- Open Access
- Authors : Anirban Goutam Mukherjee , Uddesh Ramesh Wanjari , Neha Kaulik , Piyush Jagdish Balgote
- Paper ID : IJERTV9IS070578
- Volume & Issue : Volume 09, Issue 07 (July 2020)
- Published (First Online): 29-07-2020
- ISSN (Online) : 2278-0181
- Publisher Name : IJERT
- License: This work is licensed under a Creative Commons Attribution 4.0 International License
A Review on the Present and Future Aspects of Various Prokaryotic Pigments and Metabolites Demonstrating Anti-Cancerous Properties
Anirban Goutam Mukherjee1, Uddesh Ramesh Wanjari2, Neha Kaulik3 Piyush Jagdish Balgote3
1 M.Sc Biotechnology (Third semester), Vellore Institute of Technology, Vellore, Tamil Nadu, India, 632014
2 M.Sc Biochemistry (Third semester), Kamla Nehru Mahavidyalaya, Nagpur, Maharashtra, India, 440024
3 M.Sc Molecular Biology and Genetic Engineering (Third semester) Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, Maharashtra, India, 440033
Abstract Prokaryotic organisms have always been known to produce a wide variety of metabolites and even various pigments. These pigments and metabolites are known to be associated with a wide range of properties including anti cancerous, anti-bacterial, anti-inflammatory to name a few. The biggest problem that the mankind is facing today is the different types of cancers that have become a threat to humanity. This review mainly focuses on various prokaryotic organisms like Cyanobacteria, Actinomycetes, Staphylococcus gallinarum, Streptomyces peucetius, Serratia mercescens that are widely known to produce several anti-cancerous compounds. These compounds have been observed to demonstrate cytotoxic activity in cancer cell lines. A detailed study will thus help us to understand and design several novel anti-cancerous drugs.
Keywords- Prokaryotic, metabolites, pigments, cancer, cytotoxic
A COMPLETE REVIEW
This review aims to provide some understanding related to the varied range of prokaryotes known for producing a large number of various anticancer compounds. According to Newman and Shapiro, microorganisms have always known to produce a number of anti-cancerous compounds which include actinomycin D (dactinomycin), anthracyclines, including daunorubicin, doxorubicin (adriamycin), epirubicin, pirarubicin, idarubicin, valrubicin, various types of glycopeptides (bleomycin, phleomycin), the mitosane mitomycin C, and the anthracenones (mithramycin, streptozotocin, pentostatin) [1,2].
11-hydroxyaclacinomycin A is a modified anthracycline which is produced by cloning. The genes involved for cloning are doxorubicin resistance gene and the aklavinone 11- hydroxylase gene dnrF from the doxorubicin producer, Streptomyces peucetius subsp. caesius, into the aclacinomycin A producer. This hybrid compound is found to be highly effective against leukemia and melanoma [1, 2]. 2- amino-11-hydroxyaclacinomycin Y is another hybrid compound which is reported to be highly effective against tumors. Also some innovative anthracyclines have been prepared by the introduction of DNA from Streptomyces purpurascens into Streptomyces galilaeus 
Myxobacteria are large Gram-negative rods that move by gliding or creeping. More than 400 compounds have been
derived from these organisms and one of the most effective anti tumor compound is epithilone. These are most effective against breast cancers. Epithilones are known to bind and stabibilize the microtubules that are most essentially needed for cell division and DNA replication. By the prevention of the disassembly of microtubules, epothilones successfully arrest the tumor cell cycle at the GM2/M phase and induce apoptosis [1, 3, 4].
Cyanobacteria are gram-negative photoautotrophic prokaryotes. They are known for carrying out oxygenic photosynthesis and are most commonly known as blue-green bacteria. They are known for producing C-phycocyanin. Cyanobacterial products have long been known to possess anticancer, antiviral, antibacterial, immune-modulatory and protease-inhibition activities .The anticancer activities are most widely studied. Lyngbya produces apratoxin D which is cytotoxic to human lung cancer cells . Symplocamide A, isolated from Symploca sp. exhibits potent cytotoxicity to not only lung cancer cells but also neuroblastoma cells . The anticancer drugs mainly work as apoptotic modulators [7,8]
.Apoptosis is mainly brought out by the implication of intrinsic and extrinsic signals. These can be by reactive oxygen species , the UV radiation and also by the flavonoid quercetin [10,11]. A demonstration by Martins and co-workers showed that when HL-60 cells are exposed to aqueous extracts of Synechocystis sp. and Synechococcus sp. Strains, cell shrinkage and membrane budding are evident which indicates that the cells are developing apoptosis [11,12] . Lyngbya sp., produces a macrolide called biselyngbyaside that induces apoptosis in mature osteoclasts and marine benthic Anabaena sp. extracts are found to induce apoptosis in acute myeloid leukemia cell line .
