Exploring the Anti-cancer Potential of Microalgae

Abstract

Cancer, the deadliest disease in the world, is taking away the lives of millions of people. The disease and its property of metastasis are still understudied. Various therapies have been discovered to cure this malignancy, but nearly all of them introduce a lot of side effects. Therapies such as radiation, chemotherapy, surgery, etc., are in vogue but are not so economical and approachable for many needy people. Since the nature of cancerous cells is very complex among different individuals, it becomes even more complex to treat them. In modern times, biologically active compounds extracted from plants, weeds, and, most importantly, algae (marine drugs) found in the sea have proved to possess excellent anti-cancer potential. However, the major bottlenecks are the extraction of active substances in ample quantity with high quality. This chapter describes the role of microalgae as anticancer agents. Several aspects of bioactive compounds and challenges linked to microalgae will be discussed. A brief account of nanotechnology and its role in the treatment of cancer in the context of microalgae will be highlighted. The level of algal properties that affect cell proliferation, cell arrest, and apoptosis is elaborated. The current scenario of this investigation is extensively discussed in the study, along with the chemical structure, pros and cons.

1. Introduction

Cancer, the second leading cause of death worldwide, is severely affecting the health of our society and the circumstances do not appear to improve [1]. The continuous and exponential cell division amplifies the tumor and leads to metastatic cancer [2]. Several drugs are designed to treat the disease. Therefore, the cost touches the sky, it requires that the cell lines which are isolated from the biopsy are found to be different varieties that require personalized medication [3]. The standard chemotherapy comprises radiation, medication, and drugs, that after some time show the side effects [3, 4]. Besides this, the ideology used is that the target is to destroy the cell line which is killing the natural defense cells as well as the other cells which are captured by these tumor cells and leading to proliferation [5]. Sometimes, the cancer is cured completely but after years, it comes back, and this stage is secondary metastasis [6].

Nature might have the solution to this problem as well [7]. The microalgae, which can be easily cultivated and can tolerate extreme environmental conditions, prove to be suitable for various purposes [4, 8]. The extensive variety of microalgae can open the doors for various chemical and biological interactions, which could lead to treatment pathways [4]. The unique compounds found in the microalgae are derived and experimented with cancer cell lines [9]. This treatment can be effective and has a high biological activity for the purpose [10]. The microalgae can be effortlessly cultured and nurtured in bioreactors. From this, enormous biomass is obtained, which signifies it is renewable for various purposes [11]. It is still inadequately investigated for drug innovations [12]. They utilize the energy from the sun and fix carbon dioxide, which amplifies the greenhouse gas outcomes and eliminates nitrogen and phosphorus [13]. The activity depends on the variant of replicas’ nurturing conditions. It is a maker of stable isotopes 13C, 15N, and 2H [13]. The entity has many roles to play in pharmaceuticals, cosmetics, nutraceuticals, aquaculture, etc. [14].

The components of great importance found in them are lipids, proteins, carbohydrates, and nucleic acids, supplemented by pigments, vitamins, minerals, and polysaccharides [13]. The biologically active compounds found in the variants are for example acetylic acids, β-carotene, agar, agarose, alginate, PUFAs, vitamin B, lutein, etc. [15]. For instance, sterols are utilized to cure cardiovascular diseases. Most face, skin, and sun protection cosmetics incorporate microalgae into their composition [14]. For example, Tetraselcuis suecica, which belongs to the Chlorophyceae, gives 74g PUFA per kg. It is effective against lung adenocarcinoma. A549 is an alveolar base epithelial cell and H460 is a lung tumor cell line with an operative quantity of 5-μg μL⁻¹ [16, 17]. Chlorella vulgaris arrests cell proliferation and metastasis of lines H1299, which are non-small lung cancer cells extracted from lymph nodes, A549 adenocarcinoma alveolar base cells, and H1437 which is the same caused by p53 mutations. It is treated which affects the cell arrest at 200 μg mL⁻¹ [17, 18, 19]. The cost of biomass processing is high due to its poorly researched situation. It can be further augmented to obtain maximum benefit for various purposes. The exploitation of resources is yet to be done. Proper protocols and ethical issues must be retained [12]. Nature should not be hampered by treatments, industrial requirements, and research work [6]. It possesses antimicrobial, antifungal, antiviral, anti-HIV, anti-neurological, and anti-cancer qualities [20]. It also has its part in environmental issues like wastewater management and greenhouse effects. The component here is natural, safe, and renewable which is the biggest aspect to be researched, it invites the various departments of biological sciences, and the motif of fighting the cancer is attracted towards it [17].

