Biomedicine & Pharmacotherapy 129 (2020) 110409

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Probiotics for cancer alternative prevention and treatment T

a, a,1 a,1
Tesfaye Legesse Bedada *, Tatek Kasim Feto , Kaleab Sebsibe Awoke ,
Asnake Desalegn Garedewb,1, Fitsum Tigu Yifatb,1, Dagim Jirata Birrib,1
a
Public Health Microbiology Research Team, Ethiopian Public Health Institute, P. O. Box: 1242, Addis Ababa, Ethiopia
b
Division of Microbiology and Infectious Diseases, Department of Microbial, Cellular and Molecular Biology, Addis Ababa University, Addis Ababa, P. O. Box: 1176,
Ethiopia

A R T I C LE I N FO A B S T R A C T

Keywords: Cancer is a fatal malignancy with high clinical significance and remains one of the major causes of illness and
Bacteria death. It has no suitable cure existing till now. The safety and stability of the standard chemotherapeutics drugs
Cancer and synthetic agents used to manage cancer are doubtful. These agents are affecting the quality of life or con-
Fungi tributing for development of drug resistance and are not affordable to the majority of the patients. Therefore,
Prevention
scientists are looking into clinical management of the cancer with high efficiency. This review focuses on the role
Probiotics
of probiotics as alternative prevention and treatment of cancer. In this regard, we discuss the alternative cancer
biotherapeutic drugs including live or dead probiotics and their metabolites, such as short chain fatty acids,
inhibitory compounds of protein, polysaccharide, nucleic acid and ferrichrome in in vitro, in vivo and clinical
studies. We also discuss the effectiveness of these biotherapeutics in prevention and treatment of various types of
cancer linked with probiotic bacterial or fungal strains, probiotic dose, and time of exposure. More in vivo mainly
clinical trials are necessary to further reveal and approve the significant role of live and dead probiotics as well
as their metabolic products in cancer prevention and treatment. Finally, the majority of the positive results
provided by probiotic treatments are limited to experimental settings. To minimize side effects associated with
probiotics, short and long term effect studies in the direction of methodology standardization are required.

1. Introduction state, and multiple steps of cancer cells developments are needed to
grow into tumorigenic and eventually malignant. These tumor cells
Cancer is a fatal malignancy with high clinical significance and display various physiological alterations including self-sufficiency in
remains one of the major causes of illness and death [1]. It is the second growth signals, insensitivity to signals growth inhibiting, apoptosis re-
leading cause of mortality globally [2]. The incidence and death have sistance, unlimited potential of proliferation, sustained angiogenesis
been gradually increasing throughout the past century in many areas of and metastasis [7].
the globe mainly in developing countries, with 18.1 million new cases The current clinical management of cancer is use of standard drugs.
of cancer in 2018 and 29.4 million in 2040 [3]. Some of the major types However, the long term safety and stability of these chemotherapeutics
of cancer that cause significant mortality are colorectal, prostate, lung, drugs and different synthetic agents for the treatment of cancer are
stomach, liver and breast cancers [4]. doubtful. Thus, these multi-drugs and hormonal chemotherapeutic
Cancer is caused by deficiency in DNA repair or mutations during agents not only kill the cancer cells but also damage the healthy cells
DNA replication and its major risk factors are environment exposure, and develop drug resistance [8]. In addition, these cytotoxic drugs are
lifestyle habits and genetic background of the individuals [5,6]. Some associated with life threatening side effects that mostly result worse
of these predisposing factors are infectious agents, toxic substances and than malignancy of the cancer itself [9].
UV radiation [7]. Since cancer has no suitable cure or remedy existing till now; the
Cancer is an uncontrolled cell division and generally identified at a number of patients suffering neoplastic syndrome is still rising; the
late stage its progression. It originates from a single cell and spreads current chemotherapeutic agents are affecting the quality of life or
throughout the body. Healthy cells change gradually to a neoplastic develop resistance and are not affordable to the majority of the patients,

⁎
Corresponding author.
E-mail addresses: tesfayelegesse21@gmail.com (T. Legesse Bedada), tateknice@gmail.com (T.K. Feto), kaleabsebsibe91@gmail.com (K.S. Awoke),
asnake.g2008@gmail.com (A.D. Garedew), fitsum.tigu@aau.edu.et (F.T. Yifat), dagimj@yahoo.com (D.J. Birri).
1
Equally contributed authors.

https://doi.org/10.1016/j.biopha.2020.110409
Received 11 April 2020; Received in revised form 3 June 2020; Accepted 13 June 2020
0753-3322/ © 2020 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/BY-NC-ND/4.0/).
T. Legesse Bedada, et al. Biomedicine & Pharmacotherapy 129 (2020) 110409

scientists are looking into clinical managements of the cancer with 2.1. Relationships of Probiotics, fermented foods and gut microbiota in
minimal side effects and high efficiency [10–12]. cancer prevention and treatment
To prevent and treat various types of cancer effectively, probiotics
play an important role. This is addressed in several studies [13]. The 2.1.1. Probiotics and fermented foods
term probiotic refers to functionality, not a taxonomic one. These Probiotics and fermented foods including fermented milk products
probiotic microbes are predominantly obtained from traditional fer- attract the attention of researchers from different fields [26]. Mixed
mented foods or from the gut. Probiotics should be naive strains or they microbes including bacteria, yeasts and molds are responsible for the
are genetic manipulation of any form. Probiotics are called live mi- natural fermentation [27]. Probiotics especially lactic acid bacteria
crobiological ingredients when used in dietary supplements or live including Lactobacillus, Bifidobacteria, and Streptococcus species can be
biotherapeutic agents when used as a drug. Probiotics are mostly used found naturally or ingested in fermented food products [28,29]. Fer-
by various companies including food, nutritional supplement and pro- mented foods, particularly the ones incorporating probiotic microbes,
biotic production companies [14]. Dead probiotics and their metabo- are considered to be healthy for human beings. Fermented foods possess
lites also convey significant benefits in prevention and treatment of distinctive functional properties such as production of enzymes, anti-
tumor cells [15]. microbial, peptide, and antioxidants and other probiotics properties
Currently, there are some anticancer reviews concerning probiotic [30]. These products have been found to play an important role in the
microbes that have mainly focused on live bacteria or colorectal cancer prevention and treatment of cancer [26].
(CRC) [11,12]. However, the current review is the first one to address In a case control study conducted by Veer in the Netherlands [31],
sufficiently the significance of bacterial and fungal probiotics in dif- fermented milk and cheese have been reported to prevent the incidence
ferent cancer types. It describes prevention and alternative treatment of breast cancer compared to the control, non-fermented milk. Recent
approaches of cancer. The potential roles of probiotics in cancer pre- studies suggested that, probiotics have an influence on various aspects
vention and treatment have been discussed. Finally, it provides basic of health and thus make life worth living during and after the treatment
understanding of the alternative cancer prevention and treatment of cancer [11]. Maroof et al. [10] shows that lactobacilli or other genera
means and mechanism. More in vivo mainly clinical trials are necessary of probiotics are used as an adjuvant treatment during anticancer
to further reveal and approve the significant role of live and dead chemotherapy. Further evidence indicates functional food as a source of
probiotics as well as their metabolic products in cancer prevention and probiotics can act potentially against breast cancer in in vivo animal
treatment. models by gut bacteria and the immune system modulation [32].
Other fermented products such as pomegranate juice are also re-
ported to be sources of polyphenolic compounds and have antioxidant
2. Probiotics effects used to avoid the development of K562 cancer cells [33]. Fer-
mentation process converts organic substances into different metabolic
Probiotics are live non-pathogenic microbes, that play a central role products including acids. These products inhibit the growth of patho-
in the host`s health benefits when administered in sufficient quantities genic microorganisms and degrade various toxins that may cause
[16]. Regardless of this definition, dead probiotics and their metabolic cancer. As an example, lactic acid bacteria fermentation can absolutely
secretions have the same or more response in different biological ac- abolish mycotoxins produced by fungi [34]. Another important antic-
tivities when compared to live probiotics [17]. The major character- ancer compounds are polyphenols which are commonly associated with
istics of probiotics are acid resistance, bile tolerance, mucosal or epi- fermented foodstuffs and beverages of plant origins such as vegetables,
thelial cells adhesion, antimicrobial resistance, bile salt hydrolase fruits, spices, nuts, soy, tea and wine [35–37]. Naturally occurring
potential [18], immunostimulation, antagonistic activity against pa- anthocyanins in blueberries, resveratrol in red wine, isoflavones in soy
thogens, antimutagenic and anticarcinogenic activities [19]. and epigallocatechin gallate in green tea are natural polyphenols
It is crucial to find potential strains of probiotics, effective admin- having the anticancer effects [38–40]. Polyphenols` anti-inflammatory
istration dose and prevention and treatment molecular mechanisms and antioxidant properties and modulation of molecular targets and
[20]. Probiotics and their probioactive cellular materials form several signalling pathways are associated with cell proliferation, cell survival,
beneficial effects in the gastrointestinal tract, and release different en- differentiation, angiogenesis, migration, hormone activities, detox-
zymes and form potential synergistic effects on digestion. Specific cel- ification of enzymes and immune responses. These activities are im-
lular constituents in probiotic lactic acid bacteria induce potential ad- portant for the effectiveness of natural polyphenols in potentially
juvant effects such as cell mediated immune responses modulation, fighting against cancer [41].
reticulo-endothelial system activation, cytokine pathways augmenta- The other unique features of probiotics are delaying the formation
tion, and interleukins and tumor necrosis factors regulation [21]. of tumor, inhibit the proliferation of cancer cells and prevent the life
Probiotics are mostly categorized into bacterial or lactic acid and threatening side effects that are associated with current cancer treat-
non-lactic acid bacteria strains, and yeasts. Lactobacillus, Lactococcus, ment [11]. Probiotics administration helps in prevention and treatment
Bifidobacterium and Enterococcus are common bacterial probiotics [20]. of CRC. They are helpful in the safety of traditional cancer therapies
Other potential probiotics are Clostridiales, Bacteroidales, Bacillus spp., managements such as chemotherapy, surgery and radiation therapy
Escherichia coli, enterococci and Weissella spp. [14]. Saccharomyces [42].
cerevisiae var. boulardii, Candida, Kluyveromyces, Pichia, Debaryomyces, Probiotics are mostly considered as safe, affordable than standard
Hanseniaspora, and Metschnikowia are accepted potential probiotic drugs and having a long history of usage [43,44]. Probiotic bacteria and
yeasts [22–24]. yeasts are reported as abolishing carcinogens toxicity and cancer cell
Major probiotics mechanisms of action of anticancerous and anti- death induction [45]. Probiotic lactic acid bacteria are considered as
mutagenic activity are: binding, degradation and inhibition of mutagen the most important microbes in anti-carcinogenic activities [46]. Their
by probiotics; procarcinogen prevention and conversion of harmful, effects depend on metabolic properties, strain-specific, molecules pre-
toxic and highly reactive carcinogens; gut pH lowering by short chain sented and components secreted. Anti-proliferative properties of dif-
fatty acids (SCFAs) formed during degradation of non-digestible car- ferent Lactobacillus strains and their components fight against cancer
bohydrate; host’s innate immunity modulation and enhancement cells in vitro and in vivo have been well documented [47].
through secretion of anti-inflammatory molecules [25]. Probiotic yeasts can also be used as biotherapeutics in the CRC
prevention and treatment. Yeast probiotics prevent carcinogenesis via
the mechanisms such as host immunity system alteration or apoptotic
pathways initiation, and anti-tumorigenic materials production to

