Advertisement

Applied Microbiology and Biotechnology

, Volume 97, Issue 12, pp 5189–5199 | Cite as

Engineering of bacterial strains and their products for cancer therapy

  • Nuno Bernardes
  • Ananda M. Chakrabarty
  • Arsenio M. Fialho
Mini-Review

Abstract

The use of live bacteria in cancer therapies offers exciting possibilities. Nowadays, an increasing number of genetically engineered bacteria are emerging in the field, with applications both in therapy and diagnosis. In parallel, purified bacterial products are also gaining relevance as new classes of bioactive products to treat and prevent cancer growth and metastasis. In the first part of the article, we review the latest findings regarding the use of live bacteria and products as anti-cancer agents, paying special attention to immunotoxins, proteins, and peptides. In particular, we focus on the recent results of using azurin or its derived peptide as anticancer therapeutic agents. In the second part, we discuss the challenges of using metagenomic techniques as a distinctive approach for discovering new anti-cancer agents from bacterial origin.

Keywords

Cancer Bacteria Immunotherapy Azurin Metagenomics 

Notes

Acknowledgments

N.B. acknowledges a Ph.D. grant (SFRH/BD/48763/2008) from Fundação para a Ciência e a Tecnologia (FCT). Research in the A. M. Fialho lab was supported by FCT (Grant PTDC/EBB/BIO/100326/2008).

Conflict of interest

The authors declare no conflict of interest.