2. Microalgae: a potential anticancerous source

Structurally, they are unicellular, photosynthetic microorganisms [13] and are seen as colorful plumes [21]. They have a simple cell structure [22], which is typically a marine or freshwater organism [23]. They transform sunlight, water, and carbon dioxide into algal biomass. Phosphorus, nitrogen, and carbon are the basic nutrients, which are required in high quantities for their growth and productivity [13]. They can form colonies and can also exist as filaments or spheres with the same kind of cells. The ability to carry out food making process, which is photosynthesis, is possible because of photosynthetic pigments [22]. The major chemical constituents are lipids, proteins, and carbohydrates [22]. Their ability to carry out the food making process, which is photosynthesis, is possible because of photosynthetic pigments [22]. The color is due to the pigments found in it, which are categorized as Chlorophyta (green), Rhodophyta (red), and Phaeophyta (brown) [13]. The different modes of nutrition are found in the variants whether it is autotrophs, heterotrophs, or mixotrophs [22]. They are capable of nitrogen fixation. The symbiotic relationship can also be found in fungi in lichens [22, 24]. Situations and nutrition when favorable can lead to algal bloom, which is red tide. The increased production of this releases a toxin that kills the fish. The species can absorb oxygen and hydrogen from water [6].

The microalgae have various aspects of being a potential source for medication [9]. It has several positive outlooks, which make it the best choice for people suffering from cancer [1]. The major priority basis is its production sources, bioactive substances, survival in extreme areas, adaptability, and cost efficiency [5]. The production of these species is very easy in the laboratory as well as in real-life areas. They are easily found, but their unique benefits can be reaped only when they are cultivated in different parts of the world [9]. The second aspect is the bioactive elements that are found in the variants [8]. They are proved to be very much fit to be applicable in the biotechnology sector. They are used in medications for various diseases and work as a drug delivery systems too [9]. It is a very good option for various processes, and in previous sections of this article, it is highlighted that it works effectively against malignancy with lesser or fewer side effects [25]. It is found in different areas, climates, and environmental conditions, so different varieties could be extracted and assessed to determine which element is suitable to fit in which sector and treatments [9]. It is cost-efficient because it is cheap and readily available, but everything which comes from nature expects humanity to pay the price for it [25].

The ethical issues need to be taken care of precisely. Nature should not be hampered, and it should not exceed the limit [9]. The medication for cancer and the different elements extracted from it work for different stages of the disease [26]. The concentration of that medicine needs to be altered according to the patient's stage of cancer, his body and health condition, and the characteristics of the medicine that depend on which phase it is made to act. Some medicines and compounds are naturally designed to inhibit or completely cease malignancy [27]. Some could act in an intravasation state, and some could lead to dormancy. The dormancy can lead to secondary metastasis, which then could relapse after some years [28]. The concentration of elements specifically matters, which is different for different patient’s according to the patient reports and conditions [27]. Chemo-prevention: the quality which either prevents or delays the onset of cancer [9]. Microalgae are adaptive, fast proliferation, renewable, and of interest for genetic process and modification for industrial purposes, and can be utilized as a whole [29]. It is autotrophic, which uses light for both positive and negative effects, like photo-inhibition. It requires secondary sources or metabolites for its various mechanisms, like protection, defense, etc. [9]. For instance, amino acids and peptides from Chlorella vulgaris protect the genetic evidence, hydroxyl radicals, scavenger effects, and gastrointestinal enzyme resistance, which comprises of 7.5 μm [30]. Algae variants with the mechanism of action and the cancer cell lines are presented in Table 1.

Algae name	Algal group	Mechanism of action	Cancer cell line	References
Enteromorpha intestinalis	Green algae	Invasion Cease cancer cell growth	HepG2	[31, 32, 33, 34]
Gayralia oxysperma	Green algae	Myotoxicity	U-87 MG	[35, 36, 37, 38]
Fucus evanescens	Brown algae	Anti-tumour activity	RPMI-7951	[39, 40]
Laminaria japonica	Brown algae	Induce apoptosis	HeLa cells; HT29	[41, 42]
Laurencia obtusa	Red algae	Anti-oxidative Cytotoxic Anti-metastatic	THP-1	[43, 44]
Padina tetrastromatica	Brown algae	Anti-proliferative	HeLa cells	[45, 46]
Sargassum horneri	Brown algae	Anti-Neuroinflammatory	DLD-1	[36, 38, 47, 48, 49]
Laurencia papillosa	Red algae	Cell cycle arrest Apoptosis	MCF-7	[49, 50]
Sargassum plagiophyllum	Brown algae	Anti-inflammatory action	HepG2; AG549	[49, 51]
Sargassum wightii	Brown algae	Cytotoxic	AG549; MCF7	[36, 38, 49, 51]

Table 1.