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T. Legesse Bedada, et al. Biomedicine & Pharmacotherapy 129 (2020) 110409

Table 1
Features of the experimental model in the use of live probiotics in preclinical and clinical evidences of various cancers.
Probiotics Cancer type Dose Duration Level of Study type Ref
evidence

E. faecium RM11 CRC 108 CFU 24 h Cell line Caco-2 cells Preclinical in vitro [66]
E. faecium RM28
L. casei ATCC393 CRC 108/109 CFU 13 d Cell lines: CT26, HT29 Preclinical in vitro [67]
In vivo female BALB/c mice1
L. casei BL23 CRC 5 × 109 CFU 6−8 d In vivo animal Preclinical in female mice1 [68]
L. cocktail CRC 108 CFU 120 h Cell line: HT-29 Preclinical in vitro (68
L. plantarum AS1 CRC 109 CFU 26 wks In vivo animal Preclinical in male rats1 [70]
L. acidophilus Breast cancer 2 × 108 CFU 15 d In vivo animal Preclinical in female mice2 [10]
L. lactis NK34 Colon, lung, stomach and 106 CFU 24 h Cell line: HT-29 Preclinical in vitro [74]
breast
S. thermophilues M17PTZA496 CRC 108 CFU 6d Cell line: HT-29 Preclinical in vitro [75]
S. thermophilues TH982
Recombinant L. lactis IL-17A lung 109 CFU 35 d Cell line: TH17; in vivo Preclinical in vitro and mouse3 [78]
animal
8 1
E. faecium CRL 183 CRC 10 CFU 42 wk In vivo animal Preclinical in Male rats [80]
L. casei Shirota breast 28.81 43.75 mg/d Regularly Human Clinical trial1 [82]
Lactobacillus and Bifidobacteria strains CRC 107 mg, 2 times/d 6 mth Human Clinical trial1 [83]
Yogurt probiotics CRC 85−98 g/d 12 yrs Human Clinical trial1 [84]

1 2 3
Oral administration, intraperitoneal administration, intranasal administration.

scavenge mutagens through the gut. Consuming traditional fermented Firmicutes and Bacteroidetes are found in large numbers [58]. Human
foods with sufficient dose of yeast probiotics can reduce the risk of CRC physiology is regulated by plenty of microorganisms in the guts [59].
development [42]. Gut microbiota can influence several features of the intestinal health
including its physiology, cellular features, development, metabolism
and immune homeostasis [56].
2.1.2. Probiotics, prebiotics and gut microbiota Gut microbiota possess a dual role in protecting host’s health by
Various in vitro and laboratory animal based studies show that producing various metabolites and bioproducts [60]. Intestinal resident
probiotics, prebiotics and synbiotics (combination of probiotics and commensals are able to yield hormone-like metabolites including
prebiotic) are an ideal choice for the prevention of cancer [25]. Pre- SCFAs, as a result of dietary fibers fermentation in the large intestine
biotics are defined as fermentable non-digestible food ingredients that [61]. Microbiota specific composition and diet determine the nature of
improve the health of the host [48]. Dietary unprocessed fibers, in- synthetized SCFAs. After being produced by the gut bacteria, SCFAs are
cluding prebiotics can defend against CRC [49]. Dietary fibers are transported via the bloodstream, and used as a major source of energy
fractions of edible plants or their extracts that are resistant to digestion by the liver [62].
and absorption in the small intestine with complete or partial fermen- Many microorganisms derived molecules including SCFAs (e.g. bu-
tation in the large intestine. Most of them are carbohydrates and con- tyrate and propionate) and histone deacetylases, have been implicated
sidered as prebiotics. Resistant starch, non-starch polysaccharides and in anti-cancer properties in CRC and lymphoma [63,64]. Evidence
non-digestible oligosaccharides are examples of dietary fibers [50]. In a concerning the association of microbiota with CRC is produced in the
study, feeding the non-digestible oligosaccharide lactulose to the rat preclinical and clinical data. Bacterial driven cancer can be prevented
leads to a reduction in dimethylhydrazine-induced DNA damage in the and treated by microbiota which inhibit quorum sensing and biofilm
rat colons [51]. In the experiment, rats received 1,2-dimethylydrazine [62].
carcinogen plus the symbiotic (probiotic and prebiotics) had 100 %, There is a strong relationship among diet, lifestyle and gut micro-
whereas rats that administered only the carcinogen has 70 % survival. biota composition with the onset of CRC [42,61]. Dysbiosis or bacterial
Symbiotics appear to defend against preneoplastic colon lesions in la- imbalance in the intestine because of changes in dietary or environment
boratory animals [52]. can cause CRC because of virulence factors, microbial metabolites and
Non-digestible compounds fermentation possesses a beneficial effect inflammatory pathways. In the future, gut microbiota and probiotics
through proliferation and apoptosis modulation in tumor cells. The will be helpful in the prevention and treatment of CRC [59]. When
mechanism of action of this effect is due to the participation of phenolic consumed in sufficient quantities, probiotics can prevent the develop-
fatty acids derivatives, biopetides and other compounds [53]. Prebiotics ment of CRC through the gut microflora balance [56].
protect against cancer through the mechanisms of fecal bulking, colonic
pH change, carcinogen binding to bacteria, modulation of xenobiotic
metabolising enzymes, gene expression modulation in the feces and 2.2. Live probiotics for the prevention and treatments of cancer
caecum and immune responses modulation [54].
Microflora in fermented dietary fibers enhances effective metabo- Generally, the importance of probiotics has been shown in different
lites levels which are protective against colon cancer. The addition of in vitro, in vivo animals and clinical trials in humans [65]. Thir-
specific probiotics can increase fermentation efficiency of wheat abunyanon et al. [66] studied that live whole probiotic strains of En-
aleurone, a source of dietary fibers. Fermentation products of wheat terococcus faecium (E. faecium) RM11 and Lactobacillus fermentum (L.
aleurone as a dietary fiber combined with probiotics can be an effective fermentum) RM28 from fermented milks triggered colon cancer cells
measure to increase intestinal health and decrease the risk of acquiring anti-proliferation in in vitro experiment. Therefore, both probiotics can
colon cancer in humans [55]. be used for CRC treatment or prevention or in functional food. Of 54
The relationships of probiotics and gut microflora are also im- lactic acid bacteria strains isolated from fermented milks, E. faecium
portant in modifying the composition of gut microbiota [56]. Gut mi- RM11 and L. fermentum RM28 strains showed not only potential anti-
crobiota are commensal microbes of heterogeneous population mostly tumor activities but also anti antimicrobial activities against the growth
comprise bacteria, but also fungi, archaea and viruses [57]. Among a of pathogens. The Pathways or regulation points for both strains and
1000 of various bacterial species within the gut microbiota, phyla of the other probiotics are shown in Tables 1,2.

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 T. Legesse Bedada, et al.
Table 2
Regulation points involved in anticancer effects of live and dead probiotics or their metabolites.
Probiotics Cancer type Forms of probiotics or their secretion Regulation points Ref.

