**5. Flavonoids**

The *Saccharomyces cerevisiae* strains have been developed by researchers, which synthesize various flavonoids, from the main phenolic intermediates to flavones, flavanones, flavonols and isoflavones. Phenylalanine is transformed into p-coumaric acid, a common phenylpropanoid precursor, in two sequence reactions in the initial steps of the phenylpropanoid pathway. *S. cerevisiae* is an ideal flavonoid host strain. One of the first studies on *S. cerevisiae* for flavonoid production was carried out according to [21]. The first flavonoid analysis was published on the synthesis of naringenin, major intermediate of flavonoid, from glucose in engineered *Saccharomyces cerevisiae* [22]. In *Saccharomyces cerevisiae* p-coumaric acid was used as a precursor for other flavonoids including apigenin, chrysin and luteolin. Anti-inflammatory, cardio-protective and anticancer effects were observed for quercetin, kaempferol, and fisetin [23].

More flavonoid intake has been reported to reduce cancer risk. In this respect, there have been reports of a variety of mechanisms including arresting of cell cycle, proliferation inhibition, apoptosis induction, anti-oxidation etc. These flavonoid extracts' cytotoxic activity makes them capable to produce cancer drugs. Flavonoids from *Saccharomyces cerevisiae* have potential to treat cancer treatment at all stages is therefore important for the recognition of harmless constituents against cancer as important for chemotherapy. Therefore, for producing cancer medicines, it is important to distinguish effective components from the yeast strain. Flavonoid-treated HeLa cells displayed apoptosis and loss of mitochondrial membrane potential (MMP). The toxic effect of flavonoid extracts makes them attractive candidates for cancer drug development. Such treatments have been found to inhibit growth across many lines of cancer cell, including cancer of the colon, breast cancer, carcinoma of squamous cell and hepatocellular carcinoma etc. Another study concerning bioactive flavonol "fisetin" found that fistein treatment caused cell viability by regulating the arresting G1 phase of human in melanoma cells [24].

## **6. Terpenoids**

Many terpenoids were developed by engineering the related metabolic pathways in *Saccharomyces cerevisiae*. The first study about the medically useful development of terpenoids in yeast was the amorphadiene synthesis in *Saccharomyces cerevisiae*. The sigma ling of NF- κB, the key regulator in pathogenesis for cancer and inflammation, can be inhibited by natural terpenoids. Various mechanisms, such as the induction of apoptosis, have been found in terpenoid cancer. The natural terpenoids are quite well identified as NF-κB signaling inhibitors. Yeast also produces taxol (class of di-terpenoid), which is a common cancer medicine [25]. *Saccharomyces cerevisiae* has been metabolically adapted for the synthesis of taxa diene as a primary trial for taxol synthesis in a microbial host [26]. Paclitaxel (generally called taxol) is a common and strong drug used in chemotherapy for cancer. Taxol has the anti-tumor property due to its attachment to microtubule protein i.e. β-tubulin. As a result, the micro tubular dynamics have been suppressed and acetylation of α-tubulin protein has been increased. Mitosis can be prevented by increase in micro tubular and thus contributes to the cell's death.

The carotenoids were the first kind of isoprenoids formed in the *Saccharomyces cerevisiae*. These compounds are found to cardiovascular and osteoporosis antioxidant with therapeutic effects and to have anticancer activity by the activation of the NF-κB signaling pathway. LPS are reduced by signaling caused by β-carotene. It also reduces the IκB protein and prevents p65 subunit nuclear translocation and also prevent the NF-κB complex binding with DNA. β-carotene prevents cancer progression by virtue of its proxidant function [27].

#### **7. Polyketides**

Polyketides form a large group of bioactive compounds, which vary in pharmacology and structure, and cover different drugs like antibiotics and antitumor. The polyketides are synthesized by large enzymes called polyketide (PKS) as secondary metabolites in particular by fungi and bacteria. The Synthesis of dihydrochalcones (DHCs) is an example of the polyketide development of metabolic *Saccharomyces cerevisiae* strain. One polyketide derivative with antidiabetic and antioxidant activity is DHCs such as nothofagin and phlorizin. Preclinical trials indicate that its

**115**

**Figure 3.**

*Targets of* Saccharomyces cerevisiae *secondary metabolites in tumor cells [9].*