Algae variants with mechanism of action and the cancer cell lines.

3. Types of bioactive compounds

The biological elements found in a different classes of microalgae are beneficial for various diseases, and they acts as a treatment, which further helps in lowering the complexity of the ailment. Many therapeutic and pharmacological benefits can be availed [52]. The compounds act upon the tumors and could suppress their ability to metastasize. High-value chemicals (HVC) are isolated from variants of microalgae that could toxicant the cell at the cellular level, reduce the invasiveness of the tumor, and increase the possibility of apoptosis [17]. In Table 2 different types of bioactive compounds effective against cancer cell lines are presented in Table 2. A detailed overview of the different bioactive from microalgae are summarized below:

Effective extract	Potential	Cancer line/Treatment	Reference
Fucoxanthin	Induction of Apoptosis	Apoptosis of HL-60 cell line for leukaemia. Procaspase-3 is cleaved by mitochondrial permeabilization.	[53, 54]
Cryptophycin-1	Activity against solid tumour	Mouse lymphatic cells	[55, 56]
Borophycin	Cytotoxic effect	Human epidermoid cancer Colorectal adenocarcinoma	[57, 58, 59, 60]
Lyngbya majuscule	Suppress binding capacity of tubulin polymerization.	A549 Human lung cancer cell line	[9]
Coibamide - A	Cytotoxicity	H460 Lung cancer cell	[56, 61]
Astaxanthin	DNA-topo cleavage complex	KATO-III SNU-1 Gastric cancer cell line	[17, 62]
Dicosahexoienoic acid (DHA)	Cytotoxicity; Lipid upregulation	HT29 Colon tumour cell lines	[9, 57, 63]
Yessotoxin	Apoptotic death	HeLa cells death	[53, 64]
Scytonemin	Antiproliferative; Anti-inflammatory	Human fibroblast Endothelial cells	[62, 65]
C-phycocyanin	Alteration of DNA and fragmentation; Downregulate BCL-2 expression	HeLa cells Cervical cancer line MCF-7 Breast tumour cell line	[9]
Fucoxanthin	Induction of Apoptosis	Apoptosis of HL-60 cell line for leukaemia. Procaspase-3 is cleaved by mitochondrial permeabilization.	[54, 66]
Cryptophycin-1	Activity against solid tumour	Mouse lymphatic cells	[55, 56]
Borophycin	Cytotoxic effect	Human epidermoid cancer Colorectal adenocarcinoma	[57, 58, 59, 60]
Lyngbya majuscule	Suppress binding capacity of tubulin polymerization.	A549 Human lung cancer cell line	[9]
Coibamide - A	Cytotoxicity	H460 Lung cancer cell	[56, 61]
Astaxanthin	DNA-topo cleavage complex	KATO-III SNU-1 Gastric cancer cell line	[17, 62]
Dicosahexoienoic acid (DHA)	Cytotoxicity; Lipid upregulation	HT29 Colon tumour cell lines	[9, 57, 63]
Yessotoxin	Apoptotic death	HeLa cells death	[30, 53, 64]
Scytonemin	Antiproliferative; Anti-inflammatory	Human fibroblast Endothelial cells	[62, 65]
C-phycocyanin	Alteration of DNA and fragmentation; Downregulate BCL-2 expression	HeLa cells Cervical cancer line MCF-7 Breast tumour cell line	[9]

Table 2.

Bioactive compounds effective against cancer lines.

3.1 Pigments

Fucoxanthin, which is a carotenoid, can excite the tumor suppressor genes and cease the life cycle of the cell, but unfortunately, it cannot be effective for apoptosis. It is purified from microalgae, diatom, and brown seaweeds [67, 68]. When the agent 5-fluorouracil was blended with colorectal cancer, it showed good results. It works by natural medication inhibition and cure of reactive oxygen species (ROS) [69]. The basis is the deoxyribonucleotide acid cleavage of the topoisomerases complex, which is Box-2 [70]. It is the intermediate stability in the working catalytic aspect of topoisomerase that stimulates apoptosis [62]. An example includes astaxanthin-KATO-III and SNU-1 cell lines for gastric cancer. There is an escalated expression of p27 in gastric cell lines because of the kinase regulated by the extracellular environment (ERK) [62]. To treat rats with induced colon carcinoma, astaxanthin was utilized, but it is very expensive [64]. The anti-inflammatory action of nuclear factor Kappa (Nf-kB) [55] is responsible for creating disruptions leading to cancer, and one of them is breast cancer [57, 58]. Acetylenic carotenoids like Fucoxanthin HL-60, which homosapiens leukemia cell line [58]. C-Phycocyanin is a product of Spirulina platensis, which labors for pathological amendment, the formation of fragments of the genetic material, and the regression of Bcl-2 proteins, accelerates and excites caspase 2, 3,4,6,8,9,10 HeLa MCF-7 cell line [9]. Scytonemin is a natural sunscreen, and it ceases proliferation and inflammation. It is purified from Stigonema sp. It is not in favor of human fibroblast and endothelial cells [65].