E. faecium RM11 CRC Live Cell apoptosis. [66]

L. fermentum RM28 CRC Live Cell apoptosis. [66]
L. casei ATCC 393 CRC Live apoptosis-inducing ligand TRAIL uprgulation and survivin down-regulation [67]
L. casei BL23 CRC Live Bik, caspase-7 and caspase-9 upregulation [68]
L. cocktail CRC Live Notch and Wnt/β-catenin pathways modulation [69]
L. plantarum AS1 CRC Live Carcinogen binding and degrading; antitumorigenic production or increasing the host’s immune response [70]
L. acidophilus Breast cancer Live Activating innate anti-cancer cells [10]
L. lactis NK34 Lung Live Decreases nitric oxide production and pro-inflammatory cytokines [74]
S. thermophilus MTH17CL396, TH982 and M17PTZA496 CRC Live Carcinogens binding and degrading, immune response increment, antimutagenic compounds production [75]
Recombinant L. casei CRC Live TH17 immune response [78]
L. casei Shirota Breast Live NK cell activation and NK cell mediated antitumor activity [82].
4

Lactobacillus and Bifidobacteria strains cocktail CRC Live Interfere with the signalling pathways to stimulate or suppressor the level of cytokines production [83]
S. thermophilus and Lactobacillus delbrueckii CRC Live Reduce carcinogen levels in the gut by reducing the activity of gut enzymes. [45]
Dead Nano-Sized L. plantarum CRC Dead Controlling inflammation, elevating IgA secretion and inducing cancer cell cycle arrest and apoptosis [86]
L. reuteri CRC Dead Activate caspase 3 and faster reduction of p21 expression [87]
E. faecalis CRC Dead Inhibit NLRP3 inflammasome activation in macrophages [89]
L. acidophilus 20,079 Liver EPS Apoptotic role, stimulate immune response and inactivate NF-κB inflammatory pathway [91]
Lactobacilli CRC EPS Caspase 3 and 9 and BAX increased expression and decreased Bcl-2 and survivin. [94]
K. marxianus and P. kudriavzevii CRC EPS Hinder AKT-1, mTOR, and JAK-1 pathways, and induce apoptosis [95]
B. breve lw01 Head and neck EPS Regulate cell cycle arrest and cell apoptosis promotion [96]
L. fermentum CRC SCFA propionate production [98]
Propionibacterium freuden reichii CRC SCFA Caspase-mediated inactivation of receptor-interacting protein [99]
L. acidophilus ATCC 314 and L. fermentum NCIMB 5221 CRC Proteins Down-regulation tumor proliferation markers [102]
L. casei and L. rhamnosus LGG CRC Protein, nucleic acid, or polysaccharide Decrease metalloproteinase-9 activity and increase the levels of zona occludens-1 [104]
L. reuteri NCIMB 701,359 Protein p8 CRC Inhibit p53-p21-Cyclin B1/Cdk1 signal pathway [110]

Biomedicine & Pharmacotherapy 129 (2020) 110409

A. syzygii lipid and proteins Oral cavity Induce apoptosis [111]
L. casei ATCC334 Ferrichrome CRC C-jun N-terminal kinase mediated apoptosis [115]
T. Legesse Bedada, et al. Biomedicine & Pharmacotherapy 129 (2020) 110409

Scientific study indicated that live Lactobacillus casei (L. casei) HT-29), human colon adenocarcinoma cell line (LoVo), human stomach
ATCC393 and its components exert potent anti-proliferative, growth- adenocarcinoma cell line (AGS), and human breast adenocarcinoma cell
inhibitory and pro-apoptotic effects. In vitro CT26 and HT29 human line (MCF-7 cells). Probiotic L. lactis has been used as a fermentation
colon carcinoma cells and in vitro 6–8 weeks old female BALB/c mice starter in dairy or fermented foods and is taken as a safe microbe. L.
study promises the importance of this probiotic in food intervention lactis NK34 has anti-inflammatory property by inhibiting lipopoly-
programs. The use of the cell lines and oral administration of live L. saccharide induced RAW 264.7 cells that produce nitric oxide and pro-
casei ATCC 393 and its components to the mice displayed anti-pro- inflammatory cytokines such as interleukin-18, tumor necrosis factor-α,
liferative effect. The mechanisms of this effect were tumor necrosis and cyclooxygenase-2 were decreased [74].
factor related apoptosis-inducing ligand TRAIL upregulation and sur- Fast acidifying lactic acid bacteria, Streptococcus thermophilus (S.
vivin down-regulation [67]. thermophilus) M17PTZA496 and S. thermophilus TH982 possess pro-
In vivo study done by Jacouton et al. [68] has shown that dairy biotic properties, anticancer activity and folate production in vitro and
strain of probiotic live L. casei BL23 possessed potential anti-in- in some cases they are superior to the well-known commercial available
flammatory and antitumor effects when administered orally to C57BL6 Lactobacillus rhamnosus (L. rhamnosus) GG probiotic strain. Of most
6–8 weeks old female mice. The protection of this probiotic strain commercially available strains of probiotics, thermophilic S. thermo-
happened through cell proliferation reduction and the apoptosis in- philus is extensively used as starter culture for many dairy products
duction. The use of this probiotic bacterium is used in modulating gut next to L. lactis [75].
microbiota composition, which play a pivotal role in carcinogenesis of Accordingly, S. thermophilus MTH17CL396, TH982 and
the CRC. The immunomodulatory potential of L. casei BL23 is mediated M17PTZA496 inhibited HT-29 cells significantly [75]. All these strains
through IL-22 cytokine down-regulation, and an anti-proliferative showed significant anti-proliferative potential on HT-29 cancer cells as
property, mediated through Bik, caspase-7 and caspase-9 up-regulation a result of lactic acid production. S. thermophilus MTH17CL396
[68]. showed the best antitumor property, and has the least acidification
In addition, Lactobacilli cocktail (L. cocktail) shows antitumor effects potential among the S. thermophilus strains tested in a study done by
on HT-29 cells through the Notch and Wnt/β-catenin pathways mod- Tarrah et al. [75]. Various mechanisms are revealed as to how lactic
ulation; therefore, using probiotic Lactobacilli as nutritional supple- acid bacteria prevent colon cancer, such as carcinogens binding and
ments may prevent colon cancer. When species of the Lactobacillus used degrading, immune response increment, anti-mutagenic compounds
in cocktails, they possess growth inhibitory potential by the Notch or production, and physicochemical conditions change in the colon
Wnt induced cell proliferation down-regulation. The Wnt and Notch [76,77].
pathway inhibition is because of apoptosis induction and proliferation Probiotics are used to fight against cancer by enhancing immune
alleviation in vitro. Thus, live Lactobacillus species may be considered response or protecting against gastrointestinal infections. A pro-in-
cost effective and safe means in the CRC treatment [69]. flammatory cytokine, interleukin-17A is produced by TH17-cells and
Kumar et al. [70] studied that Lactobacillus plantarum (L. plantarum) used in autoimmune disease and host defence. Recombinant L. lactis IL-
AS1 isolated from fermented food diminished a powerful carcinogen, 17A produced and secreted cytokine, Interleukin-17A in murine fibro-
1,2-dimethyl hydrazine-induced colon tumor in male albino wistar rats. blasts 3T3 L1 cells line and human papilloma virus induced cancer in
This probiotic L. plantarum AS1 modulates 1,2-dimethyl hydrazine free mouse allograft model [78]. This indicates the role of IL 17A in cancer
radical induced rat colon carcinogenesis development through the [78].
mechanism of antioxidant-dependent. Human beings get the con- Interleukin-17A secreted by L. lactis IL-17A recombinant strain sti-
tamination of 1,2-dimethyl hydrazine and other different hydrazines via mulates numerous cytokines such as IL-6 in fibroblast, immune cells
the environment. The mechanisms by which L. plantarum AS1 can in- and epithelial cells. L. lactis IL-17A administered intranasally outcomes
hibit colon cancer include production of antimutagenic or anti- in partial defence against C57BL/6 mouse lung tumor cell line in mice
mutagenic compounds; potential carcinogen binding and degrading; confirming anticancer potential of Interleukin-17A in this cancer
host’s immune response development and effects on physiology of the model. Thus, the recombinant L. lactis IL-17A strain reduced tumor
host [70]. incidence and tumor size. The mechanisms by which L. casei BL23
Lactobacilli can stimulate immune cells of the host including den- combats cancer are related to NK and TH cell via TH cell activation.
dritic or natural killer (NK) cells or T helper type 1 (TH1) response, Anticancer effects of the probiotic L. casei BL23 in mice and in vitro
which, participates in precancerous or anticancerous cells [71–73]. TH17 cells show beneficial property [78].
Oral administration of probiotic Lactobacillus acidophilus (L. acidophilus) Moreover, probiotic E. faecium CRL 183 reduced incidence of ade-
isolated from traditional home made yogurt and neonatal stool reduces nocarcinoma incidence by 40 % and decreased the colorectal tumors
tumor growth by immune response modulation or changing the cyto- volumes induced by1,2 dimethylhydrazine in the male wistar rats [79].
kine milieu reducing growth rate of tumor, increasing proliferation of The administration of probiotic bacterium during carcinogenesis stage
lymphocyte, protecting TH cells and activating antitumoral cell in in initiation inhibited colon cancer significantly. E. faecium CRL 183
vivo breast cancer murine model, 8–10 week old Balb/C female mice possesses antitumor property by provoking the immune system. The
[10]. mice that administered the same strain displayed high levels of tumor
Notably, gut L. acidophilus activates NK cells, a major source of in- necrosis factor gamma, tumor necrosis factor alpha, and IL-4 cytokines
terferon (IFN)-γ and play vital role in anti-tumor immunity [10]. Thus, for the immune response regulation [80]. IFN-γ cytokine is essential for
the mechanism by which L. acidophilus prevents tumor growth is by the immune cells maturation including dendritic cells, IL4, IL5 and IL10
innate anti-cancer cells activation. L. acidophilus produces IFN-γ from and regulates cellular proliferation in the intestine [81]. IFN-γ protects
splenocyte to increase anti-cancer property, anti-angiogenesis and NK against viruses, intracellular pathogens, and carcinogen by NK cell and
activity to assess the overall effect of L. acidophilus on the cellular im- macrophage activation mediation [79].
mune system; three doses were administered and compared. Of the
three L. acidophilu doses of 108, 2 × 108 and 3 × 108 colony forming 2.3. Clinical evidence of live probiotics for prevention and treatments of
units (CFU), 2 × 108 CFU responded considerably to tumor antigen cancer
challenge [10].
Also, probiotic Lactococcus lactis (L. lactis) NK34 with a dose 106 Most of the probiotic anticancer therapies are under preclinical
CFU showed a strong anticancer and antiinflammatory effects by in- phase. Beyond animal research activities, few studies have reported the
hibiting the proliferation of cancer cells such as human lung carcinoma effects of biotherapeutic probiotics in humans [11]. Whole live pro-
cell line (SK-MES-1), human colon adenocarcinoma cell line (DLD-1, biotics effective doses, experimental durations and routes of