The marine cyanobacteria brings about cytotoxicity in tumor cell lines mainly by the implication of several apoptotic indicators like cell cycle arrest , mitochondrial dysfunctions and oxidative damage, and by alterations in caspase cascade .Bioactive metabolites like cryptophycin 52 , calothrixin A, hectochlorin and lyngbyabellin B obtained from Nostoc spp  , Calothrix  and Lyngbya  respectively are found to induce cell cycle arrest in G2/M phase in different human cancer cell lines. Dolastatins  also exhibit a similar effect. Cyanobacterial aurilides A and B bring mitochondria fragmentation in HeLa cells and is evident by
MitoTracker Red staining.The activity of caspase -3 , the most important caspase related to apoptosis , increases after getting exposed to symplostatin 1  and glicomacrolide biselyngbyaside .Interestingly cryptophycin 1 is found to induce apoptosis in a human ovarian carcinoma cell line .Symplostatin 1 and Dolastatin 10 initiates the phosphorylation of Bcl-2 which inhibits anti-apoptotic properties in human breast cancer cells . Curacin A is also a potential anticancer and antitumor agent obtained from a marine cyanobacterium .
Polyether metabolites, halichondrins and caprolactins A, B are also known to possess anticancer properties . Caprolactins A and B exhibit mild cytotoxic activities and are produced by an unindentified Grampositive bacterium. Another compound y-Indomycinone, produced by a streptomycete exhibits cytotoxicity against the Chinese hamster ovary (CHO) cell lines . Actinomycetes are also known to produce a large number of compounds with anti- tumour properties . Streptoalloteichus hindustanus is commonly known to produce bleomycin , various glycopeptides, widely used for for Hodgkins lymphomas, squamous cell carcinomas and testis tumours . Bleomycin derivatives like blenoxane, used in combination with other compounds is used to treat lymphomas, skin carcinomas and tumours of the head, neck and testicles . SF 2575, a fourth-generation tetracycline is found to have cytotoxic activity against P388 leukaemia cells and various other cancer cells .One of the most strongest known natural anti cancer agents are enediynes. They include dynemicin A, calicheamicin, kerdarcidin , esparamicin, and neocarzinostatin [29,30].Enediyens are represented by two classes of antitumor compounds, esperamycins and calicheamicins [30,31,32]
Epothilones are commonly known 16-member ring polyketide macrolide lactones. These are produced by the myxobacterium Sorangium cellulosum [33,34] and are most commonly used as anti-tumour compounds. They generally contain methylthiazole group attached by an olefinic bond and are mostly effective against breast cancer and other forms of cancer. Angiogenesis is an important step for the proliferation of cancer cells. Aspergillus fumigates produces fumagillin which acts as an anti-angiogenesis compound [36, 37]. Elutherobin, discodermolide, bryostatins, dolastatins and cephalostatins are other common anti tumor agents obtained from marine sources .
The Staphyloxanthin pigment obtained from Staphylococcus gallinarum KX912244 exhibits DNA damage protection activity against reactive oxygen species and anticancer activity which can be easily evaluated by cytotoxicity assay against 4 different cancer cell lines .Bacterial carotenoid pigments are an interesting group of compounds studied in relation to cancer biology. Carotenoid pigments are known to possess antioxidant property that helps fight the reactive oxygen species that are destructive to cellular molecules like DNA, proteins and lipids .
An experiment conducted by Avilla et al. to isolate Staphyloxanthin molecule from Staphylococcus gallinarum KX912244, a Gut Microbe of Bombyx mori Delicia proves the cytotoxic effect of the extracted Staphyloxanthin molecule against Daltons lymphoma ascites (DLA), Ehrlich ascites carcinoma (EAC), Adenocarcinomic human alveolar basal epithelial cells (A549 Lung carcinoma) and Mus mucus skin melanoma (B16F10) and non-cancerous human fibroblast cell line (NIH3T3) cells in vitro using MTT (3- (4,5-dimethylthiaz01-2-y1)-2,5- diphenyl tetrazolium bromide) assay [39,40].Further the demonstration by Clauditz et al.  proves that Staphyloxanthin molecule scavenges free radicals with its conjugated double bonds which further boost the anti oxidant capability of staphyloxanthin [42,43,44]. In another set of experiments Liu et al. demonstrated that the pigment Staphyloxanthin is a strong antioxidant that can impart virulence character for the Staphylococci which will help to evade the neutrophil killing .But still there is no confirmation till date that Staphyloxanthin can directly be used as an anticancer agent .
Prodigiosin pigment, from Serratia marcescens  is widely studied and its role in inducing apoptosis and cell cycle inhibition of cancer cells is no longer a mystery  .A study exhibits the cytotoxic and antiproliferative effects of prodigiosin against 60 human tumor cell lines including that of lung, renal, leukaemia, brain cancer, colon and melanoma.Several research on this compound has helped us to obtain several novel compounds like novel prodigiosin analogue 2,20 -[3-methoxy-10 amyl-50 -methyl-4-(100- pyrryl)] dipyrrylmethene (MAMPDM). This possess potent cytotoxic activity towards cancer cells . The methoxy group plays the most important role  in anti-cancer effects that have been observed in several human cancer cell lines in vitro [51,52,53,54,55].This cytotoxicity is also seen in hepatocellular carcinoma xenografts  and in human primary cancer cells  Interestingly it has no marked toxicity toward non-malignant cell lines [58,53,54,55]. A wide variety of bacterial taxa including Gram-negative rods such as Serratia rubidaea , S. marcescens, Vibrio gazogenes, Pseudomonas magneslorubra, Vibrio psychroerythrous Alteromonas rubra, Rugamonas rubra and Gram-positive actinomycetes such as Streptomyces spectabilis, Streptomyces longisporus and Streptoverticillium rubrireticuli are known to produce secondary metabolites related to prodigiosins .