3.2 Polysaccharide and Polyunsaturated fatty acids (PUFAs)

Polysaccharides are intracellular storage compounds. They also include an extracellular mucilaginous matrix or exopolysaccharides (EPS’) and sulfated polysaccharides [63] They provide several health benefits, such as anti-cancer, anti-inflammatory, and immunostimulant [71]. Chrysolaminarin, a food storage polymer, inhibits the proliferation of tumoral colon cells [72]. For example, chrysolaminarin from Chaetoceros muelleri showed an immuno-stimulatory effect. Sulfated polysaccharides have radical scavenging activity that prevents oxidative stress, which otherwise cause l chronic degenerative diseases [73]. Fucoidan-sulphated, which has a high amount of fucose and is isolated from kelp, is effective against HeLa cells and human uterine cancer [74]. GA3P (D-galactose+ L-(+) Lactic acid) constrains the DNA topoisomerase I and II duties and is further obtained from the dinoflagellate Gyminidium [70]. The microalgae are rich in docosahexaenoic acid (DHA) which results in toxic accumulation in cells and highly controlled lipid peroxidation [9]. It stimulates programmed cell death of colonic malignant cell HT29 and aggregation of DHA in cardiolipin. In stomach cell lines, the compound DHA escalates in-cell cytochrome c, Bax, and p53 [57].

3.3 Toxins and polyketide

Algal species, Protoceratium reticulatum, Yessotoxins are isolated, which intensifies the apoptotic death in HeLa cells. It could upturn pathological group of cell alterations, segregation of genetic material, and changes in membrane potential of a powerhouse of the cell [53]. The neurotoxin Cryptophycin1, which is obtained from Nostoc sp. GSV 224, shows promising results against solid tumors and cell lines [56]. Cryptophycin-8 is a semi-synthetic alternative of Cryptophycin, which exhibits action on proliferation in vivo [9] Borophycin is an acetate derivative of polyketide. It is mined from marine Spongioform [59]. It shows its activity in kB cell lines, which are supposed to contain human papillomavirus18 sections, and LoVo lines, which were first found in a supraclavicular region with the diagnosis of colon cancer. It works as a cytotoxic agent against human epidermoid and colorectal tumors [60]. Bio-product by Lyngbya majuscule, Cucarin-A is operative for breast and renal carcinoma [75]. It dominates the binding capacity of the process of making polymers of tubulin into the formation of a Colchicine pocket for binding [9].

3.4 Peptides

As basic knowledge or key concept, which delivers the point that peptide, is obtained from enzymatic hydrolysis, which means the cleavage of bonds by water in which enzyme is involved [9, 76]. Dolastatin works for human ovarian and colon malignant tumors. The B16, colon 26 adenocarcinoma, and M50 76 sarcoma and HT29 [77]. The medicine is extracted from lyngbya sp. and sympleca sp. The Chlorella vulgaris isolated peptide stops AGS gastric cancer after the stage of the G1 step of the life of a cell. Algal sulfolipids, which are subjected to Nostoc ellipsosporum, are operational against HIV [78]. It can also be extracted from E.coli, which could even deactivate HIV. The glycolipids are effective against HT29 in colorectal cell lines which also use 5-fluorouracil and oxaliplatin for the cure [79].