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T. Legesse Bedada, et al. Biomedicine & Pharmacotherapy 129 (2020) 110409

administration for the prevention and treatment of various types of apoptosis in vitro. Polysaccharide, protein secretory or nucleic acid
cancer in the preclinical and clinical trials have been summarized in macromolecules exert these inhibitory properties on HT29-ShE. L. re-
Table 1. uteri involved in cell growth inhibition and apoptosis increment in
In clinical trials of 306 breast cancer cases and 662 controls aged HT29-ShE cells through regulating gene profile expression related to
40–55 years have been investigated about their lifestyle, diet, and other the progression of cell cycle and growth of tumor [87]. L. reuteri also
breast cancer risk factors using case-control study [82]. In this study, participates in NF-kB dependent genes down-regulation cyclin D1 and
the regular consumption of probiotic L. casei Shirota and soy iso- COX-2, cell proliferation, and cell survival in CRC cells [88].
flavones was significantly associated with reduced breast cancer risk in Recent report indicated that, the application of heat-inactivated
Japanese adolescent women [82]. probiotic Enterococcus faecalis (E. faecalis) protects against dextran so-
The oral administration of six viable probiotics strains of dium sulfate induced CRC and ameliorates intestinal inflammation se-
Lactobacillus and Bifidobacterium significantly reduced pro-in- verity in wild type mice [89]. This probiotic protects the experimental
flammatory cytokines, tumor necrosis factor-α, IL-6, IL-10, IL-12, IL- animals against dextran sodium sulfate induced colitis and CRC by re-
17A, IL-17C and IL-22 in 52 post-surgical CRC patients. These strains ducing intestinal inflammation severity through phagocytosis attenua-
were L. acidophilus BCMC® 12,130, L. lactis BCMC® 12,451, L. casei tion that is essential for Nod-like receptor protein 3 (NLRP3) in-
subsp. BCMC® 12,313, Bifidobacterium longum BCMC® 02120, flammasome activation completely in the Human Monocytic Leukemia
Bifidobacterium bifidum (B. bifidum) BCMC® 02,290 and Bifidobacterium Cell Line derived macrophages. In NLRP3 knockout animals, dextran
infantis BCMC® 02129. In this randomized double blind placebo con- sodium sulfate induced colitis is not protected by the E. faecalis. Heat-
trolled trial of probiotics, no surgical infection happened and no anti- killed probiotic E. faecalis is safe and useful for NLRP3 mediated colitis
biotics were required [83]. and inflammation associated colon carcinogenesis attenuation by in-
Probiotics also benefit by avoiding postoperative complications, hibition of IL-1β secondsretion induction in macrophages [89].
treatment toxicity and enhancing quality of life. A cohort study with
follow up of 12 years of yogurt intake, S. thermophilus and Lactobacillus 2.5. Probiotics metabolites for the prevention and treatments of cancer
delbrueckii in 45,241 volunteers significantly reduced CRC risk [84]. In
spite of the acceptable evidences about probiotics anticancer effects, 2.5.1. Lipopolysaccharide, exopolysaccharide (EPS) and polysaccharides
clinical research conducted in human beings is still limited. Conse- Molecules and metabolites derived from probiotics can prevent
quently, information concerning exhaustive clinical studies in human tumor development through modulation of immune systems of the host.
beings is urgently needed [45]. For instance, bacterial lipopolysaccharide (LPS), a key component of
Caco–2 cells– colon cancer cells; HPV– human papilloma virus; gram-negative bacteria outer membrane, activates toll like receptor 4,
yrs–years; mth–month; wk–weeks; d– days; CFU– colony forming unity consequently activating immune T cell mediated response against
tumor cells [90].
2.4. Dead probiotics for the prevention and treatments of cancer EPS extracted from probiotics plays a fundamental role in preven-
tion and treatment of cancer. Several scientific data indicate that lactic
In contrary to the general definition of probiotics [85], dead pro- acid bacteria found in the gut have a role in regression of cancer
biotics or its cell components can combat cancer effectively. In a study through their effect on immunomodulation. These bacteria can activate
done by Lee et al., dead L. plantarum with Nano-Sized inhibits azox- phagocytes to remove early stage tumor cells [12,55]. L. acidophilus
ymethane/dextran sulfate sodium-induced (AOM/DSS) CAC in mice 20,079 EPS has a direct cytotoxic effect on the tumor cells by me-
better than live bacterium. This is due to the effects of inflammation chanisms of apoptosis, immune response stimulation and NF-κB in-
suppression, apoptosis, and enhanced IgA secretion [86]. flammatory pathway inactivation. The effect of L. acidophilus 20,079
Meanwhile, mice feed dead Nano-Sized L. plantarum displayed extracted EPS on colon is a promising therapeutic target for cancer
considerably diminished inflammatory markers expression, mediated [91]. Cell wall components of L. acidophilus and L. casei act as antic-
the expression of apoptotic markers and cell cycle in colon, and in- ancer substances [92]. L. plantarum 70,810 extracted EPS prevents the
creased the levels of fecal IgA better than using pure live bacterium. proliferation of hepatocellular carcinoma cell line [93].
AOM/DSS injected to the mice contributed to loss of animal’s body Additionally, EPS produced by probiotic lactic acid bacteria such as
weight and colonic shortening. However, both pure live and dead L. plantarum GD2, L. rhamnosus E9, L. brevis LB63 isolated from healthy
probiotics avoid colonic shortening and body loss. Dead probiotics infant feces and Lactobacillus delbrueckii sp. bulgaricus B3 isolated from
showed fewer colonic tumors, longer colons, and less weight loss yogurt has an anticancer effect on colon cancer cells (HT-29).
compared with pure live probiotic L. plantarum [86]. Lactobacilli EPS induces apoptosis in CRC in vitro through Caspase 3 and
Interestingly, the suppressive potentials of dead probiotic were su- 9 and BAX increased expression and decreased Bcl-2 and survivin [94].
perior to those of pure live probiotic, and especially, dead probiotic Vital molecular pathways target and different forms of cell death in-
administration at high dose reduced a number of tumors considerably duction by components of probiotic yeasts are considered as potential
compared with pure live probiotic. Combined administration of pure therapeutic tools against CRC. EPSs produced by probiotic Kluyver-
live and dead probiotics significantly reduced proinflammatory cyto- omyces marxianus (K. marxianus) and Pichia kudriavzevii (P. kudriavzevii)
kines and inflammatory genes overexpression, and suppressive poten- inhibit various colon cancer cell lines [95].
tials than separate administration of either groups. All the experimental Moreover, probiotic Bifidobacterium breve (B. breve) lw01 EPS im-
AOM/DSS control animals group possessed colon tumors, but admin- proves immune development and possesses anticancer and anti-in-
istration with dead L. plantarum suppressed the development of neo- flammation effects. EPS constitutes rhamnose, galactose, glucose, ara-
plasty significantly. The mechanism by which dead probiotic sustains binose, and mannose. EPS shows anticancer property against head and
the status of mucosal immune system is by increasing levels of secretory neck squamous cell carcinoma cell line by controlling apoptosis and cell
IgA. This indicates that the antitumor property of dead probiotic is cycle arrest. The investigators believe that B. breve lw01 EPS can be
related with the easier uptake of dead probiotic by M cells than pure used to assist genetic and metabolic engineering and to play a role in
live probiotic and the stronger secretory immune responses [86]. application of functional food or drug industries [96].
Besides dead probiotic bacterium, high molecular weight secretory As pointed out by Zhang et al., L. acidophilus and L. casei produce
molecules, cell free supernatant components from heat-killed sonicated compounds that inhibit the growth of breast cancer cell line, MCF7. L.
probiotic Lactobacillus reuteri (L. reuteri) play an important role by ex- acidophilus 606 prevents the proliferation of human pancreatic tumor
erted antimetastatic and antiproliferative effects. These considerably cell line by soluble polysaccharides production. Live and heat-in-
facilitate human colon cancer, cancer stem like cells or HT29-ShE activated probiotic Lactobacillus with its secreted metabolites and