Genetically engineered organisms have also proved to be highly beneficial in the production of various anti- cancer and antitumor activities. The attenuated strains of Salmonella enterica servovar Typhimurium have several such properties [60, 61, 62]. Engineered salmonella can demonstrate IL2- expressing properties which can be used as an oncolytic agent in the highly tumorigenic B16F1 melanoma mouse model .Live bacteria has long been used to treat human cancers[63,64,65].Studies show that a proper and systemic administration of the facultative anaerobic bacteria like Salmonella typhimurium to tumor bearing mice results in a cytotoxic and finally leading to an antitumor effect[66,67].Salmonella have been engineered in a manner so that it express cytokines or various angiogenesis inhibitors [68,69,70]. Studies by Bashel et al. indicate that employing Salmonella for the treatment of tumor-bearing animals is associated with decreased angiogenesis and increased tissue necrosis within the tumors  which establish the possibility that the bacteria most probably accumulate in tumors, and thus they become targets of choice for use as vectors in order to deliver agents with antitumor activity into the tumor tissue .A recent study by Loeffler et al. shows that a Salmonella strain expressing LIGHT, a TNF- family cytokine, can be used effectively to target tumor tissue and bring about inhibition of the growth of primary, subcutaneously implanted, colon and breast carcinomas and their dissemination into the lungs. This antitumor activity of LIGHT-expressing Salmonella is found to be associated with the infiltration of inflammatory cells like IL-12 and IFN-, two critical antitumor cytokines into the tumor tissue [69,71] The most effective anticancer drugs include bryostatins, discodermolide, eleutherobin and sarcodictyin obtained from bacterial sources [72,73].
Studies done by Carte et al. and Goldin et al. indicate that Lactobacilli and Noctiluca scintillans can demonstrate cytotoxicity and thus can be used as chemopreventive effects which are highly effective against colon and melanoma cancer [74,75] . Additionaly Lactobacilli is found to possess the ability to reduce the activities of nitroreductase, – glucuronidase and azoreductase enzymes in diet of rats which is an indication that Lactobacilli can lessen the incidence of development of colon cancer [75,76, 77]. Experiments and comparative studies done by Bitzer et al. and Sagar et al. indicate that The marine-derived Halomonas spp. strain GWS-BW-H8hM can inhibit the growth of HM02 (gastric adeno-carcinoma), HepG2 (hepatocellular carcinoma) and MCF7 cell lines [78,79].Surprisingly exo-polysaccharides (EPSs) and sulfated EPSs isolated from H. Stenophila obtained from similar environment like Halomonas is reported for their pro-apoptotic effects on T-leukemia cells and most interesting element again is that they affect only only tumor cells and do not show cytotoxicity against the normal cells .Halomonas can also produce cytotoxic hydroxyphenylpyrrole dicarboxylic acids, i.e., 3-(4- hydroxyphenyl)-4-phenylpyrrole-2,5-dicarboxylic acid (HPPD-1), 3,4-di-(4-hydroxy-phenyl) pyrrole-2,5- dicarboxylic acid (HPPD-2) and the indole derivatives 3- (hydroxyacetyl)-indole, indole-3-carboxylic acid, indole-3- carboxaldehyde, and indole-3-acetic acid .HPPD-1 and HPPD-2 are both antitumor compounds which function by the inhibition of 12-O-tetradecanoylphorbol-13-acetate (TPA) induced activation of EpsteinBarr virus early antigen. It is found that the inhibitory effect of HPPD-2 is more potent when compared to HPPD-1 at all tested dose ratios .
Marine actinomycetes are nowhere behind. Their cytotoxic activities on various cancer cell lines are proved by many experiment and comparative analysis. They include members of the genera Dietzia, Rhodococcus , Streptomyces , Salinispora [84,85, 86] and Marinispora [85,86]. Nocardiopsis lucentensis (strain CNR-712) produces 3- methyl-4-ethylideneproline-containing peptides. Among them
Lucentamycins A and B is found to exhibit in vitro cytotoxicity against HCT-116 human colon carcinoma . Thicoraline is a depsipeptide isolated from Micromonospora marina. It can successfully display cytotoxic activity against both LOVO and SW620 human colon cancer cell lines
.Studies on Streptomyces species by Maskey et al. puts forward the fact that Trioxacarcins A-C obtained from Streptomyces display potent anti-tumor activity against lung cell line . The capacity of Planctomycetes to induce apoptosis and decrease cell growth in human and rat cell lines is evident by a set of experiments conducted by Calistro et al. The study further describes that Planctomycetes strains exhibit active bioactivity against one or both cancer cell lines (MOLM-13 AML cells and PC3 prostate cancer, but not tothe normal NRK kidney epithelial cells .