*Secondary Metabolites from* Saccharomyces cerevisiae *Species with Anticancer Potential*

primary effect is to disrupt the dynamics of microtubule by reducing micro tubular polymerization and contribute to apoptosis. However, the mechanisms used to regulate eribulin's action were not fully elucidated [28]. Other pre-clinical studies in eribulin have demonstrated its ability in breast and colon cancer to suppress tumor growth in xenograft models of mouse. In metastatic breast cancer trials, clinical studies have shown that this compound is viable. Additional phase III analysis showed that eribulin as though only other two therapeutic drugs (taxane and anthracyclines) increases overall survival in pre-treated patients with severe breast

Activation of the caspase is conducted along two separate routes: the cell membrane mediated pathway of the death recipient and the mitochondrial pathways. Rising Bax protein levels with a related decrease in the Bcl-2 protein have been shown by the two studies. A rise in the Bax/Bcl-2 ratio is well known to encourage cytochrome c release from mitochondria into the cytosol, culminating in the triggering of caspase-3, which is a cause for apoptosis initiation. A variety of signal transduction pathways and regulatory pathways contribute, among other things, to the upregulation of apoptosis genes are recorded to involve protein–protein interactions (PPIs) and their associated protein [30]. STAT-3 seem to have an effect on the migration of the tumor and glioblastoma cells, non-small cell lung cancer (NSCLC), renal system of human which have shown a metabolite disturb this

*DOI: http://dx.doi.org/10.5772/intechopen.95067*

cancer (**Figure 3**) [29].

*Secondary Metabolites from* Saccharomyces cerevisiae *Species with Anticancer Potential DOI: http://dx.doi.org/10.5772/intechopen.95067*

primary effect is to disrupt the dynamics of microtubule by reducing micro tubular polymerization and contribute to apoptosis. However, the mechanisms used to regulate eribulin's action were not fully elucidated [28]. Other pre-clinical studies in eribulin have demonstrated its ability in breast and colon cancer to suppress tumor growth in xenograft models of mouse. In metastatic breast cancer trials, clinical studies have shown that this compound is viable. Additional phase III analysis showed that eribulin as though only other two therapeutic drugs (taxane and anthracyclines) increases overall survival in pre-treated patients with severe breast cancer (**Figure 3**) [29].

Activation of the caspase is conducted along two separate routes: the cell membrane mediated pathway of the death recipient and the mitochondrial pathways. Rising Bax protein levels with a related decrease in the Bcl-2 protein have been shown by the two studies. A rise in the Bax/Bcl-2 ratio is well known to encourage cytochrome c release from mitochondria into the cytosol, culminating in the triggering of caspase-3, which is a cause for apoptosis initiation. A variety of signal transduction pathways and regulatory pathways contribute, among other things, to the upregulation of apoptosis genes are recorded to involve protein–protein interactions (PPIs) and their associated protein [30]. STAT-3 seem to have an effect on the migration of the tumor and glioblastoma cells, non-small cell lung cancer (NSCLC), renal system of human which have shown a metabolite disturb this

*Saccharomyces*

cells [24].

**6. Terpenoids**

tubular and thus contributes to the cell's death.

progression by virtue of its proxidant function [27].

More flavonoid intake has been reported to reduce cancer risk. In this respect, there have been reports of a variety of mechanisms including arresting of cell cycle, proliferation inhibition, apoptosis induction, anti-oxidation etc. These flavonoid extracts' cytotoxic activity makes them capable to produce cancer drugs. Flavonoids from *Saccharomyces cerevisiae* have potential to treat cancer treatment at all stages is therefore important for the recognition of harmless constituents against cancer as important for chemotherapy. Therefore, for producing cancer medicines, it is important to distinguish effective components from the yeast strain. Flavonoid-treated HeLa cells displayed apoptosis and loss of mitochondrial membrane potential (MMP). The toxic effect of flavonoid extracts makes them attractive candidates for cancer drug development. Such treatments have been found to inhibit growth across many lines of cancer cell, including cancer of the colon, breast cancer, carcinoma of squamous cell and hepatocellular carcinoma etc. Another study concerning bioactive flavonol "fisetin" found that fistein treatment caused cell viability by regulating the arresting G1 phase of human in melanoma