4. Cancer: a leading cause of death

Cancer is the leading cause of death worldwide [9]. It is a disorder, which has no standard treatment feasible for all. To treat cancer, chemotherapy, radiation, targeted drug delivery are standardized [12]. However, the matter of fact is that there are numerous cancer cell lines, which makes treatment a tedious process. As a basic fact, the structure and type of tumor line found in a person are often different for different people [80]. The cells multiply exponentially [9]. They are very invasive, and the process of extravasation goes hand in hand, which makes it even more miserable [57]. Studies show that the neoangiogenesis in these cancer cells is highly disorganized. It all is detected later [80]. In addition, by that time tumors would have invaded the primary site and even metastasized to the secondary site for invasion and development [3]. The technology and methodology we possess are not able to detect the growth at the earliest. The treatment and detection technology should increase its accuracy and should be able to detect to the earliest. That is why microalgae are combined with different technologies to treat malignancy [14]. The basic objective is to at least cease the process if it cannot be removed completely [80]. The area of marine chemotherapeutics is scarcely researched and if done it has sure that the cure of the disease lies on this planet and this land only [9]. Figure 1 depicts the hallmarks of cancer.

Figure 1.

Illustration depicting hallmarks of cancer.

4.1 Bio-engineered microalgae: systematic approach

Microalgae are produced naturally but not in so much abundance that they could help in research, medical, and other fields [66]. Therefore, it is cultured and grown artificially to meet the requirements. To protect environmental and ethical issues, the consumption of this nature’s gift is kept to a minimum [81]. Now on the take for medical fields, the compound cannot be directly taken or consumed intravenously, there is a proper procedure to use up [66]. The bioactive compound, which shows potential as an anti-cancer agent, needs to be fully accepted by the body to get maximum benefits [82]. Here comes the role of genetic engineering, which further modifies and makes microalgae and other special compounds hostile to the human body [82]. The complete transformation is a required process for the nucleus and chloroplast. However, the studies point out the biological synthesis of lipids, carotenoids, and photosynthesis. Chlamydomonas reinhardtii is the supreme class for modification and engineering processes [83]. The lipids and carotenoids have the utmost qualities, which were discussed with several examples in previous sections [84]. The latest update regarding this is the use of the CRISPR gene editing tool, but it might not work on all microalgae as it also has some of its limitations like delivery by the large size of proteins, activity of nuclease activity, etc. In this section, the study of RBCM-Algae is taken [85]. The microalgae are isolated from Chlorella vulgaris, which is engineered with red blood cells from human [86]. The purpose is to get a layer of blood on the membrane to serve some respectful purposes [87]. This engineered element promotes oxygen content and tumor tissues because the tumor grows better in hypoxia conditions and increasing the levels would make it sensitive [88]. Then it is subjected to irradiation, which many times is successful to remove the tumor completely [89]. But this is not always the case. It is effective against breast cancer [90].

4.2 Effectiveness over other therapies

The traditional protocol to treat tumor lines is radiation and chemotherapy [9]. This set does not usually affect the patient's condition in various aspects but numerous other factors in the body of the patient either benefit worsen day by day [11]. The survivor must be able to fight the tumor, but he won’t be able to fight the opportunist diseases which might take over [14]. These aspects only regress the condition of the body, which then many times leads to a relapse of the malignant tumor and then the person falls into cancer syndromes like cachexia [91]. The delay in detection of the tumor, carelessness, cost of the treatment, the ability of the cells to divide uncontrollably, metastasize to a secondary site, etc. point out the severity of the disease [91]. Research on the new drugs and different drug delivery systems is being done to provide maximum comfort and relief to the patient. The major side effect observed in the patient is that immunity is chiefly affected [9]. It is seen that the condition takes a toll toll on health [1]. The already in-market drugs, which are known as anti-malignant drugs, inhibit or cease the escalation of the outgrowth. It stimulates the action of the immune system and, along with it, triggers the killer cell activity naturally and initiates the defense mechanism of the host [9]. As it is known cancer multiplies in the hypoxia condition [3]. Cancer cells are immune to oxygen species which are reactive or scavenging capacity of the fundamental unit of cell stirs programmed cell death called apoptosis [92]. The standard chemotherapy eliminates tumor tissues, liver, nephron, nausea, anorexia, and mucous membrane inflammation [91]. The sector of nutraceuticals composed of antioxidant supplements is supposed to cover up for the side effects [9]. These are generally plant-based herbal medications, and the antioxidants polyphenols, carotenoids, etc. [25]. The chemicals produced by plants, which are called phytochemicals, work as antioxidants to perform defense against chemotherapy in normal cells by exerting pressure on radiation or other forms of treatment via oxidative stress [9].