This review aims to produce a basic understanding about the different types of prokaryotic metabolites and pigments and their effectiveness in various types of cancer. The capability of prokaryotes to produce antitumor and anti-cancerous activities is not new but the current need is to have an overall understanding so that innovative new drugs and therapeutic agents can be developed to prevent cancer. Engineered Salmonella strains, products obtained from filamentous bacteria  ,marine Halomonas and Planctomycetes species provide a lot of hope. The development in molecular biology and the sequencing of microbial genomes promises a greater understanding of the tumor tissue microenvironment .This has resulted in a high boost of interest in using obligate and facultative anaerobic bacterial species, including Salmonella, Bifidobacterium, and Clostridium spp., to control tumor growth [63,65, 93]
Demain, A. L. (2013). Importance of microbial natural products and the need to revitalize their discovery. Journal of Industrial Microbiology & Biotechnology, 41(2), 185-201,DOI 10.1007/s10295-013-1325-z
Newman DJ, Shapiro S (2008) Microbial prescreens for anticancer activity. SIM News 58:132150
Gerth K, Steinmetz H, Hofle G, Reichenbach H (2000) Studies on biosynthesis of epothilones: the biosynthetic origin of the carbon skeleton. J Antibiot 53:13731377
Goodin S (2008) Novel cytotoxic agents: epothilones. Am J Health Syst Pharm 65(10 Suppl 3):S10S15
Gutierrez, M.; Suyama, T.L.; Engene, N.; Wingerd, J.S.; Matainaho, T.; Gerwick, W.H. Apratoxin D, a potent cytotoxic cyclodepsipeptide from papua new guinea collections of the marine cyanobacteria Lyngbya majuscula and Lyngbya sordida. J. Nat. Prod. 2008, 71,10991103.
Linington, R.G.; Edwards, D.J.; Shuman, C.F.; McPhail, K.L.; Matainaho, T.; Gerwick, W.H. Symplocamide A, a potent cytotoxin and chymotrypsin inhibitor from the marine cyanobacterium Symploca sp. J. Nat. Prod. 2008, 71, 2227.
Zhang, J.Y. Apoptosis-Based anticancer drugs. Nat. Rev. Drug Discov. 2002, 1, 101102. 8Fischer, U.; Schulze-Osthoff, K. Apoptosis-Based therapies and drug targets. Cell Death Differ. 2005, 12, 942961.
Mao, Y.B.; Song, G.; Cai, Q.F.; Liu, M.; Luo, H.H.; Shi, M.X.; Ouyang, G.; Bao, S.D. Hydrogen peroxide-induced apoptosis in human gastric carcinoma MGC803 cells. Cell Biol. Int. 2006, 30,332337.
Lytvyn, D.I.; Yemets, A.I.; Blume, Y.B. UV-B overexposure induces programmed cell death in a BY-2 tobacco cell line. Environ. Exp. Bot. 2010, 68, 5157.
Chen, D.; Daniel, K.G.; Chen, M.S.; Kuhn, D.J.; Landis-Piwowar, K.R.; Dou, Q.P. Dietary flavonoids as proteasome inhibitors and
apoptosis inducers in human leukemia cells. Biochem. Pharmacol. 2005, 69, 1421 1432.
Costa, M., Costa-Rodrigues, J., Fernandes, M. H., Barros, P., Vasconcelos, V., & Martins, R. (2012). Marine Cyanobacteria Compounds with Anticancer Properties: A Review on the Implication of Apoptosis. Marine Drugs, 10(12), 2181
Martins, R.F.; Ramos, M.F.; Herfindal, L.; Sousa, J.A.; Skaerven, K.; Vasconcelos, V.M. Antimicrobial and cytotoxic assessment of marine cyanobacteriaSynechocystis and Synechococcus. Mar. Drugs 2008, 6, 111
Yonezawa, T.; Mase, N.; Sasaki, H.; Teruya, T.; Hasegawa, S.; Cha, B.Y.; Yagasaki, K.; Suenaga, K.; Nagai, K.; Woo, J.T. Biselyngbyaside, isolated from marine cyanobacteria, inhibits osteoclastogenesis and induces apoptosis in mature osteoclasts. J. Cell Biochem. 2012, 113, 440448.
Oftedal, L.; Selheim, F.; Wahlsten, M.; Sivonen, K.; Doskeland, S.O.; Herfindal, L. Marine benthic cyanobacteria contain apoptosis-inducing activity synergizing with daunorubicin to kill leukemia cells, but not cardiomyocytes. Mar. Drugs 2010, 8, 26592672.