References

  1. Avner BS, Fialho AM, Chakrabarty AM (2012) Overcoming drug resistance in multi-drug resistant cancers and microorganisms: a conceptual framework. Bioengineered 3(5):262–270. doi: 10.4161/bioe.21130 CrossRefGoogle Scholar
  2. Baban CK, Cronin M, O’Hanlon D, O’Sullivan GC, Tangney M (2010) Bacteria as vectors for gene therapy of cancer. Bioengineered 1:385–394. doi: 10.4161/bbug.1.6.13146 CrossRefGoogle Scholar
  3. Bellmunt J, Orsola A, Maldonado X, Kataja V (2010) Bladder cancer: ESMO practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 21(suppl 5):v134–v136. doi: 10.1093/annonc/mdq175 CrossRefGoogle Scholar
  4. Benoit MR, Mayer D, Barak Y, Chen IY, Hu W, Cheng Z, Wang SX, Spielman DM, Gambhir SS, Matin A (2009) Visualizing implanted tumors in mice with magnetic resonance imaging using magnetotactic bacteria visualizing implanted tumors in mice with magnetic resonance imaging using magnetotactic bacteria. Clin Cancer Res 15:5170–5177. doi: 10.1158/1078-0432.CCR-08-3206 CrossRefGoogle Scholar
  5. Bernardes N, Seruca R, Chakrabarty AM, Fialho AM (2010) Microbial-based therapy of cancer: current progress and future prospects. Bioengineered 1:178–190. doi: 10.4161/bbug.1.3.10903 CrossRefGoogle Scholar
  6. Bizarri AR, Santini S, Coppari E, Bucciantini M, D Agostino S, Yamada T, Beattie CW, Cannistraro S (2011) Interaction of an anticancer peptide fragment of azurin with p53 ad its isolated domains studied by atomic force spectroscopy. Int J Nanomed 6:3011–3019. doi: 10.2147/IJN.S26155 Google Scholar
  7. Bolhassani A, Zahedifard F (2012) Therapeutic live vaccines as a potential anticancer strategy. Int J Cancer 131(8):1733–1743. doi: 10.1002/ijc.27640 CrossRefGoogle Scholar
  8. Brader P, Stritzker J, Riedl CC, Zanzonico P, Cai S, Burnazi EM, Ghani ER, Hricak H, Szalay AA, Fong Y, Blasberg R (2008) Escherichia coli Nissle 1917 facilitates tumor detection by positron emission tomography and optical imaging. Clin Cancer Res 14:2295–2302. doi: 10.1158/1078-0432.CCR-07-4254 CrossRefGoogle Scholar
  9. Burke PJ, Theys J, Pennington O, Dubois L, Anlezark G, Vaughan T, Mengesha A, Landuyt W, Anne J (2006) Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo. Brit J Cancer 95(9):1212–1219. doi: 10.1038/sj.bjc.6603367 Google Scholar
  10. Chakrabarty AM (2003) Microorganisms and cancer: quest for a therapy. J Bacteriol 185:2683–2686. doi: 10.1128/JB.185.9.2683 CrossRefGoogle Scholar
  11. Chaudhari A, Mahfouz M, Fialho AM, Yamada T, Granja AT, Zhu Y, Hashimoto W, Schlarb-Ridley B, Cho W, Das Gupta TK, Chakrabarty AM (2007) Cupredoxin–cancer interrelationship: azurin binding with EphB2, interference in EphB2 tyrosine phosphorylation, and inhibition of cancer growth. Biochemistry 46:1799–1810. doi: 10.1021/bi061661x CrossRefGoogle Scholar
  12. Cheong I, Huang X, Thornton K, Diaz LA, Zhou S (2007) Targeting cancer with bugs and liposomes: ready, aim, fire. Cancer Res 67:9605–9608. doi: 10.1158/0008-5472.CAN-07-1565 CrossRefGoogle Scholar
  13. Choi J, Lee M, Cho Y, Park B, Kim S, Kim G (2011) The bacterial protein azurin enhances sensitivity of oral squamous carcinoma cells to anticancer drugs. 52:773–778Google Scholar
  14. Choudhary S, Mathew M, Verma RS (2011) Therapeutic potential of anticancer immunotoxins. Drug Discov Today 16:495–503. doi: 10.1016/j.drudis.2011.04.003 CrossRefGoogle Scholar
  15. Critchley-thorne RJ, Stagg AJ, Vassaux G (2006) Recombinant Escherichia coli expressing invasin targets the Peyer’s patches: the basis for a bacterial formulation for oral vaccination. Mol Ther 14:183–191. doi: 10.1016/j.ymthe.2006.01.011 CrossRefGoogle Scholar