4.3 Reactive oxygen species and its role in metastasis

As explained earlier, the electrons which are not paired up usually have one or two-electron atoms in the shell, which is the outermost shell [93]. It is formed in the body in the form of products like reactive species of oxygen, nitrogen, sulfur, etc. It is formulated by the cytosol [94]. One aspect of it is to get the form of a radical one with unpaired electrons, and the other one without unpaired electrons of these species [95]. It is also a form of secondary messenger [93]. The general question arising here is why oxidative stress occurs, and the easiest way of approaching the solution is that there is a misbalanced proportion in the generation and detoxification of the species [31]. The activation of all phases of them is by several transcription factors like NF-𝜿B, activator proteins like in AP, and p53, where most mutations take place [93]. It works in both directions; that is, it works in the tumorigenic’s favor as well as against the tumorigenic via signaling pathway of cancer MAPK/AP-1/NF- 𝜿B and it also triggers inflammation cytokines, chemokine, etc. [93]. when there is an escalation of reactive species, there is an elevation in cancer cell division. Tumor cells require higher levels of reactive oxygen species as cancer cells prefer to proliferate in hypoxia conditions without even cell death. Reactive species have a vital role to play in metastasis and angiogenesis [93]. It also provides resistance to chemotherapy [32]. The category of transporter protein P-glycoproteins which is thereby also known as a multi-drug resistant, that work on moving out of particles “efflux” of cancer-inhibiting drugs from malignant cells [31].

4.4 An experiment with Spirulina and cancer cell lines

The simplest experiment was performed with the help of Spirulina [28]. It was the key ingredient in the protocol. The easy methodology adopted was devised after considering cancer patients. The patients taking four cycles of chemotherapy were randomized into groups and categorized as “control” and “patient consuming the medication” [35]. In the first two cycles, the Spirulina was made to be consumed in 3 capsules of 100 mg each, 3 times a day [28]. The patients were taking their medications as normal, as prescribed. It influenced many things like it inhibits tumor growth interferon and interleukins like the TNF-alpha [35]. It works against HIV and increases the growth of CD4 cells and works on liver inflammation. The reduction of breast malignant is 87 to 13 percent [28, 39]. When the blood test was taken, the account of WBC and NEUTR. It was better with patients treated with spirulina and low for control [39]. The hemoglobin levels were approximately the same, whereas myelosuppression was lower in the treated patients rather than in the control group. IgM and CD8 were higher in treated patients [28]. The fact is that Spirulina slows down the MAPK pathway. When CD8 needs to be more numbered, as when it is exhausted, it increases apoptosis [39]. This was effective against HepG2, MCF-7, AG49, HT29 which are liver, breast, alveolar basal epithelial cell, and colon cancer cell lines respectively [28]. A few limitations were also reported like the population size was comparatively small, and the effects after treatment were not observed [28]. There was a lack of evidence for treatment applied to the neoplasm. Observation and research were not performed at the molecular level [35]. Vitamin extract from the algale variant is effective for metastasis treatment and its effectiveness is presented in Table 3. Coenzyme Q: Ubiquinone in combination with ɑ-lipoic acid and cisplatin ceasees colon cancer cell line HCT116 [29].

Vitamin	Algae source and potential	Cancer	Reference
Pro vitamin A	Tetraselmis suecica; Retinoland rhodopsin	Skin, Breast, Oral, Lung, Hepatic, Prostatic	[30, 96]
Cobalamin	Porphyra sp.; DNA repair, Methylation of histone, Folate elevation regress breast malignancy.	Lung cancer	[89, 97]
Ascorbic acid	Chaetocerosmuelleri; Regulate hypoxia condition via HIF1α and protects from opportunist tuberculosis infection.	Antioxidant effect in treatment	[29, 98]
Vitamin D	S. costatum; blocks cell cycle via CDK - p21, p27, preventing cancer, anti-neuro degenerative and alter insulin growth factor IGF-1	colorectal, breast, pancreatic and prostate	[29, 98]
Tocopherol	P. lutheri; per-oxidation of lipid, damage by oxidation	Pancreatic cancer	[29, 98]

Table 3.

Vitamin extract from algal variant effective for metastasis treatment and effectiveness.

5. Challenges and limitations

5.1 Life expectancy post-treatment

The cost of cancer treatment is always reported to be costly, and it is observed that the majority of the families couldn't even afford the treatment [41]. Developed countries tend to even afford it to some extent, but developing countries struggle a lot. Poor countries cannot even think of fighting cancer [9]. The treatment is not even accessible to many people. Going into depth and breaking some of the myths, the cost-bearing factor is subdivided by the stage of a cancer diagnosis [39]. It is based on how severe the malignancy is and what stage it is in transition to [41].