6
T. Legesse Bedada, et al. Biomedicine & Pharmacotherapy 129 (2020) 110409

cytoplasmic fractions employ anticancer effects. Lactobacillus sp. ex- way, monophosphoryl lipid A derived from Salmonella enterica is used
tracted metabolites in yoghurt fermentation inhibit the growth and as adjuvant in anti-cervical carcinoma vaccine formulation [112]. A
induce apoptosis in human tongue squamous carcinoma cells in vitro group B vitamin pyridoxine from bacteria stimulates antitumoral im-
Lactobacillus sp. [97]. munosurveillance host [113].
The anti-cancer potential of L. acidophilus ATCC 314 and L. fer-
2.5.2. SCFAs and lipid mentum NCIMB 5221 co-culture was considerably increased in vitro with
SCFAs, conjugated linoleic acid and other anti-carcinogenic pro- high proliferation reduction, apoptosis increasing towards tumor cells
ducts produced by Lactobacilli extracts induce apoptosis in cancer cells and normal colon cell growth protection from toxic treatment.
[53]. Probiotics L. fermentum NCIMB 5221, 2797 and 8829 are potential Intestinal tumorigenesis was changed by decreasing intestinal tumor
candidates for the treatment of CRC. They prevent proliferative activity multiplicity significantly and cellular proliferation markers down reg-
by producing SCFAs in vitro and persisting in an intestinal fluid [98]. ulating. As various evidence indicates, probiotic L. fermentum NCIMB
Furthermore, SCFAs metabolites produced by probiotic 5221 had a higher in vitro antitumor effect than several L. fermentum
Propionibacterium freuden reichii damage colorectal adenocarcinoma strains [114]. The combination of both strains secretes metabolic po-
cells by producing apoptosis in vitro [99]. Probiotics Pediococcus pen- tential synergistically and boosts capability of biotherapeutics against
tosaceus FP3, Lactobacillus salivarius FP35, Lactobacillus salivarius FP25, cancer initiation and progression by releasing anti-neoplastic com-
and E. faecium FP51 also inhibit proliferation of colon cancer cells by pounds, cancer cell death, and healthy mucosa protection [102].
SCFAs bioproduction, mostly propionic and butyric acids [100].
Similarly, conjugated linoleic acids produced by probiotic bacteria 2.5.4. Siderophores or ferrichrome
have the ability to form anticarcinogenic effects in vitro and in vivo in According to an in vitro experiment done by Konishi et al. [115],
mice [101]. Another probiotic strain, L. reuteri NCIMB 701,359 prevents probiotic L. casei ATCC 334 derived from ferrichrome had high cancer
CRC causing lesions by producing propionate [53]. Probiotic L. reuteri suppressive property on CRC through c-jun N-terminal kinase mediated
prevents the proliferation of gastric cancer cells in vitro by urokinase apoptosis. Bacterial body components of L. casei ATCC 334 did not
plasminogen activator downregulation [15]. inhibit colon cancer cells growth, indicating that the strain secreted
some cancer suppressive fraction in the experiment. The isolated cancer
2.5.3. Protein and other metabolites like nucleic acid suppressive fraction was related with metallic elements such as zinc,
Secretions of metabolite products from probiotics can prevent and iron and calcium. As other bacteria L. casei releases metal chelating
treat cancer. Kahouli et al. have discovered that pure free bacterial cell agents, siderophores or ferrichrome. Ferrichrome decreased the pro-
or secretions of probiotics L. acidophilus ATCC 314 and L. fermentum liferation of SW620 cells and Caco2 cells. Cancer suppressive property
NCIMB 5221 attenuated the risks of CRC in four week old male mice of ferrichrome was better than or equal to that of normal anticancer
ApcMin/+ CRC model and caco-2 epithelial CRC adenocarcinoma cells drugs such as cisplatin and 5-fluorouracil but it had less effect on
line. The probiotics possess anti-proliferative, antioxidant and pro- noncancerous cells in the intestine than these drugs. The inhibition of
apoptotic potentials, especially when used in combination. In addition, solid tumor growth by the ferrichrome injection in vivo shows that
a higher synergistic effect on tumor growth inhibition and proliferation ferrichrome is an attractive antitumor drug candidate [115].
modulation and epithelial markers in the CRC mice model were found,
based on proteins Ki67E cadherin, cleaved caspase-3 and β-catenin 2.6. Future challenges in the use of probiotic
expression levels [102]. Besides these, B. bifidum metabolites, cell-free
supernatants are fighting tumor cells effectively when using colon Majority of the positive results provided by probiotic treatments are
cancer cell line SW742 [103]. limited to experimental settings [116]. Some microbes used widely in
Some inhibitory compounds produced by probiotics have beneficial different countries as ‘probiotics’ in fermented food products are not
effects against tumor cells. Escamilla et al. [104] observed that cell free supported by clinical trials [117]. However, probiotics strains may be
supernatants containing secreted bioactive macromolecule from L. casei responsible for some side effects including systemic infections, gene
and L. rhamnosus LGG probiotics prevented metastasis of colon cancer transfer, deleterious metabolic activities and excessive immune stimu-
cells in vitro, the human colon carcinoma cell line (HCT-116) [104]. lation in immunocompromised subjects [118]. Therefore, a long term
This inhibitory compound might be a protein, polysaccharide or a nu- effect study in the direction of methodology standardization, future
cleic acid [105]. The reduction in the invasion of colon cancer cells challenges are required. In vitro and in vivo safety assessments including
HCT-116 metastasis reduced the activity of matrix metalloproteinase-9 acute, sub-acute and chronic toxicity studies should be done for all
(MMP-9), and enhanced zona occludens-1 (ZO-1) levels. MMP-9 is a probiotic strains [119].
proteolytic enzyme used to digest colon extracellular matrix, supporting Since probiotics are biologically active, their evolution, metabolism,
the invasion process of the cell during metastasis [106]. A reduction in physiology and probiotic properties will be appreciated [119]. Ma-
matrix MMP-9 levels indicates a decrease in MMP-9 potential due to karova et al. [120] shows that during their adaptation in high nutrient
reduced synthesis of protein [104]. ZO-1 is a protein used to maintain available environments, lactic acid bacteria (LAB) reduce their genomes
the function of epithelial barrier [107]. In metastatic tumors, ZO-1 size through evolutionary mechanisms. Moreover, the existence of
protein is down-regulated [108] and supports the function of healthy various pseudogenes in many genomes of LAB indicates the ongoing
colonic epithelial barrier [109]. decay process of their genome [120].
Research also reveals that therapeutic probiotic-derived p8 protein Stress conditions allow probiotic microbes to adapt to extreme en-
has anti-colorectal cancer effects by arresting the induction of cell cycle vironments that may affect stress related genes and other forms of life
in in vivo experiments. Protein p8 isolated from bacterial probiotics [119]. In a study conducted by Van Schaik and Abee [121], LAB un-
shows anti-cancer effects and has been clinically proven in human derwent a major evolutionary change. To adapt stress conditions, LAB
beings. It is considered as a potential candidate biopharmaceutical diverge stress genes from Bacillus subtilis that control and modify the
protein [110]. Extracts from L. reuteri NCIMB 701,359 inhibit colon expression of the genes [122]. Mutagenesis during cell stress may lead
cancer cells [53]. to antibiotic resistance and bacterial pathogenesis. Stress response of
On the other hand, probiotic Acetobacter syzygii (A. syzygii) has probiotics has not been examined most of the time. In addition, starter
prophylactic effect against carcinoma of the oral cavity, squamous cell LAB strains used as bacteriostatic or bactericidal for food spoilages and
carcinoma. This indicates the beneficial property of probiotics in oral pathogens could form stress-induced mutations. This effect may change
diseases prevention. Secretions of such strains show cytotoxicity effect functional properties of the probiotics [120].
against oral cavity cancer cells lines via apoptosis [111]. In a similar Containment system for every genetically modified organism in

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T. Legesse Bedada, et al. Biomedicine & Pharmacotherapy 129 (2020) 110409