Many terpenoids were developed by engineering the related metabolic pathways in *Saccharomyces cerevisiae*. The first study about the medically useful development of terpenoids in yeast was the amorphadiene synthesis in *Saccharomyces cerevisiae*. The sigma ling of NF- κB, the key regulator in pathogenesis for cancer and inflammation, can be inhibited by natural terpenoids. Various mechanisms, such as the induction of apoptosis, have been found in terpenoid cancer. The natural terpenoids are quite well identified as NF-κB signaling inhibitors. Yeast also produces taxol (class of di-terpenoid), which is a common cancer medicine [25]. *Saccharomyces cerevisiae* has been metabolically adapted for the synthesis of taxa diene as a primary trial for taxol synthesis in a microbial host [26]. Paclitaxel (generally called taxol) is a common and strong drug used in chemotherapy for cancer. Taxol has the anti-tumor property due to its attachment to microtubule protein i.e. β-tubulin. As a result, the micro tubular dynamics have been suppressed and acetylation of α-tubulin protein has been increased. Mitosis can be prevented by increase in micro

The carotenoids were the first kind of isoprenoids formed in the *Saccharomyces cerevisiae*. These compounds are found to cardiovascular and osteoporosis antioxidant with therapeutic effects and to have anticancer activity by the activation of the NF-κB signaling pathway. LPS are reduced by signaling caused by β-carotene. It also reduces the IκB protein and prevents p65 subunit nuclear translocation and also prevent the NF-κB complex binding with DNA. β-carotene prevents cancer

Polyketides form a large group of bioactive compounds, which vary in pharmacology and structure, and cover different drugs like antibiotics and antitumor. The polyketides are synthesized by large enzymes called polyketide (PKS) as secondary metabolites in particular by fungi and bacteria. The Synthesis of dihydrochalcones (DHCs) is an example of the polyketide development of metabolic *Saccharomyces cerevisiae* strain. One polyketide derivative with antidiabetic and antioxidant activity is DHCs such as nothofagin and phlorizin. Preclinical trials indicate that its

**114**

**7. Polyketides**

system which indicates that the mechanism is likely to slow or suppress solid tumors in the metastatic process [31].

### **8. Non-ribosomal peptides (NRPSs)**

Gurma is a 35-residue peptide widely used as a medical product in sweet-tasting transduction studies because of its ability to specifically inhibit neural responses for sweet matter in rats and mice is an example of the non-ribosomal peptide synthesis in modified yeast. Early research has shown that NRPSs are involved in the development of some of our key antiviral, anticancer, antibacterial and immunosuppressant medicines even though they are not progenitors of this ribosome. It has been determined the bleomycins are a group of glycosylated peptides which Umezawa and his colleagues found to be active against cancer in the 1960s. Bleomycin A2 and B2 is a major component of the clinical medicine, blenoxane. Carcinoma of cell squamous, lymphomas, esophageal cancer, testicular cancer and recalcitrant warts have been treated with blenoxane. This iron-bleomycin complex, mostly ferrous ions which interacts with oxygen and creates reactive free radical. Specifically, the free radicals respond to the abstraction of DNA deoxyribose hydrogen from C4' and lead to one or two-strand breaks, mainly of G-T and G-C at pyrimidines [32].

Several compounds for the production of novel anticancer drugs have recently come into being. However, the pathways involved in the cytotoxicity of these compounds in tumor cell lines are still widely ignored but many studies point to a significance in apoptosis. For example, a number of compounds impeding cell growth in a wide range of cell lines of cancer have been shown to be still poorly elucidated by which canner cells are hampered. Compounds were identified in some cases to cause cell death by the triggering of the apoptotic pathway; however, more studies were required in the mechanisms involved apoptosis. Some compounds created an imbalance in the ability of the cell redox, with mitochondria playing a key role in this phase. Further studies are required to explain this, however. A further impaired process is cell cycle, primarily as a result of actin and micro tubular filament interruption, yet only a few studies are conducted to link marine NRPs with cell cycle alterations, and further research are necessary to clarify their intervention in the process [33].

