT semi-synthetic derivative that exhibited a sound activity effect pre-clinical analysis but has not shown clinically effective anticancer activity hitherto.  In 1993, 9-AC entered in phase-I trials and revealed the dose-dependent phenomenon of myelosuppression as a major toxic effect of the respective drug. Subsequently, in phase-II trials, the drug was found to be active against malignant and ovarian lymphoma and inactive against colon or lung cancer. Consequently, in 1999, it was terminated from any further development [108]. However, some phase-I or II trials have been reviewed to predict its efficacy, safety, and tolerability separately or in combination with some other analogs [109]. Several drugs such as diflomotecan (for advanced solid tumors treatment at phase I) (Figure 2c) [110], gimatecan (for advanced solid tumors treatment at phase I) [111], (for recurrent ovarian, peritoneal, or fallopian tumor treatment at phase II) [112], elomotecan (for advanced solid tumors treatment at phase I) [113], and EZN-2208 (for advanced malignancies treatment) [114] have been reported as clinical trial-based studies.

Podophyllotoxin and Its Semi-Synthetic Analogs
Podophyllum peltatum plant is an important source of the anticancer compound Podophyllotoxin and has two key analogs, Teniposide and Etoposide (Figure 4) [115], which In 1993, 9-AC entered in phase-I trials and revealed the dose-dependent phenomenon of myelosuppression as a major toxic effect of the respective drug. Subsequently, in phase-II trials, the drug was found to be active against malignant and ovarian lymphoma and inactive against colon or lung cancer. Consequently, in 1999, it was terminated from any further development [108]. However, some phase-I or II trials have been reviewed to predict its efficacy, safety, and tolerability separately or in combination with some other analogs [109]. Several drugs such as diflomotecan (for advanced solid tumors treatment at phase I) (Figure 2c) [110], gimatecan (for advanced solid tumors treatment at phase I) [111], (for recurrent ovarian, peritoneal, or fallopian tumor treatment at phase II) [112], elomotecan (for advanced solid tumors treatment at phase I) [113], and EZN-2208 (for advanced malignancies treatment) [114] have been reported as clinical trial-based studies.

Podophyllotoxin and Its Semi-Synthetic Analogs
Podophyllum peltatum plant is an important source of the anticancer compound Podophyllotoxin and has two key analogs, Teniposide and Etoposide (Figure 4) [115], which are useful in the treatment of different types of cancer acts by inhibiting the function of the topoisomerase II enzyme [5]. The above two analogs combat some problems and issues, such as a metabolic inactivation, poor water solubility, and acquired drug resistance. The improved efficacy and potency led to the development of some semi-synthetic derivatives, including azatoxin, NK-611, Top-53, tafluposide, GL-331, and etoposide phosphate, either as clinical drugs or new trial candidates for cancer treatment [116].

Taxane Diterpenoids
Paclitaxel discovery from the bark extract of the Yew tree further provided evidence for a successful drug discovery through natural products. Taxol was the first compound discovered for a microtubule synthesis promotion. It has been known to be used in treating several types of cancers, particularly breast, ovarian, and NSCLC [117]. A wide range of its derivatives has been produced ( Figure 5). Docetaxel was the first to be clinically used with significant clinical activity against different tumors [118,119]. Both of the authorized taxane drugs, paclitaxel and docetaxel, still have limitations of use, and the researchers are trying to overcome their side effects by synthesizing the modified derivatives. Alterations in their structures has led to the discovery of new agents with a diminished toxicity, enhanced solubility, and refined cytotoxicity. The restricted ability of docetaxel and paclitaxel to cross the blood-brain barrier is concluded to be generated by the P-glycoprotein efflux pump tremendously expressed in the BBB [120][121][122]. In 2010, another FDAapproved taxane derivative, Cabazitaxel, was established in combination with prednisone for treating hormone-refractory prostate and prostate cancers. Cabazitaxel suppresses the proliferation of cancer cells by stabilizing tubulin and inhibiting the depolymerization of microtubules [123]. Nanoparticle formulations are also being applied to obtain better results. Abraxane is the albumin-bound nanoparticle-based formulation of paclitaxel free of any solvent, which acts as a mitotic inhibitor, and shows that it can have dramatically improved effects. New taxanes are also being developed to improve the therapeutic effect and pharmacology and replace docetaxel and paclitaxel which are currently used for the treatment of NSCLC [124].