  16. Cronin M, Akin AR, Collins S a, Meganck J, Kim J-B, Baban CK, Joyce S a, Van Dam GM, Zhang N, Van Sinderen D, O’Sullivan GC, Kasahara N, Gahan CG, Francis KP, Tangney M (2012) High resolution in vivo bioluminescent imaging for the study of bacterial tumour targeting. PloS One 7:e30940. doi: 10.1371/journal.pone.0030940
  17. Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B (2001) Combination bacteriolytic therapy for the treatment of experimental tumors. PNAS 98:15155–15160CrossRefGoogle Scholar
  18. De Grandis V, Bizzarri AR, Cannistraro S (2007) Docking study and free energy simulation of the complex between p53 DNA-binding domain and azurin. J Mol Recognit 20:215–226. doi: 10.1002/jmr CrossRefGoogle Scholar
  19. Fialho AM, Bernardes N, Chakrabarty AM (2012a) Recent patents on live bacteria and their products as potential anticancer agents. Recent Patents on Anti-Cancer Drug Discovery 7:31–55. doi: 10.2174/157489212798357949 CrossRefGoogle Scholar
  20. Fialho AM, Chakrabarty AM (2010) Emerging cancer therapy: microbial approaches and biotechnological tools, 1st edn. Wiley, SingaporeCrossRefGoogle Scholar
  21. Fialho AM, Salunkhe P, Manna S, Mahali S, Chakrabarty AM (2012b) Glioblastoma multiforme: novel therapeutic approaches. ISRN Neurol 2012:642345. doi: 10.5402/2012/642345
  22. Forbes NS (2010) Engineering the perfect (bacterial) cancer therapy. Nat Rev Cancer 10:785–794. doi: 10.1038/nrc2934 CrossRefGoogle Scholar
  23. Fu G, Yin Y, Hu B, Xu G (2010) Bifidobacterium as a delivery system of functional genes for cancer gene therapy. In: Fialho AM, Chakrabarty AM (eds) Emerging cancer therapy: microbial approaches and biotechnological tools, 1st edn. Wiley, Singapore, pp 99–118CrossRefGoogle Scholar
  24. Fu W, Chu L, Han X, Liu XRD (2008) Synergistic antitumoral effects of human telomerase reverse transcriptase-mediated dual-apoptosis-related gene vector delivered by orally attenuated Salmonella enterica serovar Typhimurium in murine tumor models. J Gene Med 10:690–701. doi: 10.1002/jgm CrossRefGoogle Scholar
  25. Hoffman RM (2010) Salmonella typhimurium mutants selected to grow only in tumors and eradicate them in nude mouse models. In: Fialho AM, Chakrabarty AM (eds) Emerging cancer therapy: microbial approaches and biotechnological tools, 1st edn. Wiley, Singapore, pp 1–17CrossRefGoogle Scholar
  26. Huang A, Quinn H, Glover C, Henderson DC, Allen-mersh TG (2002) The presence of interleukin-2 receptor alpha in the serum of colorectal cancer patients is unlikely to result only from T cell up-regulation. Cancer Immunol Immun 51:53–57. doi: 10.1007/s00262-001-0250-6 CrossRefGoogle Scholar
  27. Jia L, Gorman GS, Coward LU, Noker PE, Mccormick D, Horn TL, Harder JB, Muzzio M (2011) Preclinical pharmacokinetics, metabolism, and toxicity of azurin-p28 (NSC745104) a peptide inhibitor of p53 ubiquitination. Cancer Chemoth Pharm 28:513–524. doi: 10.1007/s00280-010-1518-3 CrossRefGoogle Scholar
  28. Kanno S, Maeda N, Tomizawa A, Yomogida S, Katoh T, Ishikawa M (2012) The potent histone deacetylase inhibitor spiruchostatin B towards susceptible NALM-6 human B cell leukemia cells. Int J Oncol 40:1391–1396. doi: 10.3892/ijo.2011.1323 Google Scholar
  29. Keyhanian K, Mansoori GA, Rahimpour M (2010) Prospects for cancer nanotechnology treatment by azurin. Dynamic Biochemistry, Process Biotechnology and Molecular Biology 4:48–66Google Scholar
  30. Kresowik TP, Griffith TS (2010) Bacillus Calmete–Guerin (BCG) for urothelial carcinoma of the bladder. In: Fialho AM, Chakrabarty AM (eds) Emerging cancer therapy: microbial approaches and biotechnological tools, 1st edn. Wiley, Singapore, pp 319–335Google Scholar
