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The Role of Genetic Engineering in Natural Product-Based Anticancer Drug Discovery

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Natural Products and Cancer Drug Discovery

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Genetic engineering is the process of altering, in a premeditated fashion, the genetic makeup of an organism and has started to play an increasing role in the production and development of clinically significant antitumor compounds. Genes can be introduced into the microbial producer of medicinally relevant secondary metabolites or inactivated to achieve changes in the metabolic profile. The pharmaceutical use of natural products with anticancer activity is most often limited by factors such as low production titers or poor solubility. Genetic engineering has provided an alternative to circumvent such difficulties by affording recombinant strains capable of high titers, as well as, recombinant strains able to produce novel analogs with characteristics superior to those of the parent natural product. This chapter highlights recent genetic engineering advances that have been successfully applied to the development of natural product and natural product-based anticancer agents. Titer improvement and combinatorial biosynthesis in actinomycetes to produce new compounds will be discussed in detail.

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References

  • Adrio JL, Demain AL (2006) Genetic improvement of processes yielding microbial products. FEMS Microbiol Rev 30:187–214

    Article  PubMed  CAS  Google Scholar 

  • Beerman TA, Gawron LS, Shin S, Shen B, McHugh MM (2009) C-1027, a radiomimetic enediyne anticancer drug, preferentially targets hypoxic cells. Cancer Res 69:593–598

    Article  PubMed  CAS  Google Scholar 

  • Berdy J (2005) Bioactive microbial metabolites. J Antibiot 58:1–26

    Article  PubMed  CAS  Google Scholar 

  • Berdy J (2012) Thoughts and facts about antibiotics: where we are now and where we are heading. J Antibiot 65:385–395

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Wendt-Pienkowski E, Shen B (2008a) Identification and utility of FdmR1 as a Streptomyces antibiotic regulatory protein activator for fredericamycin production in Streptomyces griseus ATCC 49344 and heterologous hosts. J Bacteriol 190:5587–5596

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Deng W, Wu J, Qian J, Chu J, Zhuang Y, Zhang S, Liu W (2008b) Genetic modulation of the overexpression of tailoring genes eryK and eryG leading to the improvement of erythromycin A purity and production in Saccharopolyspora erythraea fermentation. Appl Environ Microbiol 74:1820–1828

    Article  PubMed  CAS  Google Scholar 

  • Chen Y, Smanski MJ, Shen B (2010) Improvement of secondary metabolite production in Streptomyces by manipulating pathway regulation. Appl Microbiol Biotechnol 86:19–25

    Article  PubMed  CAS  Google Scholar 

  • Cui Z, Wang L, Wang S, Li G, Hong B (2009) Disruption of cagA, the apoprotein gene of chromoprotein antibiotic C-1027, eliminates holo-antibiotic production, but not the cytotoxic chromophore. FEMS Microbiol Lett 301:57–68

    Article  PubMed  CAS  Google Scholar 

  • Du L, Sanchez C, Chen M, Edwards DJ, Shen B (2000) The biosynthetic gene cluster for the antitumor drug bleomycin from Streptomyces verticillus ATCC15003 supporting functional interactions between nonribosomal peptide synthetases and a polyketide synthase. Chem Biol 7:623–642

    Article  PubMed  CAS  Google Scholar 

  • Eustaquio AS, Moore BS (2008) Mutasynthesis of fluorosalinosporamide, a potent and reversible inhibitor of the proteasome. Angew Chem Int Ed 47:3936–3938

    Article  CAS  Google Scholar 

  • Eustaquio AS, O’Hagan D, Moore BS (2010) Engineering fluorometabolite production: fluorinase expression in Salinispora tropica yields fluorosalinosporamide. J Nat Prod 73:378–382

    Article  PubMed  CAS  Google Scholar 

  • Galm U, Shen B (2006) Expression of biosynthetic gene clusters in heterologous hosts for natural product production and combinatorial biosynthesis. Expert Opin Drug Discov 1:409–437