Taxane Diterpenoids
Paclitaxel discovery from the bark extract of the Yew tree further provided evidence for a successful drug discovery through natural products. Taxol was the first compound discovered for a microtubule synthesis promotion. It has been known to be used in treating several types of cancers, particularly breast, ovarian, and NSCLC [117]. A wide range of its derivatives has been produced ( Figure 5). Docetaxel was the first to be clinically used with significant clinical activity against different tumors [118,119]. Both of the authorized taxane drugs, paclitaxel and docetaxel, still have limitations of use, and the researchers are trying to overcome their side effects by synthesizing the modified derivatives. Alterations in their structures has led to the discovery of new agents with a diminished toxicity, enhanced solubility, and refined cytotoxicity. The restricted ability of docetaxel and paclitaxel to cross the blood-brain barrier is concluded to be generated by the P-glycoprotein efflux pump tremendously expressed in the BBB [120][121][122]. In 2010, another FDA-approved taxane derivative, Cabazitaxel, was established in combination with prednisone for treating hormone-refractory prostate and prostate cancers. Cabazitaxel suppresses the proliferation of cancer cells by stabilizing tubulin and inhibiting the depolymerization of microtubules [123]. Nanoparticle formulations are also being applied to obtain better results. Abraxane is the albumin-bound nanoparticle-based formulation of paclitaxel free of any solvent, which acts as a mitotic inhibitor, and shows that it can have dramatically improved effects. New taxanes are also being developed to improve the therapeutic effect and pharmacology and replace docetaxel and paclitaxel which are currently used for the treatment of NSCLC [124].

Some Other Plant-Derived Anticancer Agents
Omacetaxine mepesuccinate is an alkaloid anticancer agent extracted from Cephalotaxus harringtonia and approved by the FDA; it is a translation process inhibitor. Omacetaxine inhibits the translation of proteins by inhibiting the elongation of the protein synthesis process by interfering the A-site and averting the correct amino acid positioning to aminoacyl tRNA [125]. Ingenol mebutate is found in the plant sap of Euphorbia peplus, and in January 2012, it was approved by the US FDA and EMA in gel form for the acid keratosis treatment. This compound is an ester of angelic acid and diterpene [126]. Betulinic acid is a secondary metabolite of Betula species from the Betulaceae family, occurring in natural form as pentacyclic triterpenoid. It was isolated from the Zizyphus plant species, like Mauritiana oenoplia and Mauritiana rugose [127,128], exhibiting numerous biological activities such as anti-oxidant, antibacterial, anti-inflammatory, anti-retroviral, and anti-HIV properties [129,130]. Dai et al. conducted the in vivo and in vitro studies to determine the anticancer potential of Taxus chinensis var. mairei (TC) against lung cancer. The aqueous extract of TC showed a significant anticancer effect by degrading CD47 with less toxicity [131]. Wu et al. investigated the antitumor efficacy of a polysaccharide (CPTC-2) isolated from Taxus chinensis var. mairei against gastric cell lines (SGC-7901). The outcomes obtained by the flow cytometry and MTS assay revealed significant antitumor activity in a dose-dependent way [132].
Flavopiridol is a synthetic compound having an identical structural similarity with rohitukine extracted from an Indian indigenous plant, Dysoxylum binectariferum [133]. It is known for targeting the cyclin-dependent kinase activity, including the cyclin T complex or CDK9, suppressing the regulation of Mc1-1 and anti-apoptotic proteins, and inducing changes in the permeability of mitochondria [134][135][136]. It is also known as the first potential inhibitor of cyclin-dependent kinases to gain clinical trials [137]. Curcuma longa plant, also known as turmeric, is derived from the polyphenol Curcumin and has a wide range of therapeutic properties, including anti-inflammatory, analgesic, antiseptic, and

