Bacteriotherapy of Cancer

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ISSN : 0974 - 7532 Volume 10 Issue 8

Research & Reviews in


BioSciences
Review
RRBS, 10(8), 2015 [310-314]

Bacteriotherapy of cancer
M.A.Nagy1*, M.M.Mahmoud2, E.R.Tawfiek3
1
Drug Information Center, El Minia Psychiatric Hospital, (EGYPT)
2
Manager of El Minia Psychiatric Hospital, (EGYPT)
3
Department of urology, Faculty of medicine, El Minia University, (EGYPT)
E-mail: nagy_bio@yahoo.com

ABSTRACT KEYWORDS
Resistance to conventional anticancer therapies in patients with advanced Bacteriotherapy;
solid tumors has prompted the need of alternative cancer therapies. More- Cancer.
over, the success of novel cancer therapies depends on their selectivity
for cancer cells with limited toxicity to normal tissues. Bacteriotherapy
is the treatment of disease by the use of bacteria or their products. It may
have potential applications for cancer therapy as it is the most potential
and promising strategy is bacteria based gene-directed enzyme prodrug
therapy.  2015 Trade Science Inc. - INDIA

INTRODUCTION agents for anticancer drugs, and as vectors for gene


therapy. Bacterial toxins can be used for tumour de-
Conventional anticancer therapies such as che- struction and cancer vaccines can be based on
motherapy are losing their sheen in the battle against immunotoxins of bacterial origin. The most promis-
cancer. Therefore, strategies for treatment of cancer ing approaches are the use of genetically modified
need to be constantly modified to fulfill the growing bacteria for selective destruction of tumours, and
demands of alternative therapies[17]. bacterial gene-directed enzyme prodrug therapy.
Specific delivery of therapeutic enzymes to can- Knowledge gained from study of bacterial genomes
cer cells for subsequent activation of anticancer forms an important basis of use of bacteria as anti-
drugs in the tumor microenvironment is a promising cancer agents[10].
approach to improve the selectivity of cancer che- For at least two centuries, there have been re-
motherapy. Different vehicles including viruses, li- ports that cancer patients infected with various bac-
posomes and antibodies have been evaluated to de- teria had what appeared to be spontaneous remis-
liver therapeutic enzymes to cancer cells[6]. sion. In the late nineteenth and early twentieth cen-
Historically, bacteria were used as oncolytic turies, W.B. Coley, of what is now the Memorial
agents for malignant brain tumours. Advances in bac- Sloan-Kettering Cancer Center, pioneered bacterial
teriology and molecular biology have widened the therapy of cancer in the clinic with considerable suc-
scope of bacterial approaches to cancer therapy and cess. After Coley died in 1936, bacterial therapy of
various possibilities include the use of bacteria as cancer started to go out of favor. In the current twenty-
sensitising agents for chemotherapy, as delivery first century, there is great resurgent interest in de-
RRBS 10(8) 2015 M.A.Nagy et al. 311