A person who gets diagnosed at the very first or early stage can fully recover from it and the billing amount is very less but if the stage is the second, third, or fourth stage, the bill amount tends to increase [28]. The body of the patient is often not even capable of surviving the chemo and radiation it becomes hollow [39]. The body loses its virtues and qualities, and eventually, the fight to defeat cancer fails and a high number of deaths have been reported in recent years [43]. The company for cancer drugs has increased several folds and the point to highlight here is that the treatment is costly due to the commercialization and industrialization of the medications [41]. People tend to believe the brand names of medications as safest but in fact, both the substances are the same [45].

The life expectancy factor comes into play when the treatment is done, and the patient is free from any kind of medication related to cancer [28]. The condition of the patient improves to some extent in the first or second stage, but it hasn't proven to be very beneficial for other stages or severe cases like leukemia [9]. The therapy if includes microalgae will increase the cost as well. The ethical issues need to be kept in check [8]. The availability and incorporation into the therapy will require new technology as well as a new system to sustain its shelf life as well [9]. The only way to have cheap treatment is to find out the fittest technology and techniques and fulfill the requirements as well as to have multiple units in countries so there is no stress for the production of medication [35]. Proper analysis and molecular studies need to be done for future updates [9].

5.2 Limiting factors of the treatment

Each treatment has its pros and cons, and so this also has the same [41]. The limitations reported were very few, and the research is being done to have a deeper knowledge of this aspect [45]. The high intake of nutraceuticals can be toxic, which can cause side effects rather than improvising the condition [9]. There should be a proper balance between the protection of healthy and tumor cells called prophylaxis and inhibition of the growth of only cancer cells known as therapeutic doses [31]. When the concentration of antioxidants increases, the low concentrations of free radicals escalate [3]. The supplements which are derived from plants and herbs are observed to have a higher risk of pharmacokinetic interaction with agents of chemotherapy [92]. The synergic effect is by concentration, which decides whether it is beneficial or harmful. The mixture of antioxidants increases that effect in several phases and is more important than a single one [9]. A limiting factor is an aspect that lowers the possibility of achieving the best. Here, comes the most important aid to getting the treatment, which is the cost [28]. The amount we pay includes goods and services tax (GST), hospital amenities and services, and imported medicines [35]. The medicines are very expensive because only developed countries have the services and industry to manufacture their medicines and could afford these medicines to some extent. But a large proportion of the world starves for it [41]. The technology and pharma industries take up their roles, which builds up their money graphs. Medicines and treatment are costly due to technology and less accessible to most people. The elite classes of society could afford them easily [43]. The point is the world doesn’t revolve around a small proportion. Many people use up all their savings, but very few can win the battle [28]. Supportive aids like antiemetics and other medications are already at higher rates. For instance, in the case of colorectal cancer, the use of cisplatin and fluorouracil types of drugs will increase the cost, and then the synthesis will increase it. Chemotherapy, diagnostics, and all add up to it [29].

5.3 Cultivation issues with microalgae

The cultivation of microalgae is required on a large scale considering its potential benefits for developing the target medicine and other applications. The need for arable land, light, oxygen, pH and other climatic conditions is required [12]. They can grow in various places, but they will possess various properties and potential [12]. If a specific industry requires a specific compound extract that is only found in a particular area, then these conditions are mandatory to be fulfilled [28]. Now, considering this, the laboratory where attempts are made to cultivate them, but they show setbacks. The setbacks include not being able to provide all conditions, chemicals to some extent, and obviously, the technology which makes it even harder to process [9]. The ability to protect it from contamination is a tough task as well [70]. Proper instruments are not there to aid in this. Nature is incredible as the laboratories are trying hard. To take a step further large bioreactors have opted, but they are not getting beneficial results [12].

5.4 Lack of technology and awareness

Cancer treatment requires more sophisticated technology. The invention is the mother of all innovations, so the technology has upgraded itself a lot. The biotechnology industries have grown so much because of the tools and medication [47]. The technology is an expensive brand, which costs a lot. It takes a lot for a technology to be launched and reach out to the people [50]. The technicians working on the prevention and treatment of cancer sometimes become clueless because proper protocol and complete research on a disease like cancer are still incomplete. The disease is an elaborative and extensive field that requires many aspects of treatment but is still not researched [51]. Technology and awareness are missing; therefore, the requirement is for a higher level that could diagnose cancer at the earliest stage, and surgery and chemotherapy should have alternative ways as well [36].

6. Recent advances and technology

The innovations take technology and techniques to sustain them. The betterment lies in the up-gradation of the recent technology and creating innovations in the current timeframe [12]. The more progressive the medication gets, the more effective it will become but more supplements are required to overcome the side effects [9]. Till now, no treatment has been found which is free of side effects [5]. The role of Spirulina is always vital and valued, even in space technology. The food additives like Chlorella vulgaris and Spirulina pacifica [28] their biomass production is used in several areas of biotechnology because of the bioactive molecules and composition that are beneficial. The primary and secondary metabolic products have found the place where they fits perfectly [19].