Drew, L.; Fine, R.L.; Do, T.N.; Douglas, G.P.; Petrylak, D.P. The novel antimicrotubule agent cryptophycin 52 (LY355703) induces apoptosis via multiple pathways in human prostate cancer cells. Clin. Cancer Res. 2002, 8, 39223932.
Chen, X.X.; Smith, G.D.; Waring, P. Human cancer cell (Jurkat) killing by the cyanobacterial metabolite calothrixin A. J. Appl. Phycol. 2003, 15, 269277.
Marquez, B.L.; Watts, K.S.; Yokochi, A.; Roberts, M.A.; Verdier- Pinard, P.; Jimenez, J.I.;Hamel, E.; Scheuer, P.J.; Gerwick, W.H. Structure and absolute stereochemistry of hectochlorin,a potent stimulator of actin assembly. J. Nat. Prod. 2002, 65, 866871.
Luesch, H.; Moore, R.E.; Paul, V.J.; Mooberry, S.L.; Corbett, T.H. Isolation of dolastatin10 from the marine cyanobacterium Symploca species VP642 and total stereochemistry and biological evaluation of its analogue symplostatin 1. J. Nat. Prod. 2001, 64, 907910.
Sato, S.; Murata, A.; Orihara, T.; Shirakawa, T.; Suenaga, K.; Kigoshi, H.; Uesugi, M. Marine natural product aurilide activates the OPA1- mediated apoptosis by binding to prohibitin. Chem.Biol. 2011, 18, 131139.
Mooberry, S.L.; Leal, R.M.; Tinley, T.L.; Luesch, H.; Moore, R.E.; Corbett, T.H. The molecular pharmacology of symplostatin 1: A new antimitotic dolastatin 10 analog. Int. J. Cancer 2003,104, 512521.
Mooberry, S.L.; Busquets, L.; Tien, G. Induction of apoptosis by cryptophycin 1, a new antimicrotubule agent. Int. J. Cancer 1997, 73, 440448.
Kalemkerian, G.P.; Ou, X.L.; Adil, M.R.; Rosati, R.; Khoulani, M.M.; Madan, S.K.; Pettit, G.R.Activity of dolastatin 10 against small-cell lung cancer in vitro and in vivo: Induction of apoptosis and bcl-2 modification. Cancer Chemother. Pharm. 1999, 43, 507515.
Davidson, B. (1995). New dimensions in natural products research: cultured marine microorganisms. Current Opinion in Biotechnology, 6(3), 284291. doi:10.1016/0958-1669(95)80049-2
Hirata Y, Uemura D: Halichondrins-antitumor polyether macrolides from a marine sponge. Pure Appl Chem 1986,58:701-710.
Demain, A. L., & Vaishnav, P. (2010). Natural products for cancer chemotherapy. Microbial Biotechnology, 4(6), 687
Zhen, Y.-S., and Li, D.-D. (2009) Antitumor antibiotic pingyangmycin: research and clinical use for 40 years. Chin JAntibiot 34: 577580.
Tao, M., Wang, L., Wendt-Pienkowski, E., Zhang, N., Yang,D., Galm, U., et al. (2010) Functional characterization of tlmH in Streptoalloteichus hindustanus E465-94 ATCC 31158 unveiling new insight into tallysomycin biosynthesis and affording a novel bleomycin analog. Mol Biosyst 6: 349356.
Pickens, L.B., Kim, W., Wang, P., Zhou, H., Watanabe, K., Gomi, S., and Tay, Y. (2009) Biochemical analysis of the biosynthetic pathway of an anticancer tetracycline SF2575. J Am Chem Soc 131: 17677 17689.
Kraka, E., and Cremer, D. (2000) Computer design of anticancer drugs. A new enediyne warhead. J Am Chem Soc 122: 82458264.
Kraka, E., Tuttle, T., and Cremer, D. (2008) Design of a new warhead for the natural enediyne dynemicin A. An increase of biological activity. J Phys Chem B 112: 26612670
M. D. Lee; G. A. Ellestad; D. B. Borders, Acc. Chem. Res. 1991, 24, 235243 D. Lindley, Nature 1987, 329, 752.
Gerth, K., Bedorf, N., Hoefle, G., Irschik, H., and Reichenbach, H. (1996) Epothilones A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (myxobacteria); production, physico-chemical and biological properties. J Antibiot 49: 560563.
Gerth, K., Steinmetz, H., Hofle, G., and Reichenbach, H. (2000) Studies on biosynthesis of epothilones: the biosynthetic origin of the carbon skeleton. J Antibiot 53: 13731377.
Chou, T.C., Zhang, X.G., Harris, C.R., Kduk, S.D., Balog, A.,Savin, K.A., et al. (1998) Desoxyepothilone B is curative against human tumor xenografts that are refractive to paclitaxel. Proc Natl Acad Sci USA 95: 96429647.
Corey, E.J., Guzman-Perez, A., and Noe, M.C. (1994) Short enantioselective synthesis of (-)-ovalicin, a potent inhibitor of angiogenesis, using substrate-enhanced catalytic asymmetricdihydroxylation. J Am Chem Soc 116: 1210912110
Ingber, D., Fujita, T., Kishimoto, S., Sudo, K., Kanamaru, T., Brem, H., and Folkman, J. (1990) Synthetic analogues of fumagillin that inhibit angiogenesis and suppress tumour growth. Nature 348: 555 557.