Review
veloping bacterial therapy for treating cancer using Salmonella typhimurium A1-R is auxotrophic for
either obligate or facultative anaerobic bacteria. arg and leu, which attenuates growth in normal tis-
There is also controversy about which bacteria are sue but allows high tumor targeting and virulence.
optimum for cancer treatment and whether bacteria A1-R is effective against metastatic human prostate,
should be used as tumor-targeting vectors, immune breast, and pancreatic cancer as well as osteosar-
stimulators, or for direct tumor killing[7]. coma, fibrosarcoma, and glioma in clinically-rel-
Recently, bacteria directed enzyme prodrug evant mouse models.
therapy (BDEPT) has been investigated for cancer Cancer treatment with attenuated Salmonella
therapy. Bacteria are well-suited to serve as anti- enterica Typhimurium (S. Typhimurium) has gained
cancer agents due to their intrinsic preferential ac- momentum in recent years. S. Typhimurium attenu-
cumulation within the anoxic tumour environment, ated by deletion of cyclic adenosine monophosphate
mobility, cell toxicity and immunogenicity. Further- signaling, SalpNG.1. S. Typhimurium treatment re-
more, advances in biotechnology and molecular tech- duces tumor burden and increases survival in an au-
niques have made it easier than ever to engineer bac- tochthonous breast cancer model[5].
teria as both therapeutic agents themselves and as An alternative approach taken here is to use
therapeutic vectors[21]. recombineering to make Salmonella not viable in
Clostridium normal tissues by placing an essential gene, asd,
under the control of a hypoxia-induced promoter. The
Spores of some species of the strictly anaerobic asd gene ofSalmonella encodes an enzyme essen-
bacteria Clostridium naturally target and partially tial for the synthesis of Diaminopimelic acid (DAP),
lyse the hypoxic cores of tumors, which tend to be which is itself an essential component of the bacte-
refractory to conventional therapies. The anti-tumor rial cell wall and not present in mammalian sys-
effect can be augmented by engineering strains to tems. With asd expressed only in hypoxic conditions
convert a non-toxic prodrug into a cytotoxic drug the bacterium is able to grow readily under hypoxia,
specifically at the tumor site by expressing a prodrug- but will lyse under normal growth conditions[12].
converting enzyme (PCE) [8].
The efficacy of Clostridium-Directed Enzyme Bifidobacterium infantis
Prodrug Therapy (CDEPT) using nitroreductase Bifidobacterium Infantis is a kind of
(NTR) was demonstrated in a mouse xenograft Bifidobacteria that is non-pathogenic and anaero-
model of human colon carcinoma. Substantial tumor bic, and thus they can selectively localize and pro-
suppression was achieved, and several animals liferate in the hypoxic environment in several types
were cured. These encouraging data suggest that the of solid tumors after systemic application[24]. The
novel enzyme and strain engineering approach rep- fms-like tyrosine kinase receptor (Flt) is a trans-
resent a promising platform for the clinical devel- membrane receptor of the tyrosine kinase family,
opment of CDEPT. which has been identified as a receptor for VEGF. It
Salmonella typhimurium have an important role in tumor growth and metasta-
sis, and are associated with poor prognosis in clini-
Using bacteria as therapeutic agents against solid
tumors is emerging as an area of great potential in cal human tumors. First identified in 1993, the
the treatment of cancer. Obligate and facultative soluble Flt (sFlt-1) was immediately found to exert
anaerobic bacteria have been shown to infiltrate the powerful antiangiogenesis function. As the soluble
hypoxic regions of solid tumors, thereby reducing form of extracellular part of VEGF receptor-1
their growth rate or causing regression. However, a (VEGFR-1), sFlt-1 can compete with VEGFR-1 for
major challenge for bacterial therapy of cancer with VEGF and exert its function. It has been confirmed
facultative anaerobes is avoiding damage to normal that sFlt-1 can suppress both the growth and[16]me-
tissues. Consequently the virulence of bacteria must tastasis of solid tumor by many investigations .
be adequately attenuated for therapeutic use[22]. Bifidobacterium Infantis-mediated sFlt-1 gene
312 Bacteriotherapy
. of cancer RRBS 10(8) 2015