  31. Lee C, Wu C, Shiau A (2005a) Systemic administration of attenuated Salmonella choleraesuis survival in the murine melanoma model. Cancer Gene Ther 12:175–184. doi: 10.1038/sj.cgt.7700777 CrossRefGoogle Scholar
  32. Lee DG, Hahm K, Park Y, Kim H, Lee W, Lim S, Seo Y, Choi C (2005) Functional and structural characteristics of anticancer peptide Pep27 analogues. Cancer Cell Int 14:1–14. doi: 10.1186/1475-2867-5-21 Google Scholar
  33. Liu SC, Minton NP, Giaccia AJ, Brown JM (2002) Anticancer efficacy of systemically delivered anaerobic bacteria as gene therapy vectors targeting tumor hypoxia/necrosis. Gene Ther 9:291–296CrossRefGoogle Scholar
  34. Lorberboum-Galski H (2011) Human toxin-based recombinant immunotoxins/chimeric proteins as a drug delivery system for targeted treatment of human diseases. Expert Opin Drug Deliv 8:605–621. doi: 10.1517/17425247.2011.566269 CrossRefGoogle Scholar
  35. MacDiarmid JA, Brahmbhatt H (2011) Minicells: versatile vectors for targeted drug or si/shRNA cancer therapy. Curr Opin Biotech 22:909–916. doi: 10.1016/j.copbio.2011.04.008 CrossRefGoogle Scholar
  36. Mehta RR, Yamada T, Taylor BN, Christov K, King ML, Majumdar D, Lekmine F, Tiruppathi C, Shilkaitis A, Bratescu L, Gree A, Beattie CW, Das Gupta TK (2011) A cell penetrating peptide derived from azurin inhibits angiogenesis and tumor growth by inhibiting phosphorylation of VEGFR‐2, FAK and Akt. Angiogenesis 14:355–369. doi: 10.1007/s10456‐011‐9229‐6 Google Scholar
  37. Mellaert L, Wei M, Anné J (2010) Live Clostridia: a powerful tool in tumor biotherapy. In: Fialho AM, Chakrabarty AM (eds) Emerging cancer therapy: microbial approaches and biotechnological tools, 1st edn. Wiley, Singapore, pp 71–98CrossRefGoogle Scholar
  38. Micewicz EDJ, C-L SD, Luong H, McBride WH, Ruchala P (2011) Small azurin derived peptide targets ephrin receptors for radiotherapy. Int J Pept Res Ther 17:247–257. doi: 10.1007/s10989-011-9265-9 CrossRefGoogle Scholar
  39. Morrissey D, O’Sullivan GC, Tangney M (2010) Tumour targeting with systemically administered bacteria. Curr Gene Ther 10:3–14CrossRefGoogle Scholar
  40. Nemunaitis J, Cunningham C, Senzer N, Kuhn J, Litz C, Cavagnolo R, Cahill A, Clairmont C, Sznol M (2003) Expressing the Escherichia coli cytosine deaminase gene in refractory cancer patients. Cancer Gene Ther 10:737–744. doi: 10.1038/sj.cgt.7700634 CrossRefGoogle Scholar
  41. Pastan I, Hassan R, FitzGerald DJ, Kreitman RJ (2007) Immunotoxin treatment of cancer. Annu Rev Med 58:221–237. doi: 10.1146/annurev.med.58.070605.115320 CrossRefGoogle Scholar
  42. Patyar S, Joshi R, Byrav DSP, Prakash A, Medhi B, Das BK (2010) Bacteria in cancer therapy: a novel experimental strategy. J Biomed Sci 17:21. doi: 10.1186/1423-0127-17-21 CrossRefGoogle Scholar
  43. Punj V, Bhattacharyya S, Saint-dic D, Vasu C, Cunningham EA, Graves J (2004) Bacterial cupredoxin azurin as an inducer of apoptosis and regression in human breast cancer. Oncogene 23:2367–2378CrossRefGoogle Scholar
  44. Punj V, Gupta TK, Das CAM (2003) Bacterial cupredoxin azurin and its interactions with the tumor suppressor protein p53. Biochem Biophys Res Comm 312:109–114. doi: 10.1016/j.bbrc.2003.09.217 CrossRefGoogle Scholar
  45. Rath CM, Janto B, Earl J, Ahmed A, Hu FZ, Hiller L, Dahlgren M, Kreft R, Yu F, Wolff JJ, Kweon HK, Christiansen MA, Kristina H, Williams RM, Ehrlich GD, Sherman DH (2011) Meta-omic characterization of the marine invertebrate microbial consortium that produces the chemotherapeutic natural product ET-743. ACS Chem Biol 743:1244–1256. doi: 10.1021/cb200244t CrossRefGoogle Scholar
  46. Rothman J, Wallecha A, Maciag P, Rivera S, Sahabi V, Paterson Y (2010) The use of Listeria monocytogenes as an active immunotherapy for the treatment of cancer. In: Fialho AM, Chakrabarty AM (eds) Emerging cancer therapy: microbial approaches and biotechnological tools, 1st edn. Wiley, Singapore, pp 13–48CrossRefGoogle Scholar