human beings is also very important. This influence is serious in im- [13] Y. Nazir, S.A. Hussain, A. Abdul Hamid, Y. Song, Probiotics and their potential
munocompromised individuals especially in children’s health. preventive and therapeutic role for cancer, High serum cholesterol, and allergic
and HIV diseases, Biomed Res. Int. 2018 (2018) 1–17.
Therefore, short and long term safety studies on this age group should [14] P.W. O’Toole, J.R. Marchesi, C. Hill, Next-generation probiotics: the spectrum
be closely evaluated [122]. Evaluation must include the adverse effects from probiotics to live biotherapeutics, Nat. Microbiol. 2 (2017) 4169–4175.
including antibiotics resistance transmission to pathogens. Prior to [15] I.G. Rasouli, B.S. Ghadimi, A. Darsajini, R. Nekouian, In vitro activity of probiotic
Lactobacillus reuteri against gastric cancer progression by down-regulation of ur-
applying genetically modified probiotics in the clinical phases, the okinase plasminogen activator/urokinase plasminogen activator receptor gene
ecological balances of the human gut should be fully understood [123]. expression, J. Cancer Res. Ther. 13 (2017) 246–251.
[16] World Health Organization-Food and Agricultural Organization, Probiotics in
Food: Health and Nutritional Properties and Guidelines for Evaluation, FAO Food
3. Conclusion and Nutritional Paper. FAO/WHO, Rome, 2006 No.8592-5-105513-0.
[17] C.A. Adams, The probiotic paradox: live and dead cells are biological response
In conclusion, this review describes the anticancer effect of live and modifiers, Nutr. Res. Rev. 23 (2010) 37–46.
[18] World Health Organization-Food and Agricultural Organization, Guidelines for the
inactivated probiotics or their cells components and/or metabolic
Evaluation of Probiotics in Food, FAO/WHO joint report., London, 2002.
products including SCFAs and inhibitory proteins, polysaccharides, [19] R. Crittenden, G. Mogensen, Technological challenges for future probiotic foods,
nucleic acids and siderophores or ferrichrome. As vital dietary supple- Int. Dairy J. 12 (2002) 173–182.
ments, probiotics are useful in eliminating the risk of various types of [20] K. Georgiev, M. Georgieva, Antiproliferative effect of bulgarian spring water
probiotics (laktera nature probiotic®) against human colon carcinoma cell line,
cancer and managing the safety of existing chemotherapy, radiation World J Pharm Pharm Sci. 4 (2015) 130–136.
therapy and surgery with negligible side effects, if any. Probiotics are [21] M. Kumar, A. Kumar, R. Nagpal, D. Mohania, P. Behare, V. Verma, P. Kumar,
more effective when used with prebiotics than probiotics alone in D. Poddar, P.K. Aggarwal, C.J.K. Henry, S. Jain, H. Yadav, Cancer-preventing at-
tributes of probiotics: an update, Int. J. Food Sci. Nutr. 61 (2010) 473–496.
prevention and treatment of different cancer. Moreover, the effective [22] I.M. Smith, A. Baker, N. Arneborg, L. Jespersen, Non-Saccharomyces yeasts protect
prevention and treatment of various cancer types are linked to probiotic against epithelial cell barrier disruption induced by Salmonella enterica subsp.
bacterial or fungal strains, probiotic dose, and time of exposure. Enterica serovar Typhimurium, Lett. Appl. Microbiol. 61 (2015) 491–497.
[23] A. Ricci, A. Allende, D. Bolton, M. Chemaly, R. Davies, R. Girones, et al., Update of
Majority of these constructive results provided by different probiotic the list of QPS, recommended biological agents intentionally added to food or feed
treatments may be limited to experimental settings. Therefore, reg- as notified to EFSA 5: suitability of taxonomic units notified to EFSA until
ulatory issues related to probiotics need to be established at local and September 2016, EFSA J. 15 (2017) 1–20.
[24] A. Saber, B. Alipour, Z. Faghfoori, A. Yari Khosroushahi, Cellular and molecular
international basis. Finally, to minimize side effects associated with effects of yeast probiotics on cancer, Crit. Rev. Microbiol. 43 (2017) 96–115.
probiotics, short and long term effect studies in the direction of meth- [25] M. Raman, P. Ambalam, K.K. Kondepudi, S. Pithva, M. Raman, P. Ambalam,
odology standardization and more clinical trials are required in the K.K. Kondepudi, S. Pithva, C. Kothari, A.T. Patel, Potential of probiotics, prebiotics
and synbiotics for management of colorectal cancer, Gut Microbes 4 (2013)
future urgently.
181–192.
[26] M. Sharifi, A. Moridnia, D. Mortazavi, M. Salehi, Kefir : a powerful probiotics with
Funding anticancer properties, Med. Oncol. 34 (2017) 1–7.
[27] U. Antony, T.S. Chandra, Microbial population and biochemical changes in fer-
menting finger millet (Eleusine coracana), World J. Microbiol. Biotechnol. 13
No funds received for this manuscript. (1997) 533–537.
[28] R. Satish Kumar, P. Kanmani, N. Yuvaraj, K.A. Paari, V. Pattukumar,
Declaration of Competing Interest C. Thirunavukkarasu, V. Arul, Lactobacillus plantarum AS1 isolated from South
Indian fermented food Kallappam suppress 1,2-dimethyl hydrazine (DMH)-in-
duced colorectal cancer in male wistar rats, Appl. Biochem. Biotechnol. 166
None. (2012) 620–631.
[29] A. Sheikha, D. Hu, Molecular techniques reveal more secrets of fermented foods,
Crit. Rev. Food Sci. Nutr. 60 (2020) 11–32.
References [30] J.P. Tamang, D.H. Shin, S.J. Jung, S.W. Chae, Functional properties of micro-
organisms in fermented foods, Front. Microbiol. 7 (2016) 1–13.
[31] P. Van Veer, J.M. Dekker, J.W.J. Lamers, F.J. Kok, E.G. Schouten, H.A.M. Brants,
[1] J. Ferlay, E. Steliarova-Foucher, J. Lortet-Tieulent, S. Rosso, J.W.W. Coebergh,
F. Sturmans, R.J.J. Hermus, Consumption of fermented milk products and breast
H. Comber, D. Forman, F. Bray, Cancer incidence and mortality patterns in
Cancer: a case-control study in the Netherlands, Cancer Res. 49 (1989)
Europe: estimates for 40 countries in 2012, Eur. J. Cancer 49 (2013) 1374–1403.
4020–4023.
[2] C. Fitzmaurice, C. Allen, R.M. Barber, L. Barregard, Z.A. Bhutta, H. Brenner, et al.,
[32] P. Guiomar, D.A. Brasiel, S. Cristina, P. Dutra, L. Maria, G. Peluzio, Preclinical
Global, regional, and national cancer incidence, mortality, years of life lost, years
evidence of probiotics in colorectal carcinogenesis: a systematic review, Dig. Dis.
lived with disability, and disability-adjusted life-years for 32 Cancer groups, 1990
Sci. (2020), https://doi.org/10.1007/s10620-020-06062-3.
to 2015: a systematic analysis for the global burden of disease study, JAMA Oncol.
[33] P. Filannino, L. Azzi, I. Cavoski, O. Vincentini, C.G. Rizzello, M. Gobbetti, R. Di
3 (2017) 524–548.
Cagno, Exploitation of the health-promoting and sensory properties of organic
[3] World Health Organization, WHO Report on Cancer: setting Priorities, Investing
pomegranate (Punica granatum L.) juice through lactic acid fermentation, Int. J.
Wisely and Providing Care for All, WHO, Geneva, 2020.
Food Microbiol. 163 (2013) 184–192.
[4] J. Ferlay, I. Soerjomataram, R. Dikshit, S. Eser, C. Mathers, M. Rebelo,
[34] A.L.F. Pereira, W.S.C. Feitosa, V.K.G. Abreu, Tde O. Lemos, W.F. Gomes,
D.M. Parkin, D. Forman, F. Bray, Cancer incidence and mortality worldwide:
N. Narain, S. Rodrigues, Impact of fermentation conditions on the quality and
sources, methods and major patterns in GLOBOCAN 2012, Int. J. Cancer 136
sensory properties of a probiotic cupuassu (Theobroma grandiflorum) beverage,
(2015) E359–E386.
Food Res. Int. 100 (2017) 603–611.
[5] M. Shaheen, C. Allen, J.A. Nickoloff, R. Hromas, Synthetic lethality: exploiting the
[35] Y. Zhou, Y. Li, T. Zhou, J. Zheng, S. Li, H. Bin Li, Dietary natural products for
addiction of cancer to DNA repair, Blood 117 (2011) 6074–6082.
prevention and treatment of liver cancer, Nutrients 8 (2016) 1–23.
[6] P. Anand, A.B. Kunnumakkara, C. Sundaram, K.B. Harikumar, S.T. Tharakan,
[36] L. Fu, B.T. Xu, X.R. Xu, X.S. Qin, R.Y. Gan, H. Bin Li, Antioxidant capacities and
O.S. Lai, B. Sung, B.B. Aggarwal, Cancer is a preventable disease that requires
total phenolic contents of 56 wild fruits from South China, Molecules. 15 (2010)
major lifestyle changes, Pharm. Res. 25 (2008) 2097–2116.
8602–8617.
[7] D. Hanahan, R.A. Weinberg, Hallmarks of cancer: the next generation, Cell. 144
[37] G. Deng, X. Lin, X. Xu, L. Gao, J. Xie, H. Li, Antioxidant capacities and total
(2011) 646–674.
phenolic contents of 56 vegetables, J. Funct. Foods 5 (2012) 260–266.
[8] S. Raguz, E. Yagüe, Resistance to chemotherapy: new treatments and novel in-
[38] H. Kausar, J. Jeyabalan, F. Aqil, D. Chabba, J. Sidana, I.P. Singh, R.C. Gupta, Berry
sights into an old problem, Br. J. Cancer 99 (2008) 387–391.
anthocyanidins synergistically suppress growth and invasive potential of human
[9] S. Vivarelli, R. Salemi, S. Candido, L. Falzone, M. Santagati, S. Stefani, F. Torino,
non-small-cell lung cancer cells, Cancer Lett. 325 (2012) 54–62.
G.L. Banna, G. Tonini, M. Libra, Gut microbiota and cancer: from pathogenesis to
[39] A. Li, S. Li, Y. Zhang, X. Xu, Y. Chen, H. Li, Resources and biological activities of
therapy, Cancer. 11 (2019) 1–26.
natural polyphenols, Nutrients 6 (2014) 6020–6047.
[10] H. Maroof, Z.M. Hassan, A.M. Mobarez, M.A. Mohamadabadi, Lactobacillus acid-
[40] J. Shi, F. Liu, W. Zhang, X. Liu, B. Lin, X. Tang, Epigallocatechin-3-gallate inhibits
ophilus could modulate the immune response against breast cancer in murine
nicotine-induced migration and invasion by the suppression of angiogenesis and
model, J. Clin. Immunol. 32 (2012) 1353–1359.
epithelial-mesenchymal transition in non-small cell lung cancer cells, Oncol. Rep.
[11] Z. Hassan, Anti-cancer and biotherapeutic potentials of probiotic bacteria, J.
33 (2015) 2972–2980.
Cancer Sci. Ther. 11 (2019) 9–13.
[41] F. Li, S. Li, H. Bin Li, G.F. Deng, W.H. Ling, X.R. Xu, Antiproliferative activities of
[12] A. Górska, D. Przystupski, M.J. Niemczura, J. Kulbacka, Probiotic bacteria: a
tea and herbal infusions, Food Funct. 4 (2013) 530–538.
promising tool in cancer prevention and therapy, Curr. Microbiol. 76 (2019)
[42] S. Shamekhi, H.L.J. Abdolalizadeh, E.B.N. Zarghami, An overview of yeast pro-
939–949.
biotics as cancer biotherapeutics : possible clinical application in colorectal