    Article  CAS  Google Scholar 

  • Goss RJM, Lanceron S, Roy AD, Sprague S, Nur-e-Alam M, Hughes DL, Wilkinson DL, Moss SJ (2010) An expeditious route to fluorinated rapamycin analogues by utilizing mutasynthesis. Chembiochem 11:698–702

    Article  PubMed  CAS  Google Scholar 

  • Gruschow S, Rackham EJ, Elkins B, Newill PLA, Hill LM, Goss RJM (2009) New pacidamycin antibiotics through precursor-directed biosynthesis. Chembiochem 10:355–360

    Article  PubMed  CAS  Google Scholar 

  • Gupta S, Lakshmanan V, Seok KB, Fecik R, Reynolds KA (2008) Generation of novel pikdromycin antibiotic products through mutasynthesis. Chembiochem 9:1609–1616

    Article  PubMed  CAS  Google Scholar 

  • Hesketh A, Ochi K (1997) A novel method for improving Streptomyces coelicolor A3(2) for ­production of actinorhodin by introduction of rpsL (encoding ribosomal protein S12) ­mutations conferring resistance to streptomycin. J Antibiot 50:532–535

    Article  PubMed  CAS  Google Scholar 

  • Huang S-X, Feng Z, Wang L, Galm U, Wendt-Pienkowski E, Yang D, Tao M, Coughlin JM, Duan Y, Shen B (2012) A designer bleomycin with significantly improved DNA cleavage activity. J Am Chem Soc 134:13501–13509

    Article  PubMed  CAS  Google Scholar 

  • Huh JH, Kim DJ, Zhao XQ, Li M, Jo YY, Yoon TM, Shin SK, Yong JH, Ryu YW, Yang YY, Suh JW (2004) Widespread activation of antibiotic biosynthesis by S-adenosylmethionine in streptomycetes. FEMS Microbiol Lett 238:439–447

    Article  PubMed  CAS  Google Scholar 

  • Ju J, Rajski SR, Lim S-K, Seo J-W, Peters NR, Hoffman FM, Shen B (2008) Evaluation of new migrastatin and dorrigocin congeners unveils cell migration inhibitors with dramatically improved potency. Bioorg Med Chem Lett 18:5951–5954

    Article  PubMed  CAS  Google Scholar 

  • Ju J, Rajski SR, Lim S-K, Seo J-W, Peters NR, Hoffmann FM, Shen B (2009) Lactimidomycin, iso-migrastatin and related glutarimide-containing 12-membered macrolides are extremely potent inhibitors of cell migration. J Am Chem Soc 131:1370–1371

    Article  PubMed  CAS  Google Scholar 

  • Keller U, Schauwecker F (2003) Combinatorial biosynthesis of non-ribosomal peptides. Comb Chem High Throughput Screen 6:527–540

    PubMed  CAS  Google Scholar 

  • Kennedy DR, Gawron LS, Ju J, Liu W, Shen B, Beerman TA (2007) Single chemical modifications of the C-1027 enediyne core, a radiomimetic antitumor drug, affect both drug potency and the role of ataxia-telangiectasia mutated in cellular responses to DNA double-strand breaks. Cancer Res 67:773–781

    Article  PubMed  CAS  Google Scholar 

  • Kim BS, Sherman DH, Reynolds KA (2004) An efficient method for creation and functional analysis of libraries of hybrid type I polyketide synthases. Protein Eng Des 17:277–284

    Article  CAS  Google Scholar 

  • Kwon SJ, Kim MI, Ku B, Coulombel L, Kim JH, Shawky JH, Linhardt RJ, Dordick JS (2010) Unnatural polyketide analogues selectively target the HER signaling pathway in human breast cancer cells. Chembiochem 11:573–580

    Article  PubMed  CAS  Google Scholar 

  • Li Y, He W, Wang Y, Wang Y, Shao R (2008) A new post-PKS modification process in the carbamoyltransferase gene inactivation strain of Streptomyces hygroscopicus 17997. J Antibiot 61:347–355