Review
transferring system was successfully constructed and mutagenic effects. The macrophagocytes provided
could express sFlt-1 at the levels of gene and pro- with L. plantarum strengthened phagocytosis, and
tein. This system could significantly inhibit growth displayed anticancer effects in aseites carcinoma and
of HUVECs induced by VEGF in vitro. Moreover, solid tumor due to the polysaccharide chains of mu-
it could inhibit the tumor growth and prolong sur- ramic acid in the L. plantarum’s cell well. Among
vival time of LLC C57BL/6 mice safely. This may lactic acid bacteria’s cell wall substances, polysac-
be a promising therapeutic strategy for cancer pa- charide types rather than glycopeptide play a piv-
tients. otal role in cancer suppression[18]
Lactic acid bacteria (LAB) Daily consumption of Bifidobacterium spp (B.
longum SPM1207) can help in managing mild to
Lactic acid bacteria (LAB) are beneficial moderate hypercholesterolemia, with potential to
probiotic organisms that contribute to improved nu- improve human health by helping to prevent colon
trition, microbial balance, and immuno-enhancement cancer and constipation.
of the intestinal tract, as well as lower cholesterol.
Escherichia coli nissle
Although present in many foods, most trials have
been in spreads or dairy products[14]. Facultative anaerobic bacteria like E. coli can
colonize solid tumors often resulting in tumor growth
Weissella cibaria
retardation or even clearance. Little mechanistic
Weissella is a newly separated lactic acid bac- knowledge is available for this phenomenon which
teria of lactobacillus family that was identified by a is however crucial for optimization and further imple-
recent DNA technique. It is a Gram-positive and mentation in the clinic.
catalase negative bacteria included in geneally rec- Escherichia coli Nissle 1917 may be developed
ognized as safe. Studies have reported that microor- as an orally administered diagnostic that can
ganisms, including lactic acid bacteria, secreted noninvasively indicate the presence of liver metasta-
exopolysaccharides (EPS) with the anticancer, anti- sis by producing easily detectable signals in urine.
inflammatory, immune modulating, and blood cho- Our microbial diagnostic generated a high-contrast
lesterol declining functions[1]. urine signal through selective expansion in liver
Lactobacillus plantarum metastases (10(6)-fold enrichment) and high expres-
sion of a lacZ reporter maintained by engineering a
Lactobacillus genus is a microorganism which stable plasmid system. The lacZ reporter cleaves a
does not form spores and is an anaerobic and fac- substrate to produce a small molecule that can be
ultative anaerobic gram-positive bacterium. This detected in urine[4].
bacterium is not only widely dispersed in nature but
is also found in human oral cavity and digestive or- Butyrate
gans. This bacterium is a beneficial microorganism Butyrate as an important short chain fatty acid
that is widely used as a starter for various fermented has been shown to affect different kinds of cancer
dairy products cells. Butyrate exerts its anti-cancerous effects by
L. plantarum, isolated from kimchi, also exhib- several mechanisms and has lead to successful out-
ited a strong antimutagenic effect against N-methyl- comes in phase I and II clinical trials. Moreover,
N’-nitro-N-nitrosoguanidine, 4-Nitroquinoline-1- since solid tumors grow rapidly, multiple regions of
oxide. Furthermore, L. Plantarum, had stronger anti- hypoxia and anoxia forms within them that provide
TABLE 1 : Differences between Ad/mâG and E. coli (lux/âG)[9]
Therapy Ad/mâG E. coli (lux/âG)
Tumor distribution Live cells Border between live cells and necrotic areas
Enzyme location Cancer cell surface E. coli periplasmic space
Enzyme source Mouse beta-glucuronidase E. coli beta-glucuronidase
RRBS 10(8) 2015 M.A.Nagy et al. 313

Review
good niches for the growth of anaerobic bacteria. It capacity to produce butyrate could be the focus of
has been shown that bacterial tumor targeting is an future research.
applicable strategy for tumor-selective therapy[20].
Sodium butyrate has an effect on AR coregulators CONCLUSION
expression, transcription activity and histone acety-
lation in cancer cells, but there is only minimal ef- Bacteriotherapy as mentioned above will be the
fect in normal cells. In addition, the results of changes most safe and selective treatment of cancer in the
in acetylation level on lysine residues of histone H4 future especially with the development of biotech-
after sodium butyrate treatment confirm its epige- nology techniques Acknowledgements:
netic effect on prostate cancer cells[15]. We thank Dr Amr Saad, Head of the Egyptian
Although the underlying mechanisms by which Pharmaceutical vigilance Center and the Head of the
butyrate regulates cell proliferation and/or differ- Arabic higher technical committee for medicines for
entiation are not fully understood, it has been shown his kind advice and support.
that butyrate action could involve various effects on
gene expression, which are often attributed to its ABBREVIATIONS
capacity to act as an inhibitor of histone deacetylases
(HDACs). This effect leads to a hyperacetylation of Prodrug converting enzyme (PCE)
histones and increased accessibility of transcription Clostridium-Directed Enzyme Prodrug Therapy
factors to promoters in the DNA[11]. (CDEPT)
Moreover, butyrate influences post-traductional Nitroreductase (NTR)
modifications including DNA methylation, histone Diaminopimelic acid (DAP)
methylation, histone phosphorylation1 and Fms-like tyrosine kinase receptor(Flt)
hyperacetylation of nonhistone proteins. Those di- vascular endothelial growth factor(VEGF)
verse effects may explain the impact of butyrate on Bacteria directed enzyme prodrug therapy
the expression of key regulators of apoptosis and (BDEPT)
cell cycle such as the proapoptotic protein BAK12 Exopolysaccharide (EPS)
and the cell cycle proteins, cyclins D and p21[13].
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