The bioactive elements have to cope with environmental stress, which stands out as a challenge. Some of the variant features are known and discovered and tested, while many are anonymous to the field till now [19]. The food industry, repair mechanisms, defense, etc. fields are very much flourishing but alterations and modifications cannot harm them [14]. The best way to use microalgae as a drug delivery system is fine, but combining it with nanotechnology can do wonders [98]. Nanotechnology promises a better future because of its compact size and dimensions and its adaptability to various metals and compounds, making it industrially and biologically acceptable and compatible [96]. The nanotubes or nanostructure can be successfully engineered and incorporated with other treatments [99]. Already, nanotechnology is working with various diseases and treatments. This combination can lead to better innovations and the betterment of humanity without even hampering nature [98].

At present, Nanotechnology is the leading technology that has evolved with time and is considered to be the best one to cure malignancy at a nanoscale level [99]. The biopolymer synthesized from carbon, platinum, and gold colloids can be taken up to cure the disease [100]. The nanorods prove to be beneficial for small tumors [9] as well as various sizes and morphologies of nanoparticles can be directly incorporated into the treatment [98]. The biological synthesis of the nanoparticle is not a complex phenomenon because no reducing, as well as capping agents, are involved. Instead, the bioactive compounds present in microalgae themselves act as strong reducing and capping agents leading to the synthesis of nanoparticles [100]. Sometimes both reducing, as well as capping agents, could also be added as a reactant to form the desired and most efficacious products. The reducing agent can be sodium citrate, sodium borohydride, or ascorbic acid, and the capping agent could be polymers like polyvinyl chloride, thiols, or citrate [98, 97]. The passivating agent is to prevent aggregation and promotes nucleation. The therapeutic molecule can also be kept inside the molecule synthesis so that it could target the tumor [28]. The schematic representation of nanoparticle synthesis from microalgae extracts is presented in Figure 2.

Figure 2.

Schematic representation of nanoparticle synthesis from algae.

Microalgae have various biotechnological applications. There is a need to have supplements and capsules that could be consumed to prevent cancer and are also proved to be human-friendly [9]. The algal extracts could directly be incorporated into them just like we intake probiotics [101]. Rapid advancement in pharmaceutical and diagnostic technology allow rapid blood tests could detect malignancy on an early stage [96]. A recent study shows promising results with this concept, it is proven to be effective against a few cancer cells lines [9]. There should be an advancement in technology to cultivate microalgae on a large scale without exploitation of nature, considering the ethical issue at top priority [9, 51]. People should be made aware of the benefits to humanity and the environment. Microalgae could be a gift and a curse to many issues be it environment, pharmaceutical, biotechnology, chemical industries, etc. [102]. This is a nature’s gift that is meant to cherished and protected [73, 103].

7. Conclusion

Microalgae are rich in industrial and human consumption needs and requirements. The present study is an attempt to highlight the importance and potential of bioactive compounds isolated from microalgae as an anti-cancer agent. The aim of presenting a suitable treatment with unique features and lesser side effects using nanotechnology and other technologies was discussed concerning the species of microalgae. The incorporation of bioactive compounds can be useful when the proper dosage required by the patient is known. The concentration of bioactive compounds added to the final formulation as anti-cancerous compounds should be added carefully in order to get the desired results. The antioxidants found in the microalgae prove to be anti-inflammatory, anti-cancer, anti-diabetic, and skin protectors as well. The microalgae have evolved to such an extent that they can thrive in extreme conditions, but still, they are a major oxygen supplier to the environment. Extensive and deep investigations need to be carried out to explore more varieties of microalgae so that they can be taken down for more experiments with cancer cell lines. A technology that could cultivate microalgae in the lab needs to be developed so that ethical issues are controlled and its proper utilization could lead to significant benefits. The role of nanotechnology can be important as the smaller the scale, the bigger the possibility of treating the disease. The aim is to assess and analyze the root cause, which has to be inhibited and removed to ensure a better lifestyle. A significant view is that technology is required for the cultivation of microalgae in a short period and diagnostic tools to identify tumor growth in the body.

Acknowledgments

This work was supported by the Department of Biotechnology (Grant No: BT/PR 15650/AAQ/3/815/2016).

Conflict of interest

The authors declare no conflict of interest.