Barretto, D. A., & Vootla, S. K. (2018). In Vitro Anticancer Activity of Staphyloxanthin Pigment Extracted from Staphylococcus gallinarum KX912244, a Gut Microbe of Bombyx mori. Indian Journal of Microbiology, 58(2), 146158. doi:10.1007/s12088-018-0718-0
Venil CK, Zakaria ZA, Ahmad WA (2013) Bacterial pigments and their applications. Process Biochem 48:10651079. https:// doi.org/10.1016/j.procbio.2013.06.006
Gerlier D, Thomasset N (1986) Use of MTT colorimetric assay to measure cell activation. J Immunol Methods 94:5763. https:// doi.org/10.1016/0022-1759(86)90215-2
Clauditz A, Resch A, Wieland KP, Peschel A, Goltz F (2006) Staphyloxanthin plays a role in the fitness of Staphylococcus aureus and its ability to cope with oxidative stress. Infect Immun 74:4950 4953. https://doi.org/10.1128/IAI.00204-06
Zaini RG, Brandt K, Clench MR, Le Maitre CL (2012) Effects of bioactive compounds from carrots (Daucus carota L.), polyacetylenes, beta-carotene and lutein on human lymphoid leukaemia cells. Anti- Cancer Agents Med Chem 12:640652. https://doi.org/10.2174/187152012800617704
El-Agamey A, Lowe GM, McGarvey DJ, Mortensen A, Phillip DM, Truscott TG, Young AJ (2004) Carotenoid radical chemistry and antioxidant/pro-oxidant properties. Arch Biochem Biophys 430:3748. https://doi.org/10.1016/j.abb.2004.03.007
Kim SH, Kim MS, Lee BY, Lee PC (2016) Generation of structurally novel short carotenoids and study of their biological activity. Sci Rep 6:17. https://doi.org/10.1038/srep21987
Liu GY, Essex A, Buchanan JT, Datta V, Hoffman HM, Bastian JF, Fierer J, Nize V (2005) Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J Exp Med 202:209215. https://doi.org/ 10.1084/jem.20050846
Montaner B, Navarro S, PiqueÂ´ M, Vilaseca M, Martinell M, Giralt E, Gil J, PeÂ´rez-TomaÂ´s R (2000) Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines. Br J Pharmacol 3:585593. https://doi.org/10.1038/sj.bjp.0703614
Pandey R, Chander R, Sainis KB (2007) Prodigiosins: a novel family of immunosuppressants with anti-cancer activity. Indian J Biochem Biophys 44:295302
Venil CK, Lakshmanaperumalsamy P (2009) An insightful overview on microbial pigment, prodigiosin. Elect J Biol 5:4961
Deorukhkar, A. A., Chander, R., Ghosh, S. B., & Sainis, K. B. (2007). Identification of a red-pigmented bacterium producing a potent anti-tumor N-alkylated prodigiosin as Serratia marcescens. Research in Microbiology, 158(5), 399404. doi:10.1016/j.resmic.2007.02.010 \
D.L. Boger, M. Patel, Total synthesis of prodigiosin, prodigiosene and desmethoxyprodigiosin: Diels-Alder reactions of heterocyclic azadienes and development of an effective palladium (II)-promoted 2,20 -bipyrrole coupling procedure, J. Org. Chem. 53 (1988) 1405e1415.
C. Campas, M. Dalmau, B. Montaner, M. Barragan, B. Bellosillo, D. Colomer, G. Pons, R. Perez-Tomas, J. Gil, Prodigiosin induces apoptosis of B and T cells from B-cell chronic lymphocytic leukemia, Leukemia 17 (2003) 746e750.
R. DAlessio, A. Rossi, Short synthesis of undecylprodigiosin. A new route to 2.20 -bipyrrolyl-pyrromethene systems, Synlett 6 (1996) 513e514.
C. Diaz-Ruiz, B. Montaner, R. Perez-Tomas, Prodigiosin induces cell death and morphological changes indicative of apoptosis in gastric cancer cell line HGT-1, Histol. Histopathol. 16 (2001) 415e421.
K. Kawauchi, K. Shibutani, H. Yagisawa, H. Kaimata, H. Nakatsuji, H. Anzai, Y. Yokoyama, Y. Ikegami, Y. Moriyama, H. Hirata, A possible immunosuppressant, cycloprodigiosin hydrochloride, obtained from Pseudoalteromonas denitrificans, Biochem. Biophys. Res. Commun. 237 (1997) 543e547.
B. Montaner, S. Navarro, M. Pique, M. Vilaseca, M. Martinell, E. Giralt, J. Gil, R. Perez-Tomas, Prodigiosin from the supernatant of Serratia marcescens induces apoptosis in haematopoietic cancer cell lines, Br. J. Pharmacol. 131 (2000) 585e593.