Some Other Plant-Derived Anticancer Agents
Omacetaxine mepesuccinate is an alkaloid anticancer agent extracted from Cephalotaxus harringtonia and approved by the FDA; it is a translation process inhibitor. Omacetaxine inhibits the translation of proteins by inhibiting the elongation of the protein synthesis process by interfering the A-site and averting the correct amino acid positioning to aminoacyl tRNA [125]. Ingenol mebutate is found in the plant sap of Euphorbia peplus, and in January 2012, it was approved by the US FDA and EMA in gel form for the acid keratosis treatment. This compound is an ester of angelic acid and diterpene [126]. Betulinic acid is a secondary metabolite of Betula species from the Betulaceae family, occurring in natural form as pentacyclic triterpenoid. It was isolated from the Zizyphus plant species, like Mauritiana oenoplia and Mauritiana rugose [127,128], exhibiting numerous biological activities such as antioxidant, antibacterial, anti-inflammatory, anti-retroviral, and anti-HIV properties [129,130]. Dai et al. conducted the in vivo and in vitro studies to determine the anticancer potential of Taxus chinensis var. mairei (TC) against lung cancer. The aqueous extract of TC showed a significant anticancer effect by degrading CD47 with less toxicity [131]. Wu et al. investigated the antitumor efficacy of a polysaccharide (CPTC-2) isolated from Taxus chinensis var. mairei against gastric cell lines (SGC-7901). The outcomes obtained by the flow cytometry and MTS assay revealed significant antitumor activity in a dose-dependent way [132].
Flavopiridol is a synthetic compound having an identical structural similarity with rohitukine extracted from an Indian indigenous plant, Dysoxylum binectariferum [133]. It is known for targeting the cyclin-dependent kinase activity, including the cyclin T complex or CDK9, suppressing the regulation of Mc1-1 and anti-apoptotic proteins, and inducing changes in the permeability of mitochondria [134][135][136]. It is also known as the first potential inhibitor of cyclin-dependent kinases to gain clinical trials [137]. Curcuma longa plant, also known as turmeric, is derived from the polyphenol Curcumin and has a wide range of therapeutic properties, including anti-inflammatory, analgesic, antiseptic, and antioxidant activity [138]. Turmeric plants contain some compounds called curcuminoids contain-ing curcumin, bisdemethoxycurcumin, and demethoxicurcumin. Of all curcuminoids, curcumin has a significant therapeutic effect [139]. It has also been found to have anticancer activity by affecting the biological pathways connected with oncogene expression, mutagenesis, metastasis, apoptosis, and the regulation of the cell cycle [139].