## **9. Vitamin C**

L-ascorbic acid (Vitamin C and L-AA or) is a water-soluble effective antioxidant used as a ROS scavenger to defend against or at least reduce the harmful effects caused by ROS in most eukaryotic species. ROS is a common source of various types of cancer and considered vitamin C have a beneficial impact on reductions of lung, colorectal and stomach cancer [34]. On the other hand, vitamin C can, under some circumstances, enhance the production of ROS and may have adverse effects under some circumstances [35].

However, the ability of yeast cells to generate L-AA is normal. Erythro-ascorbic acid is instead present at a low concentration in yeast cells as a structurally connected substance with chemical composition identical to L-AA. The vitamin C biosynthesis from D-glucose in *S. cerevisiae* cells that was recombinant by using a plant paths is first recorded according to [36]. In two distinct strains, ascorbic acid accumulation was shown to be effective, and the effect from a distinct genetic context was studied in parallel [37].

**117**

*Secondary Metabolites from* Saccharomyces cerevisiae *Species with Anticancer Potential*

Further studies on the kinds of chemical components and the purification of different bioactive groupings could show the full capacity for certain pathogenic microbes inhibited by the *Saccharomyces cerevisiae* extract. The creation of a catalog of *Saccharomyces cerevisiae* processing hosts which are produced for the supply by the overproduction of central metabolites of sufficient precursors for heterologous pathways introduced can be aimed at future efforts in the sector. These modified strains often have the effect of modifying the functioning of organelle and cell membrane processes in order to enable the efficient use of substrates, product

Additional crucial components are the compatibility between the introduced foreign secondary metabolite genes and the *Saccharomyces cerevisiae* host, including highly enhanced host pathway expression, metabolic stress/contamination, sufficient resistance/export of secondary metabolites etc. The strengthening of the hierarchical regulatory waterfalls within the host cell and the incorporation of appropriate promoters into the inserted BGC could help to improve the BGC expression for the secondary bioactive metabolite of an engineered host. Then, the resistant and exporting genes derived from or from original biosynthetic gene clusters or selected from other clusters of genes, other secondary source metabolites or even environment metagenomes might reduce the toxicity and metabolic burden on the host cell due to synthesis of secondary metabolites. In the coming years activities in other yeast species will be further investigated in order to identify additional results and obtain more high-performance products in this area instead

of *Saccharomyces cerevisiae* in pharmaceutical secondary metabolites.

In summing up this paper, remarkable developments in the field of yeast cell and molecular biology have taken place in the last two decades, especially as cell engineering, genome sequencing and synthetic technology have grown rapidly. Many useful pharmaceuticals and metabolites were developed using modified *Saccharomyces cerevisiae*. These results support a strong prediction that secondary metabolites from *Saccharomyces cerevisiae* can be perceived to occur as single pharmacological compounds. The metabolites also target key regulatory pathways in cancer cells, normal cells and tissues. Until human trials are launched on cancer subjects, fungal metabolites must, however, undergo stringent quality control and pharmacological dose-scaling evaluations. In addition, high-end screening methods need to be standardized because new metabolites are constantly identified for the yeast metabolite library survey. Isolating and altering these secondary metabolites would

*DOI: http://dx.doi.org/10.5772/intechopen.95067*

exports, intermediate retention and partitioning.

enable the development of chemotherapy drugs.

**10. Future perspectives**

**11. Conclusion**

*Secondary Metabolites from* Saccharomyces cerevisiae *Species with Anticancer Potential DOI: http://dx.doi.org/10.5772/intechopen.95067*

## **10. Future perspectives**

*Saccharomyces*

pyrimidines [32].

in the process [33].

some circumstances [35].

context was studied in parallel [37].

**9. Vitamin C**

in the metastatic process [31].

**8. Non-ribosomal peptides (NRPSs)**

system which indicates that the mechanism is likely to slow or suppress solid tumors

Gurma is a 35-residue peptide widely used as a medical product in sweet-tasting transduction studies because of its ability to specifically inhibit neural responses for sweet matter in rats and mice is an example of the non-ribosomal peptide synthesis in modified yeast. Early research has shown that NRPSs are involved in the development of some of our key antiviral, anticancer, antibacterial and immunosuppressant medicines even though they are not progenitors of this ribosome. It has been determined the bleomycins are a group of glycosylated peptides which Umezawa and his colleagues found to be active against cancer in the 1960s. Bleomycin A2 and B2 is a major component of the clinical medicine, blenoxane. Carcinoma of cell squamous, lymphomas, esophageal cancer, testicular cancer and recalcitrant warts have been treated with blenoxane. This iron-bleomycin complex, mostly ferrous ions which interacts with oxygen and creates reactive free radical. Specifically, the free radicals respond to the abstraction of DNA deoxyribose hydrogen from C4' and lead to one or two-strand breaks, mainly of G-T and G-C at