B. Montaner, R. Perez-Tomas, Prodigiosin induced apoptosis in human colon cancer cell lines, Life Sci. 68 (2001) 2025e2036.
D. Yamamoto, Y. Kiyozuka, Y. Uemura, C. Yamamoto, H. Takemoto,
H. Hirata, K. Tanaka, K. Hioki, A. Tsubura, Cycloprodigiosin hydrochloride, a HÃ¾/Cl symporter, induces apoptosis in human breast cancer cell lines, J. Cancer Res. Clin. Oncol. 126 (2000) 191e197.
D. Yamamoto, Y. Uemura, K. Tanaka, K. Nakai, C. Yamamoto, H. Takemoto, K. Kamata, H. Hirata, K. Hioki, Cycloprodigiosin hydrochloride HÃ¾/Cl symporter induces apoptosis and differentiation in HL-60 cells, Int. J. Cancer 88 (2000) 121e128.
D. Austin, M.O. Moss, Numerical taxonomy of red-pigmented bacteria isolated from a lowland river, with the description of a new taxon, Rugamonas rubra gen. nov., sp. nov, J. Gen. Microbiol. 132 (1986) 1899e1909.
Pawelek, J. M., Sodi, S., Chakraborty, A. K., Platt, J. T., Miller, S., Holden, D. W., Low, K. B. (2002). Salmonella pathogenicity island- 2 and anticancer activity in mice. Cancer Gene Therapy, 9(10), 813 818. doi:10.1038/sj.cgt.7700501
Lucas RL, Lee CA. Unravelling the mysteries of virulence gene regulation in Salmonella typhimurium. Mol Microbiol. 2000;36:1024 1033.
Al-Ramadi, B. K., Fernandez-Cabezudo, M. J., El-Hasasna, H., Al- Salam, S., Bashir, G., & Chouaib, S. (2009). Potent anti-tumor activity of systemically-administered IL2-expressing Salmonella correlates with decreased angiogenesis and enhanced tumor apoptosis. Clinical Immunology, 130(1), 8997. doi:10.1016/j.clim.2008.08.021
L.H. Dang, C. Bettegowda, D.L. Huso, K.W. Kinzler, B. Vogelstein, Combination bacteriolytic therapy for the treatment of experimental tumors, Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 1515515160.
R.K. Jain, N.S. Forbes, Can engineered bacteria help control cancer? Proc. Natl. Acad. Sci. U. S. A. 98 (2001) 1474814750.
A. Thomas-Tikhonenko, C.A. Hunter, Infection and Cancer: the common vein, Cytokine Growth Factor Rev. 14 (2003) 6777.
J.M. Pawelek, K.B. Low, D. Bermudes, Tumor-targeted Salmonella as a novel anticancer vector, Cancer Res. 57 (1997) 45374544.
S.A. Rosenberg, P.J. Spiess, D.E. Kleiner, Antitumor effects in mice of the intravenous injection of attenuated Salmonella typhimurium, J. Immunother. 25 (2002) 218225.
D.A. Saltzman, E. Katsanis, C.P. Heise, D.E. Hasz, V. Vigdorovich,
S.M. Kelly, R.r. Curtiss, A.S. Leonard, P.M. Anderson, Antitumor mechanisms of attenuated Salmonella typhimurium containing the gene for human interleukin-2: a novel antitumor agent? J. Pediatr. Surg. 32 (1997) 301306.
M. Loeffler, G. Le'Negrate, M. Krajewska, J.C. Reed, Attenuated Salmonella engineered to produce human cytokine LIGHT inhibit tumor growth, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 12879 12883.
C.H. Lee, C.L. Wu, A.L. Shiau, Systemic administration of attenuated Salmonella choleraesuis carrying thrombospondin1 gene leads to tumor-specific transgene expression, delayed tumor growth and prolonged survival in the murine melanoma model, Cancer Gene Ther. 12 (2005) 17518
E.B. Rankin, D. Yu, J. Jiang, H. Shen, E.J. Pearce, M.H. Goldschmidt,
D.E. Levy, T.V. Golovkina, C.A. Hunter, A. Thomas-Tikhonenko, An essential role of Tp responses and interferon gamma in infection- mediated suppression of neoplastic growth, Cancer Biol. Ther. 2 (2003) 687693
Sithranga Boopathy, N.; Kathiresan, K. Anticancer drugs from marine flora: An overview. J. Oncol. 2010, 2010, 18.
Malaker, A.; Ahmad, S.A.I. Therapeutic potency of anticancer peptides derived from marine organism. Int. J.Eng. 2013, 2, 23058269.
Carte, B.K. Biomedical potential of marine natural products. Bioscience 1996, 46, 271286.
Goldin, B.; Gorbach, S.L. Alterations in fecal microflora enzymes related to diet, age, lactobacillus supplements, and dimethylhydrazine.
Cancer 1977, 40, 24212426
Mitall, B.K.; Garg, S.K. Anticarcinogenic, hypocholesterolemic, and antagonistic activities of Lactobacillus acidophilus. Crit. Rev.