    Article  PubMed  CAS  Google Scholar 

  • Liu W, Christenson SD, Standage S, Shen B (2002) Biosynthesis of the enediyne antitumor antibiotic C-1027. Science 297:1170–1173

    Article  Google Scholar 

  • Lutz H (2009a) Genetic engineering of antibiotic biosynthesis for the generation of new aminocoumarins. Biotechnol Adv 27:1006–1014

    Article  Google Scholar 

  • Lutz H (2009b) Aminocoumarins: mutasynthesis, chemoenzymatic synthesis, and metabolic engineering. Methods Enzymol 459:437–455

    Article  Google Scholar 

  • Madduri K, Kennedy J, Rivola G, Inventi-Solari A, Filippini S, Zanuso G, Colombo AL, Gewain KM, Occi JL, MacNeil DJ, Hutchinson CR (1998) Production of the antitumor drug epirubicin (4′-epidoxorubicin) and its precursor by a genetically engineered strain of Streptomyces peucetius. Nat Biotechnol 16:69–74

    Article  PubMed  CAS  Google Scholar 

  • Maharjan S, Oh TJ, Lee HC, Sohng JK (2009) Identification and functional characterization of an afsR homolog regulatory gene from Streptomyces venezuelae ATCC 15439. J Microbiol Biotechnol 19:121–127

    Article  PubMed  CAS  Google Scholar 

  • Malla S, Niraula NP, Liou K, Sohng JK (2009) Enhancement of doxorubicin production by expression of structural sugar biosynthesis and glycosyltransferase genes in Streptomyces peucetius. J Biosci Bioeng 108:92–98

    Article  PubMed  CAS  Google Scholar 

  • Malla S, Niraula NP, Liou K, Sohng JK (2010a) Improvement in doxorubicin productivity by overexpression of regulatory genes in Streptomyces peucetius. Res Microbiol 161:109–117

    Article  PubMed  CAS  Google Scholar 

  • Malla S, Niraula NP, Liou K, Sohng JK (2010b) Self-resistance mechanism in Streptomyces peucetius: overexpression of drrA, drrB and drrC for doxorubicin enhancement. Microbiol Res 165:259–267

    Article  PubMed  CAS  Google Scholar 

  • Mo S, Kim BS, Reynolds KA (2005) Production of branched-chain alkylprodiginines in S. ­coelicolor by replacement of the 3-ketoacyl ACP synthase III initiation enzyme, RedP. Chem Biol 12:191–200

    Article  PubMed  CAS  Google Scholar 

  • Mo S, Ban YH, Park JW, Yoo YJ, Yoon YJ (2009) Enhanced FK506 production in Streptomyces clavuligerus CKD1119 by engineering the supply of methylmalonyl-CoA precursor. J Ind Microbiol Biotechnol 36(12):1473–1482

    Article  PubMed  CAS  Google Scholar 

  • Mutka SC, Carney JR, Liu Y, Kennedy J (2006) Heterologous production of epothilone C and D in Escherichia coli. Biochemistry 45:1321–1330

    Article  PubMed  CAS  Google Scholar 

  • Nagaoka K, Demain AL (1975) Mutational biosynthesis of a new antibiotic, streptomutin A, by an idiotroph of Streptomyces griseus. J Antibiot 28:627–635

    Article  PubMed  CAS  Google Scholar 

  • Olano C, Lombó F, Méndez C, Salas JA (2008) Improving production of bioactive secondary metabolites in actinomycetes by metabolic engineering. Metab Eng 10(5):281–292

    Article  PubMed  CAS  Google Scholar 

  • Oliynyk M, Brown MJ, Cortes J, Staunton J, Leadlay PF (1996) A hybrid modular polyketide synthase obtained by domain swapping. Chem Biol 3:833–839

    Article  PubMed  CAS  Google Scholar 

  • Onaka H, Taniguchi S, Igarashi Y, Furumai T (2002) Cloning of the staurosporine biosynthetic gene cluster from Streptomyces sp. TP-A0274 and its heterologous expression in Streptomyces lividans. J Antibiot 55:1063–1071