8
T. Legesse Bedada, et al. Biomedicine & Pharmacotherapy 129 (2020) 110409

cancer, Clin. Transl. Oncol. (2020), https://doi.org/10.1007/s12094-019- Immunopathol. Dis. Therap. 7 (2016) 41–55.
02270-0. [73] A. Takagi, H. Ikemura, T. Matsuzaki, M. Sato, K. Nomoto, M. Morotomi, et al.,
[43] S.S. Choi, Y. Kim, K.S. Han, S. You, S. Oh, S.H. Kim, Effects of Lactobacillus strains Relationship between the in vitro response of dendritic cells to Lactobacillus and
on cancer cell proliferation and oxidative stress in vitro, Lett. Appl. Microbiol. 42 prevention of tumorigenesis in the mouse, J. Gastroenterol. 43 (2008) 661–669.
(2006) 452–458. [74] K.J. Han, N. Lee, H. Park, H.D. Paik, Anticancer and anti-inflammatory activity of
[44] J.E. Kim, J.Y. Kim, K.W. Lee, H.J. Lee, Cancer chemopreventive effects of lactic probiotic Lactococcus lactis NK34, J. Microbiol. Biotechnol. 25 (2015) 1697–1701.
acid bacteria, J. Microbiol. Biotechnol. 17 (2007) 1227–1235. [75] A. Tarrah, J. De Castilhos, R.C. Rossi, S. Duarte, D.R. Ziegler, V. Corich, In vitro
[45] H. Albookarami, Investigating the role of probiotics in coping with Cancer and probiotic potential and anti-cancer activity of newly isolated folate-producing
health in society, Cancer Press. 3 (2017) 188–196. Streptococcus thermophilus strains bacterial strains and standard growth, Front.
[46] L. Zhong, X. Zhang, M. Covasa, Emerging roles of lactic acid bacteria in protection Microbiol. 9 (2018) 2214, https://doi.org/10.3389/fmicb.2018.02214.
against colorectal cancer, World J. Gastroenterol. 20 (2014) 7878–7886. [76] K. Hirayama, J. Rafter, The role of probiotic bacteria in cancer prevention,
[47] C. Liu, F. Chu, C. Chou, R. Yu, Mutation Research/ Genetic Toxicology and Microbes Infect. 2 (2000) 681–686.
Environmental Mutagenesis Antiproliferative and anticytotoxic effects of cell [77] M. Kumar, V. Verma, R. Nagpal, A. Kumar, P.V. Behare, B. Singh, P.K. Aggarwal,
fractions and exopolysaccharides from Lactobacillus casei 01, Mutat. Res. Genet. Anticarcinogenic effect of probiotic fermented milk and chlorophyllin on afla-
Toxicol. Environ. Mutagen. 721 (2011) 157–162. toxin-B1-induced liver carcinogenesis in rats, Br. J. Nutr. 107 (2012) 1006–1016.
[48] G.R. Gibson, M.B. Roberfroid, Dietary modulation of the human colonic micro- [78] E. Jacouton, E.T. Maravilla, A. Boucard, N. Pouderous, A. Paula, P. Vilela, I. Naas,
biota: introducing the concept of prebiotics, J. Nutr. 125 (1995) 1401–1412. F. Chain, V. Azevedo, P. Langella, L.G. Bermúdez-humarán, S.K. Durum, Anti-tu-
[49] P.J. Harris, L.R. Ferguson, Dietary fibre: its composition and role in protection moral effects of recombinant Lactococcus lactis strain secreting IL-17A cytokine,
against colorectal cancer, Mutat. Res. 290 (1993) 97–110. Front. Microbiol. 9 (2019) 1–7.
[50] C.C. Lim, L.R. Ferguson, G.W. Tannock, Dietary fibres as “prebiotics”: implications [79] B. Lund, I. Adamsson, C. Edlund, Gastrointestinal transit survival of an
for colorectal cancer, Mol. Nutr. Food Res. 49 (2005) 609–619. Enterococcus faecium probiotic strain administered with or without vancomycin,
[51] I.R. Rowland, C.A. Bearne, R. Fischer, B.L. Pool-Zobel, The effect of lactulose on Int. J. Food Microbiol. 77 (2002) 109–115.
DNA damage induced by DMH in the colon of human flora-associated rats, Nutr. [80] K. Sivieri, A.L.T. Spinardi-Barbisan, L.F. Barbisan, R. Bedani, N.D. Pauly,
Cancer 26 (1996) 37–47. I.Z. Carlos, F. Benzatti, R.C. Vendramini, E.A. Rossi, Probiotic Enterococcus faecium
[52] F. Gavresea, C. Vagianos, M. Korontzi, G. Sotiropoulou, P. Dadioti, CRL 183 inhibit chemically induced colon cancer in male wistar rats, Eur. Food
J.K. Triantafillidis, A.E. Papalois, Beneficial effect of synbiotics on experimental Res. Technol. 228 (2008) 231–237.
colon cancer in rats, Turk. J. Gastroenterol. 29 (2018) 494–501. [81] C. Maldonado Galdeano, A. De Moreno De Leblanc, G. Vinderola, M.E. Bibas
[53] I. Kahouli, N.R. Handiri, Characterization of L. Reuteri NCIMB 701359 probiotic Bonet, G. Perdigón, Proposed model: mechanisms of immunomodulation induced
features for potential use as a colorectal cancer biotherapeutic by identifying fatty by probiotic bacteria, Clin. Vaccine Immunol. 14 (2007) 485–492.
acid profile and anti-proliferative action against colorectal cancer cells, Drug Des. [82] M. Toi, S. Hirota, A. Tomotaki, N. Sato, Y. Hozumi, K. Anan, T. Nagashima,
5 (2016) 1–11. Y. Tokuda, N. Masuda, S. Ohsumi, S. Ohno, M. Takahashi, H. Hayashi,
[54] P.J. Harris, L.R. Ferguson, Dietary fibre: its composition and role in protection S. Yamamoto, Y. Ohashi, Probiotic beverage with soy isoflavone consumption for
against colorectal cancer, Mutat. Res. 290 (1993) 97–110. breast Cancer prevention: a case-control study, Curr. Nutr. Food Sci. 9 (2013)
[55] A. Borowicki, A. Michelmann, K. Stein, D. Scharlau, K. Scheu, U. Obst, 194–200.
A. Michelmann, K. Stein, D. Scharlau, et al., Fermented wheat aleurone enriched [83] L. Zaharuddin, N.M. Mokhtar, K. Najmi, M. Nawawi, R. Affendi, R. Ali, A rando-
with probiotic strains LGG and Bb12 modulates markers of tumor progression in mized double-blind placebo- controlled trial of probiotics in post-surgical color-
human colon cells LGG and Bb12 modulates markers of tumor progression in ectal cancer, BMC. 19 (2019) 131.
human colon cells, Nutr. Cancer 63 (2012) 151–160. [84] V. Pala, S. Sieri, F. Berrino, P. Vineis, C. Sacerdote, D. Palli, G. Masala, S. Panico,
[56] S.A. dos Reis, L.L. da Conceição, N.P. Siqueira, D.D. Rosa, L.L. da Silva, M. do C.G. A. Mattiello, R. Tumino, M.C. Giurdanella, C. Agnoli, S. Grioni, V. Krogh, Yogurt
Peluzio, Review of the mechanisms of probiotic actions in the prevention of col- consumption and risk of colorectal cancer in the Italian European prospective
orectal cancer, Nutr. Res. 37 (2017) 1–19. investigation into cancer and nutrition cohort, Int. J. Cancer 129 (2011)
[57] J. Vaahtovuo, E. Munukka, M. Korkeamäki, R. Luukkainen, P. Toivanen, Fecal 2712–2719.
microbiota in early rheumatoid arthritis, J. Rheumatol. 35 (2008) 1500–1505. [85] J.M. Wells, Immunomodulatory mechanisms of lactobacilli, Microb. Cell Fact. 10
[58] S.L. Russell, M.J. Gold, M. Hartmann, B.P. Willing, L. Thorson, M. Wlodarska, (2011) 1–15.
N. Gill, et al., Early life antibiotic-driven changes in microbiota enhance sus- [86] H.A. Lee, H. Kim, K. Lee, K. Park, Dead nano-sized Lactobacillus plantarum inhibits
ceptibility to allergic asthma, EMBO Rep. 13 (2012) 440–447. azoxymethane/dextran sulfate sodium-induced colon cancer in Balb/c Mice, J.
[59] T. First, A. Hospital, T. First, A. Hospital, Role of gut microbiota in the develop- Med. Food 18 (2015) 1400–1405.
ment and treatment of colorectal Cancer, Digestion. 100 (2018) 72–78. [87] F. Maghsood, B. Johari, M. Rohani, H. Madanchi, Z. Saltanatpour, M. Kadivar,
[60] C. Manichanh, N. Borruel, F. Casellas, F. Guarner, The gut microbiota in IBD, Nat. Anti-proliferative and anti-metastatic potential of high molecular weight secretory
Rev. Gastroenterol. Hepatol. 9 (2012) 599–608. molecules from probiotic Lactobacillus reuteri cell-free supernatant against human
[61] B.D. Muegge, J. Kuczynski, D. Knights, J.C. Clemente, A. González, L. Fontana, colon cancer stem-like cells (HT29-ShE), Int. J. Pept. Res. Ther. (2020) 1–13,
B. Henrissat, R. Knight, J.I. Gordon, Diet drives convergence in gut microbiome https://doi.org/10.1007/s10989-020-10049-z.
functions across mammalian phylogeny and within humans, Science 332 (2011) [88] C. Baldwin, M. Millette, D. Oth, M.T. Ruiz, F.M. Luquet, M. Lacroix, Probiotic
970–974. Lactobacillus acidophilus and L. casei mix sensitize colorectal tumoral cells to 5-
[62] H. Raskov, J. Burcharth, H.C. Pommergaard, Linking gut microbiota to colorectal fluorouracil-induced apoptosis, Nutr. Cancer 62 (2010) 371–378.
cancer, J. Cancer 8 (2017) 3378–3395. [89] I. Chung, C. Ouyang, S. Yuan, H. Lin, K. Huang, Pretreatment with a heat-killed
[63] G.B. Gorbach, L. Sherwood, Diet and the excretion and enterhepatic cycling of probiotic modulates the NLRP3 inflammasome and attenuates colitis-associated
estrogens, Prev. Med. 16 (1987) 525–531. colorectal Cancer in mice, Nutrients. 11 (2019) 1–16.
[64] J. Fu, M.J. Bonder, M.C. Cenit, E.F. Tigchelaar, A. Maatman, J.A.M. Dekens, [90] T. Cd, C.M. Paulos, C. Wrzesinski, A. Kaiser, C.S. Hinrichs, M. Chieppa, L. Cassard,
E. Brandsma, J. Marczynska, F. Imhann, R.K. Weersma, L. Franke, T.W. Poon, D.C. Palmer, A. Boni, P. Muranski, Z. Yu, L. Gattinoni, P.A. Antony,
R.J. Xavier, D. Gevers, M.H. Hofker, C. Wijmenga, A. Zhernakova, The gut mi- S.A. Rosenberg, N.P. Restifo, Microbial translocation augments the function of
crobiome contributes to a substantial proportion of the variation in blood lipids, adoptively transferred self / tumor-specific, J. Clin. Invest. 117 (2007) 2197–2204.
Circ. Res. 117 (2015) 817–824. [91] N.M. El-Deeb, A.M. Yassin, L.A. Al-Madboly, A. El-Hawiet, A novel purified
[65] M. Eslami, Importance of probiotics in the prevention and treatment of colorectal Lactobacillus acidophilus 20079 exopolysaccharide, LA-EPS-20079, molecularly
cancer, J. Cell. Physiol. 234 (2019) 17127–17143. regulates both apoptotic and NF-KB inflammatory pathways in human colon
[66] M. Thirabunyanon, P. Boonprasom, P. Niamsup, Probiotic potential of lactic acid cancer, Microb. Cell Fact. 17 (2018), https://doi.org/10.1186/s12934-018-
bacteria isolated from fermented dairy milks on antiproliferation of colon cancer 0877-z.
cells, Biotechnol. Lett. 31 (2009) 571–576. [92] I.G. Bogdanov, P.G. Dalev, A.I. Gurevich, M.N. Kolosov, V.P. Mal’kova,
[67] A. Tiptiri-Kourpeti, K. Spyridopoulou, V. Santarmaki, G. Aindelis, E. Tompoulidou, L.A. Plemyannikova, I.B. Sorokina, Antitumour glycopeptides from Lactobacillus
E.E. Lamprianidou, D. Dimitrellou, K. Chlichlia, et al., Lactobacillus casei exerts bulgaricus cell wall, FEBS Lett. 57 (1975) 259–261.
anti-proliferative effects accompanied by apoptotic cell death and up-regulation of [93] C. Wang, T. Wu, S. Hsieh, Y. Tsai, C. Yeh, C. Huang, Antioxidant activity and
TRAIL in colon carcinoma cells, PLoS One 11 (2016) 1–20. growth inhibition of human colon cancer cells by crude and purified fucoidan
[68] L.G. Bermúdez-humarán, Probiotic strain Lactobacillus casei Bl23 prevents colitis- preparations extracted from Sargassum cristaefolium, J. Food Drug Anal. 23 (2015)
associated colorectal cancer, Front. Immunol. 8 (2017) 1–10. 766–777.
[69] R. Ghanavati, P. Asadollahi, M.B. Shapourabadi, S. Razavi, M. Talebi, M. Rohani, [94] U. Tukenmez, B. Aktas, B. Aslim, S. Yavuz, The relationship between the structural
Inhibitory effects of Lactobacilli cocktail on HT-29 colon carcinoma cells growth characteristics of lactobacilli-EPS and its ability to induce apoptosis in colon
and modulation of the Notch and Wnt/β-catenin signaling pathways, Microb. cancer cells in vitro, Sci. Rep. 9 (2019) 1–14.
Pathog. 139 (2019), https://doi.org/10.1016/j.micpath.2019.103829. [95] Y. Rahbar, A. Yari, A. Akbar, M. Talebi, Modulatory role of exopolysaccharides of
[70] R.S. Kumar, P. Kanmani, N. Yuvaraj, Lactobacillus plantarum AS1 isolated from Kluyveromyces marxianus and Pichia kudriavzevii as probiotic yeasts from dairy
south indian fermented food kallappam suppress 1, 2-Dimethyl hydrazine (DMH)- products in human colon cancer cells, J. Funct. Foods 64 (2020) 1–9.
Induced colorectal Cancer in male wistar rats, Appl. Biochem. Biotechnol. 166 [96] L. Wang, Y. Wang, Q. Li, K. Tian, L. Xu, G. Liu, C. Guo, Exopolysaccharide, isolated
(2012) 620–631. from a novel strain Bifidobacterium breve lw01 possess an anticancer effect on head
[71] A. Poggi, R. Benelli, R. Venè, D. Costa, N. Ferrari, F. Tosetti, et al., Human gut- and neck Cancer - genetic and biochemical evidences, Front. Microbiol. 10 (2019)
associated natural killer cells in health and disease, Front. Immunol. 10 (2019) 1044, https://doi.org/10.3389/fmicb.2019.01044.
1–18. [97] G. Zhang, J. Zhang, X. Wang, W. Yang, Z. Sun, C.N. Kumar, H. Guan, J. Guan,
[72] A. Nabil, B. Bonavida, Activation of natural killer cells by probiotics, For. Apoptosis of human tongue squamous cell carcinoma cell (CAL-27) induced by