Microbiol. 1995, 21, 175214
Wollowski, I.; Rechkemmer, G.; Pool-Zobel, B.L. Protective role of probiotics and prebiotics in colon cancer. Am. J. Clin. Nutr. 2001, 73, 451s455s.
Bitzer, J.; GroÃŸe, T.; Wang, L.; Lang, S.; Beil, W.; Zeeck, A. New aminophenoxazinones from a marine sp.: Fermentation, structure elucidation, and biological activity. J. Antibiot. (Tokyo) 2006, 59, 86.
Sagar, S.; Esau, L.; Holtermann, K.; Hikmawan, T.; Zhang, G.; Stingl, U.; Bajic, V.B.; Kaur, M. Induction of apoptosis in cancer cell lines by the Red Sea brine pool bacterial extracts. BMC Complement. Altern. Med. 2013, 13, 344.
Ruiz-Ruiz, C.; Srivastava, G.K.; Carranza, D.; Mata, J.A.; Llamas, I.; SantamarÃa, M.; Quesada, E.; Molina, I.J.
Erba, E.; Bergamaschi, D.; Ronzoni, S.; Faretta, M.; Taverna, S.; Bonfanti, M.; Catapano, C. V; Faircloth, G.;Y.Br induces apoptosis in human T leukaemia cells. Appl. Microbiol. Biotechnol. 2011, 89, 345 355
Heald, S.C.; BrandÃ£o, P.F.B.; Hardicre, R.; Bull, A.T. Physiology, biochemistry and taxonomy of deep-sea nitrile metabolising Rhodococcus strains. Antonie Van Leeuwenhoek 2001, 80, 169183
Moran, M.A.; Rutherford, L.T.; Hodson, R.E. Evidence for indigenous Streptomyces populations in a marine environment determined with a 16S rRNA probe. Appl. Environ. Microbiol. 1995, 61, 36953700
Jensen, P.R.; Mincer, T.J.; Williams, P.G.; Fenical, W. Marine actinomycete diversity and natural product discovery. Antonie Van Leeuwenhoek 2005, 87, 4348
Maldonado, L.A.; Fenical, W.; Jensen, P.R.; Kauffman, C.A.; Mincer, T.J.; Ward, A.C.; Bull, A.T.; Goodfellow, M. Salinispora arenicola gen. nov., sp. nov. and Salinispora tropica sp. nov., marine actinomycetes belonging to the family Micromonosporaceae. Int. J. Syst. Evol.
Mincer, T.J.; Fenical, W.; Jensen, P.R. Culture-dependent and culture- independent diversity within the oobligate marine actinomycete genus Salinispora. Appl. Environ. Microbiol. 2005, 71, 70197028
Cho, J.Y.; Williams, P.G.; Kwon, H.C.; Jensen, P.R.; Fenical, W. Lucentamycins AD, cytotoxic peptides from the marine-derived actinomycete Nocardiopsis lucentensis. J. Nat. Prod. 2007, 70, 1321 1328
Erba, E.; Bergamaschi, D.; Ronzoni, S.; Faretta, M.; Taverna, S.; Bonfanti, M.; Catapano, C. V; Faircloth, G.; Jimeno, J.; Dincalci, M. Mode of action of thiocoraline, a natural marine compound with anti- tumor activity. Br. J. Cancer 1999, 80, 971.
Maskey, R.P.; Helmke, E.; Kayser, O.; Fiebig, H.H.; Maier, A.; Busche, A.; Laatsch, H. Anti-cancer and antibacterial trioxacarcins with high anti-malaria activity from a marine streptomycete and their absolute stereochemistry. J. Antibiot. (Tokyo) 2004, 57, 771779.
Calisto, R., SÃ¦bÃ¸, E. F., Storesund, J. E., Ã˜vreÃ¥s, L., Herfindal, L., & Lage, O. M. (2019). Anticancer Activity in Planctomycetes. Frontiers in Marine Science, 5. doi:10.3389/fmars.2018.00499
Singh, S. B., Genilloud, O., & PelÃ¡ez, F. (2010). Terrestrial Microorganisms Filamentous Bacteria. Comprehensive Natural Products II, 109140. doi:10.1016/b978-008045382-8.00036-8
Wang, L.; Groe, T.; Stevens, H.; Brinkhoff, T.; Simon, M.; Liang, L.; Bitzer, J.; Bach, G.; Zeeck, A.; Tokuda, H. Bioactive hydroxyphenylpyrrole-dicarboxylic acids from a new marine Halomonas sp.: Production and structure elucidation. Appl. Microbiol. Biotechnol. 2006, 72, 816822.
A.B. Alexanderoff, A.M. Jackson, M.A. O'Donnell, K. James, BCG immunotherapy of bladder cancer: 20 years on, Lancet 353 (1999) 16891694.  J.M. Pawelek, K.B. Low, D. Bermudes, Bacteria as tumortargeting vectors, Lancet Oncol. 4 (2003) 548556.