Several compounds for the production of novel anticancer drugs have recently

L-ascorbic acid (Vitamin C and L-AA or) is a water-soluble effective antioxidant

However, the ability of yeast cells to generate L-AA is normal. Erythro-ascorbic acid is instead present at a low concentration in yeast cells as a structurally connected substance with chemical composition identical to L-AA. The vitamin C biosynthesis from D-glucose in *S. cerevisiae* cells that was recombinant by using a plant paths is first recorded according to [36]. In two distinct strains, ascorbic acid accumulation was shown to be effective, and the effect from a distinct genetic

used as a ROS scavenger to defend against or at least reduce the harmful effects caused by ROS in most eukaryotic species. ROS is a common source of various types of cancer and considered vitamin C have a beneficial impact on reductions of lung, colorectal and stomach cancer [34]. On the other hand, vitamin C can, under some circumstances, enhance the production of ROS and may have adverse effects under

come into being. However, the pathways involved in the cytotoxicity of these compounds in tumor cell lines are still widely ignored but many studies point to a significance in apoptosis. For example, a number of compounds impeding cell growth in a wide range of cell lines of cancer have been shown to be still poorly elucidated by which canner cells are hampered. Compounds were identified in some cases to cause cell death by the triggering of the apoptotic pathway; however, more studies were required in the mechanisms involved apoptosis. Some compounds created an imbalance in the ability of the cell redox, with mitochondria playing a key role in this phase. Further studies are required to explain this, however. A further impaired process is cell cycle, primarily as a result of actin and micro tubular filament interruption, yet only a few studies are conducted to link marine NRPs with cell cycle alterations, and further research are necessary to clarify their intervention

**116**

Further studies on the kinds of chemical components and the purification of different bioactive groupings could show the full capacity for certain pathogenic microbes inhibited by the *Saccharomyces cerevisiae* extract. The creation of a catalog of *Saccharomyces cerevisiae* processing hosts which are produced for the supply by the overproduction of central metabolites of sufficient precursors for heterologous pathways introduced can be aimed at future efforts in the sector. These modified strains often have the effect of modifying the functioning of organelle and cell membrane processes in order to enable the efficient use of substrates, product exports, intermediate retention and partitioning.

Additional crucial components are the compatibility between the introduced foreign secondary metabolite genes and the *Saccharomyces cerevisiae* host, including highly enhanced host pathway expression, metabolic stress/contamination, sufficient resistance/export of secondary metabolites etc. The strengthening of the hierarchical regulatory waterfalls within the host cell and the incorporation of appropriate promoters into the inserted BGC could help to improve the BGC expression for the secondary bioactive metabolite of an engineered host. Then, the resistant and exporting genes derived from or from original biosynthetic gene clusters or selected from other clusters of genes, other secondary source metabolites or even environment metagenomes might reduce the toxicity and metabolic burden on the host cell due to synthesis of secondary metabolites. In the coming years activities in other yeast species will be further investigated in order to identify additional results and obtain more high-performance products in this area instead of *Saccharomyces cerevisiae* in pharmaceutical secondary metabolites.

## **11. Conclusion**

In summing up this paper, remarkable developments in the field of yeast cell and molecular biology have taken place in the last two decades, especially as cell engineering, genome sequencing and synthetic technology have grown rapidly. Many useful pharmaceuticals and metabolites were developed using modified *Saccharomyces cerevisiae*. These results support a strong prediction that secondary metabolites from *Saccharomyces cerevisiae* can be perceived to occur as single pharmacological compounds. The metabolites also target key regulatory pathways in cancer cells, normal cells and tissues. Until human trials are launched on cancer subjects, fungal metabolites must, however, undergo stringent quality control and pharmacological dose-scaling evaluations. In addition, high-end screening methods need to be standardized because new metabolites are constantly identified for the yeast metabolite library survey. Isolating and altering these secondary metabolites would enable the development of chemotherapy drugs.