  47. Santini S, Bizzarri AR, Salvatore C (2011) Modelling the interaction between the p53 DNA-binding domain and the p28 peptide fragment of azurin. J Mol Recognit 24:1043–1055. doi: 10.1002/jmr.1153 CrossRefGoogle Scholar
  48. Schloissnig S, Arumugam M, Sunagawa S, Mitreva M, Tap J, Zhu A (2013) Genomic variation landscape of the human gut microbiome. Nature 493:45–50. doi: 10.1038/nature11711 CrossRefGoogle Scholar
  49. Soghomonyan SA, Doubrovin M, Pike J, Luo X, Ittensohn M, Runyan JD, Balatoni J, Finn R, Tjuvajev JG, Blasberg R, Bermudes D (2005) Positron emission tomography (PET) imaging of tumor-localized Salmonella expressing HSV1-TK. Cancer Gene Ther 12:101–108. doi: 10.1038/sj.cgt.7700779 CrossRefGoogle Scholar
  50. Tangney M, Van Pijkeren JP, Gahan CGM (2010) The use of Listeria monocytogenes as a DNA delivery vector for cancer gene therapy. Bioengineered 1:284–287. doi: 10.4161/bbug.1.4.11725 CrossRefGoogle Scholar
  51. Taranta M, Bizzarri AR, Cannistraro S (2008) Probing the interaction between p53 and the bacterial protein azurin by single molecule force spectroscopy. J Mol Recognit 21:63–70. doi: 10.1002/jmr.869 CrossRefGoogle Scholar
  52. Taranta M, Bizzarri AR, Cannistraro S (2009) Modeling the interaction between the N-terminal domain of the tumor suppressor p53 and azurin. J Mol Recognit 22:215–222. doi: 10.1002/jmr.934 CrossRefGoogle Scholar
  53. Tartour E, Mosseri V, Jouffroy T, Deneux L, Jaulerry C, Brunin F, Fridman WH, Rodriguez J (2001) Serum soluble interleukin-2 receptor concentrations as an independent prognostic marker in head and neck cancer. Res Lett 357:1263–1264Google Scholar
  54. Taylor BN, Mehta RR, Yamada T, Lekmine F, Christov K, Chakrabarty AM, Green A, Bratescu L, Shilkaitis A, Beattie CW, Das Gupta TK (2009) Noncationic peptides obtained from azurin preferentially enter cancer cells. Cancer Res 69:537–546. doi: 10.1158/0008-5472.CAN-08-2932 CrossRefGoogle Scholar
  55. Theys J, Landuyt W, Nuyts S, Van Mellaert L, Van Oosterom A, Lambin P, Anne J (2001) Specific targeting of cytosine deaminase to solid tumors by engineered Clostridium acetobutylicum. Cancer Gene Ther 8:294–297CrossRefGoogle Scholar
  56. Uhua LY, Unyuan GK, Ui CH, Ongmei XY, Haoyang SC, Un TX, Aming RD (2001) Oral cytokine gene therapy against murine tumor using attenuated Salmonella typhimurium. Int J Cancer 443:438–443. doi: 10.1002/ijc.1489 CrossRefGoogle Scholar
  57. Vinodhkumar R, Song Y, Devaki T (2008) Romidepsin (depsipeptide) induced cell cycle arrest, apoptosis and histone hyperacetylation in lung carcinoma cells (A549) are associated with increase in p21 and hypophosphorylated retinoblastoma proteins expression. Biomed Pharmacother 62:85–93. doi: 10.1016/j.biopha.2007.06.002 CrossRefGoogle Scholar
  58. Walenkamp AME, Bestebroer J, Boer IGJ, Kruizinga R (2010) Staphylococcal SSL5 binding to human leukemia cells inhibits cell adhesion to endothelial cells and platelets. Neoplasia 32:1–10. doi: 10.3233/CLO-2009-0486 Google Scholar
  59. Walenkamp AME, Boer IGJ, Bestebroer J, Rozeveld D, Timmer-Bosscha H, Hemrika W, van Strijp JAG, de Haas CJC (2009) Staphylococcal superantigen-like 10 inhibits CXCL12-induced. Neoplasia 11:333–344. doi: 10.1593/neo.81508 Google Scholar
  60. Wang L, Chow K, Li W, Squamous E, Carcinoma C (2000) Clinical significance of serum soluble interleukin 2 receptor-α in esophageal squamous cell carcinoma. Clinical Cancer Res 6:1445–1451Google Scholar