Mushrooms as a Source of Anticancer Agents
Mushrooms carrying medicinal properties have an established history as a traditional medicine. Mushroom-derived therapeutic substances can function in human bodies and are progressively being grown [140]. Numerous traditionally utilized mushrooms from the genera of Trametes, Ganoderma, Auricularia, Tremella, and Flammulina are known to have remarkable medicinal properties [141]. Many medicinal properties of mushrooms have dragged researchers' attention to explore the finding of new mushrooms and their important metabolites, bearing profound anticancer and antioxidant properties [142]. In 1975, Lucas and his fellows first described the anticancer activity of higher Basidiomycetes [141]. The considerable physiological properties and pharmacological efficacy of medicinal mushrooms are of a homeostasis maintenance, the enhancement of the immune response (bioregulation), the biorhythm regulation, the prevention and cure of different diseases, and the amelioration of human health from life-threatening diseases such as heart diseases, cancer, and cerebral stroke, etc. Mushrooms are also known to have antibacterial, anti-mycotic, antiviral, anti-tumor, anti-inflammatory, antithrombotic, antidiabetic, hypotensive, and hypolipidemic activities [143]. Rutckeviski [146]. Thimmaraju et al. studied the anti-tumor effect of polysaccharide (HUP-2) isolated from Hypsizygus ulmarius. HUP-2 was isolated using the hot water extraction method. HUP-2 revealed considerable cytotoxicity and inhibition against PC3 prostate cells [147]. Fekry et al. determined the anticancer potential of Pleurotus ostreatus (selenium enriched mushroom) in colon cancer. The outcomes showed significant anticancer activity by enhancing the production of IL-6 and IL-10, reducing the production of TNF-α and the targeting of the Raf-1 pathway [148]. Meng et al. studied the antitumor effect of water-soluble polysaccharide obtained from Boletus edulis (BE) mushroom against breast cancer cells (Ca761, MDA-MB-231) using an MTT assay. The obtained outcomes revealed that BE can significantly induce mitochondrial apoptosis and proliferation inhibition [149]. Another study revealed the potential anticancer effect of the silver nanoparticles (Ag NPs) prepared by Boletus edulis and Coriolus versicolor mushrooms against colorectal, breast, and hepatocellular carcinoma cells (HT-29, MCF-7, and HUH-7 cells, respectively). The outcomes showed significant anticancer activity by inhibiting proliferation and ROS-generated apoptosis [150].
Some examples of significant medicinal mushrooms with anti-tumor properties are given in Table 2. Apoptosis induced by cell cycle arrest at G2/M and increased expression of caspase-3 and -9.
[161] Anti-tumor effect [168] Antrodia cinnamonea Crude ethanol extract Bladder In vitro (tsgh-8301, RT4, T24 cells) Cell death was mediated by anti-migratory activity and down-regulation of cyclin B1 and CDC2 [169] Several researchers have reported the anti-tumor potentials of different mushroom species and reduced the adverse effects like anemia, nausea, insomnia, drug resistance, and bone marrow suppression after radiation and chemotherapy [170]. Additionally, some potential mushroom species have been evaluated in clinical trials (Table 3) [171].
A medicinally reported mushroom, Agaricus blazei, has been revealed to possess significant anti-tumor activity by an enlarged number of T-regulatory and plasmacytoid dendritic cells and an enhanced level of human leukocyte, immunoglobulin, and killerimmunoglobulin receptor genes [172]. Misgiati et al. isolated ergosterol using n-hexane extracts prepared with Agaricus blazei Murill mushroom. The anticancer activity of the ergosterol using an MTT assay was identified against MCF-7 cells. The outcomes showed significant anticancer activity with an IC50 of 43.10 µg/mL by inhibiting the cell cycle and inducing apoptosis [173]. Sun et al. extracted an RNA-protein complex (FA-2-b-B) using Agaricus blazei Murill to evaluate the anticancer potential against chronic myeloid leukemia. The outcomes exhibited that the FA-2-b-B protein complex has a significant proapoptotic and antiproliferative effect, suggesting that the intake of Agaricus blazei Murill may provide an effective alternative approach for the management and treatment of chronic myeloid leukemia [174]. Table 3. List of some significant mushroom species evaluated in clinical trials [171]. Jeitler et al. reported a considerable decrease in anorexia over time after 6 cycles of Agaricus sylvaticus combined with chemotherapy; simultaneously, some side effects such as anorexia, vomiting, diarrhea, nausea, and constipation were observed in the placebo group [175]. Coriolus versicolor was used for the treatment of hepatocellular carcinoma patients that are mostly inoperable. No difference was observed with the Coriolus versicolor treatment compared to the placebo group, possessing an improved quality of life compared to the placebo on the treatment. This study suggested using a supplementation for palliative care [176].

Mushroom
The Agaricus bisporus (white button mushroom) powder was used for the treatment of prostate cancer. A continuous rise in the levels of a prostate-specific antigen (PSA) was observed in patients with prostate cancer; an escalation in the PSA level may direct the recurrence of the disease. The results showed a therapy-induced drop in myeloid-derived suppressor cells, and patients with partial and complete responses exhibited increased baseline interleukin-15 levels compared to the non-respondents [177]. Torkelson et al. conducted a phase-I trial using Trametes versicolor against immune-compromised patients of breast cancer. They reported an improved immune status with the enhanced activity of natural killer cells, lymphocyte counts, and a dose-dependent increase in CD 8+ T-cells and CD 19+ B-cells. It can be suggested that a Trametes versicolor treatment can be used to improve the immunity levels in the immune-compromised patients of breast cancer [178].

Conclusions
The extracts or bioactive compounds from plants and fungi exhibit several mechanisms with anti-tumor effects. The mushroom and plant-derived bioactive compounds may regulate or activate the immune system, by disturbing the immune cell's maturation, differentiation, and proliferation mechanisms, thus inhibiting the growth of cancer cells. Plant-derived compounds may not directly be used as drugs, but they encouraged the researchers to design and develop novel anticancer agents. A thorough understanding of the mechanisms of action of plant and mushroom-derived bioactive compounds with anticancer properties is essentially required for cancer treatment, providing cancer patients with an improved quality of life. However, the clinical studies of numerous plant and mushroom-derived bioactive compounds reveal significant anticancer potentials with immunomodulation and the reduced side effects of conventional treatments. Consequently, more clinical studies must be conducted, particularly by applying a prime methodology, standard preparations, large sample sizes, and long-lasting follow-ups. Future studies should also focus on establishing the preventive or defensive aspects of plants and mushrooms for reducing the development of cancers, by including them in one's daily life for a healthy diet.