9
T. Legesse Bedada, et al. Biomedicine & Pharmacotherapy 129 (2020) 110409

Lactobacillus sp. A-2 metabolites, J. Appl. Oral Sci. 22 (2014) 282–286. [110] R.Y. Chull, B.S. Hong, H.J. Park, B.K. Kim, J.Y. Ahn, C.M.J. Hyung, Anti-colorectal
[98] I. Kahouli, M. Malhotra, C. Tomaro-Duchesneau, L.S. Rodes, M.A. AlouiJamali, Cancer effects of probiotic-derived p8 protein, Genes (Basel). 10 (2019) 1–16.
Satya Prakash, Identification of Lactobacillus fermentum strains with potential [111] Z. Aghazadeh, F. Pouralibaba, A.Y. Khosroushahi, The prophylactic effect of
against colorectal Cancer by characterizing short chain fatty acids production, Acetobacter syzygii probiotic species against squamous cell carcinoma, J. Dent. Res.
anti-proliferative activity and survival in an intestinal fluid: in vitro analysis, J. Dent. Clin. Dent. Prospects 11 (2017) 208–214.
Bioanal. Biomed. 7 (2015) 104–115. [112] M. Pancione, A. Remo, V. Colantuoni, Genetic and epigenetic events generate
[99] L.D. Lagadic-gossmann, C. Lemaire, C. Brenner, Acidic extracellular pH shifts multiple pathways in colorectal cancer progression, Patholog. Res. Int. 2012
colorectal cancer cell death from apoptosis to necrosis upon exposure to propio- (2012) 1–11.
nate and acetate, major end-products of the human probiotic propionibacteria, [113] Q. Wu, T. Ishikawa, R. Sirianni, H. Tang, J.G. McDonald, I.S. Yuhanna1, et al., 27-
Apoptosis. 12 (2007) 573. hydroxycholesterol promotes cell-autonomous ER-positive breast Cancer growth,
[100] M. Thirabunyanon, P. Hongwittayakorn, Potential probiotic lactic acid Bacteria of Cell Rep. 5 (2012) 637–645.
human origin induce anti-proliferation of colon cancer cells via synergic actions in [114] I.K. Meenakshi, In-Vitro Characterization of the anti-cancer activity of the pro-
adhesion to cancer cells and short-chain fatty acid bioproduction, Appl. Biochem. biotic bacterium Lactobacillus Fermentum NCIMB 5221 and potential against col-
Biotechnol. 169 (2013) 511–525. orectal cancer, J. Cancer Sci. Ther. 7 (2015) 224–235.
[101] J.B. Ewaschuk, J.W. Walker, H. Diaz, K.L. Madsen, Bioproduction of conjugated [115] H. Konishi, M. Fujiya, H. Tanaka, N. Ueno, K. Moriichi, J. Sasajima, K. Ikuta,
linoleic acid by probiotic bacteria occurs In Vitro and In Vivo in mice, J. Nutr. 136 H. Akutsu, H. Tanabe, Y. Kohgo, Probiotic-derived ferrichrome inhibits colon
(2006) 1483–1487. cancer progression via JNK-mediated apoptosis, Nat. Commun. 7 (2016) 1–12.
[102] I. Kahouli, M. Malhotra, S. Westfall, M.A. Alaoui-Jamali, S. Prakash, Design and [116] K. Siva Kumar, Colon Cancer prevention through probiotics: an overview, J.
validation of an orally administered active L. fermentum-L. acidophilus probiotic Cancer Sci. Ther. 7 (2015) 81–92.
formulation using colorectal cancer Apc Min/+ mouse model, Appl. Microbiol. [117] M.E. Sanders, T.R. Klaenhammer, Invited Review: The Scientific Basis
Biotechnol. 101 (2016) 1999–2019. ofLactobacillus acidophilus NCFM Functionality as a Probiotic, J. Dairy Sci. 84
[103] G. Mcintosh, Probiotics and colon cancer prevention, Asia Pacific J Clin Nutr. 5 (2001) 319–331.
(1996) 48–52. [118] B.P. Marteau, Safety aspects of probiotic products, Scand J
[104] J. Escamilla, M.A. Lane, V. Maitin, J. Escamilla, M.A. Lane, V. Maitin, Cell-Free NutrAVaringsforskning. 45 (2001) 22–24.
Supernatants from probiotic Lactobacillus casei and Lactobacillus rhamnosus GG [119] K. Papadimitriou, J. Kok, Future challenges in lactic acid Bacteria stress phy-
Decrease colon cancer cell invasion In Vitro, Nutr. Cancer 64 (2012) 871–878. siology research, Food Microbiol. Food Saf. 21 (2011) 507–518.
[105] M. Kleerebezem, P. Hols, E. Bernard, T. Rolain, M. Zhou, R.J. Siezen, et al., The [120] K. Makarova, A. Slesarev, Y. Wolf, A. Sorokin, B. Mirkin, E. Koonin, et al.,
extracellular biology of the lactobacilli, FEMS Microbiol. Rev. 34 (2010) 199–230. Comparative genomics of the lactic acid bacteria, PNAS. 103 (2006)
[106] O.R.F. Mook, W.M. Frederiks, C.J.F. Van Noorden, The role of gelatinases in col- 15611–15616.
orectal cancer progression and metastasis, Biochim. Biophys. Acta 1705 (2004) [121] W. Van Schaik, T. Abee, The role of s B in the stress response of Gram-positive
69–89. bacteria – targets for food preservation and safety, Curr. Opin. Biotechnol. 16
[107] N. Sawada, Tight junction-related human diseases, Pathol. Int. 63 (2013) 1–12. (2005) 18–224.
[108] S. Ohtani, M. Terashima, J. Satoh, N. Soeta, Z. Saze, S. Kashimura, F. Ohsuka, [122] G. Reid, Probiotics and prebiotics – progress and challenges, Int. Dairy J. 18
Y. Hoshino, M. Kogure, M. Gotoh, Expression of tight-junction-associated proteins (2008) 969–975.
in human gastric cancer: down-regulation of claudin-4 correlates with tumor ag- [123] M.L.Y. Wan, S.J. Forsythe, H. El-nezami, Probiotics interaction with foodborne
gressiveness and survival, Gastric Cancer 12 (2009) 43–51. pathogens: a potential alternative to antibiotics and future challenges, Crit. Rev.
[109] K.A. Donato, M.G. Gareau, Y.J.J. Wang, P.M. Sherman, Lactobacillus rhamnosus GG Food Sci. Nutr. 59 (20) (2019) 3320–3333, https://doi.org/10.1080/10408398.
attenuates interferon-γ and tumor necrosis factor-α-induced barrier dysfunction 2018.1490885.
and pro-inflammatory signalling, Microbiology 156 (2010) 3288–3297.

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