  61. Weldon JE, Pastan I (2011) A guide to taming a toxin-recombinant immunotoxins constructed from Pseudomonas exotoxin A for the treatment of cancer. FEBS J 278:4683–4700. doi: 10.1111/j.1742-4658.2011.08182.x CrossRefGoogle Scholar
  62. Wolf P, Elsässer-Beile U (2010) Pseudomonas Exotoxin A-based immunotoxins for cancer. In: Chakrabarty AM, Fialho AM (eds) Emerging cancer therapy: microbial approaches and biotechnological tools, 1st edn. Wiley, Singapore, pp 269–288CrossRefGoogle Scholar
  63. Wood LM, Vafa ZP, Paterson Y (2010) Listeria-derived ActA is an effective adjuvant for primary and metastatic tumor immunotherapy. Cancer Immunol Immunother 59:1049–1058. doi: 10.1007/s00262-010-0830-4 CrossRefGoogle Scholar
  64. Xu J, Liu XS, Zhou S, Wei MQ (2009) Combination of immunotherapy with anaerobic bacteria for immunogene therapy of solid tumours. Gene Ther Mol Biol 13:36–52Google Scholar
  65. Xu Y, Zhu L, Hu B, Fu G, Zhang H, Wang J, Xu G (2007) A new expression plasmid in Bifidobacterium longum as a delivery system of endostatin for cancer gene therapy. Cancer Gene Ther 14:151–157. doi: 10.1038/sj.cgt.7701003 CrossRefGoogle Scholar
  66. Yamada T, Fialho AM, Punj V, Bratescu L, Gupta TK, Das CAM (2005) Internalization of bacterial redox protein azurin in mammalian cells: entry domain and specificity. Cell Microbiol 7:1418–1431. doi: 10.1111/j.1462-5822.2005.00567.x CrossRefGoogle Scholar
  67. Yamada T, Goto M, Punj V, Zaborina O, Chen ML, Kimbara K, Majumdar D, Cunningham E, Das Gupta TK, Chakrabarty AM (2002) Bacterial redox protein azurin, tumor suppressor protein p53, and regression of cancer. PNAS 99:14098–14103. doi: 10.1073/pnas.222539699 CrossRefGoogle Scholar
  68. Yamada T, Hiraoka Y, Ikehata M, Kimbara K, Avner BS, Gupta TK, Das CAM (2004) Apoptosis or growth arrest: modulation of tumor suppressor p53 specificity by bacterial redox protein azurin. PNAS 101:4770–4775CrossRefGoogle Scholar
  69. Yamada T, Christov K, Das Gupta TK BC (2011) Mechanism of action of p28, a first-in-class, non-HDM2 mediated peptide inhibitor of p53 ubiquitination. J Clin Oncol 29. p suppl; abstr e13513Google Scholar
  70. Yu YA, Zhang Q, Szalay AA (2008) Establishment and characterization of conditions required for tumor colonization by intravenously delivered bacteria. Biotechnol Bioeng 100:567–578. doi: 10.1002/bit.21785 CrossRefGoogle Scholar
  71. Yuk J, Lim K, Kim K, Kim J, Lee J, Paik T, Kim J (2010) Bacillus Calmette–Guerin cell wall cytoskeleton enhances colon cancer radiosensitivity through autophagy. Autophagy 6:46–60CrossRefGoogle Scholar
  72. Zaborina O, Dhiman N, Chen ML, Kostal J, Holder IA, Chakrabarty AM (2000) Secreted products of a nonmucoid Pseudomonas aeruginosa strain induce two modes of macrophage killing: external-ATP-dependent, P2Z-receptor-mediated necrosis apoptosis. Microbiology 146:2521–2530Google Scholar
  73. Zago C, Lefevre F, Robe P, Jarrin C, Auriol D, Vogel TM, Simonet P, Nalin R (2008) Drugs from hidden bugs: their discovery via untapped resources. Res Microbiol 159:153–161. doi: 10.1016/j.resmic.2007.12.011 CrossRefGoogle Scholar
  74. Zhang Y, Zhang Y, Xia L, Zhang X, Ding X, Yan F, Wu F (2012) Escherichia coli Nissle 1917 targets and restrains mouse B16 melanoma and 4 T1 breast tumor through the expression of azurin protein. Appl Environ Microbiol 78:7603–7610. doi: 10.1128/AEM.01390-12 Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Nuno Bernardes
    • 1
  • Ananda M. Chakrabarty
    • 2
  • Arsenio M. Fialho
    • 1
  1. 1.Institute for Biotechnology and Bioengineering (IBB), Center for Biological and Chemical EngineeringInstituto Superior TécnicoLisbonPortugal
  2. 2.Department of Microbiology & ImmunologyUniversity of Illinois College of MedicineChicagoUSA

Personalised recommendations