    Article  PubMed  CAS  Google Scholar 

  • Perez L, Danishefsky SJ (2007) Chemistry and biology in search of antimetastatic agents. ACS Chem Biol 2:159–162

    Article  PubMed  CAS  Google Scholar 

  • Schneider TL, Walsh CT, O’Connor SE (2002) Utilization of alternate substrates by the first three modules of the epothilone synthetase assembly line. J Am Chem Soc 124:11272–11273

    Article  PubMed  CAS  Google Scholar 

  • Schwarzer D, Mootz HD, Marahiel MA (2001) Exploring the impact of different thioesterase domains for the design of hybrid peptide synthetases. Chem Biol 8:997–1010

    Article  PubMed  CAS  Google Scholar 

  • Smanski MJ, Peterson RM, Rajski SR, Shen B (2009) Engineered Streptomyces platensis strains that overproduce antibiotics platensimycin and platencin. Antimicrob Agents Chemother 53:1299–1304

    Article  PubMed  CAS  Google Scholar 

  • Srinivasan P, Palani SN, Prasad R (2010) Daunorubicin efflux in Streptomyces peucetius modulates biosynthesis by feedback regulation. FEMS Microbiol Lett 305:18–27

    Article  PubMed  CAS  Google Scholar 

  • Tang L, Shah S, Chung L, Carney J, Katz L, Khosla C, Julien B (2000) Cloning and heterologous expression of the epothilone gene cluster. Science 287:640–642

    Article  PubMed  CAS  Google Scholar 

  • Tang Y, Lee TS, Khosla C (2004) Engineered biosynthesis of regioselectively modified aromatic polyketides using bimodular polyketide synthases. PLoS Biol 2:227–238

    Article  CAS  Google Scholar 

  • Van Lanen SG, Shen B (2006) Progress in combinatorial biosynthesis for drug discovery. Drug Discov Today Technol 3:285–292

    Article  Google Scholar 

  • Wang G, Hosaka T, Ochi K (2008) Dramatic activation of antibiotic production in Streptomyces coelicolor by cumulative drug resistance mutations. Appl Environ Microbiol 74:2834–2840

    Article  PubMed  CAS  Google Scholar 

  • Weissman KJ (2007) Mutasynthesis—uniting chemistry and genetics for drug discovery. Trends Biotechnol 25:139–142

    Article  PubMed  CAS  Google Scholar 

  • Wendt-Pienkowski E, Huang Y, Zhang J, Li B, Jiang H, Kwon H, Hutchinson CR, Shen B (2005) Cloning, sequencing, analysis, and heterologous expression of the fredericamycin biosynthetic gene cluster from Streptomyces griseus. J Am Chem Soc 127:16442–16452

    Article  PubMed  CAS  Google Scholar 

  • Wenzel SC, Muller R (2005) Recent developments towards the heterologous expression of complex bacterial natural product biosynthetic pathways. Curr Opin Biotechnol 16:594–606

    Article  PubMed  CAS  Google Scholar 

  • Xu Y, Wijeratne EMK, Espinosa-Artiles E, Gunatilaka AAL, Molnar I (2009) Combinatorial mutasynthesis of scrambled beauvericins, cyclooligomer depsipeptide cell migration inhibitors from Beauveria bassiana. Chembiochem 10:345–354

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Studies on natural product biosynthesis, engineering, and drug discovery in the Shen laboratories are supported in part by National Institutes of Health grants AI051689, CA078747, CA094426, CA106150, CA113297, and GM086184.

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Authors and Affiliations

  1. School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin, 777 Highland Avenue, Madison, WI, 53705-2222, USA

    Claudia Eva-Maria Unsin & Scott R. Rajski

  2. Departments of Chemistry and Molecular Therapeutics, Natural Products Library Initiative at The Scripps Research Institute, The Scripps Research Institute, 130 Scripps Way, #3A1, Jupiter, FL, 33458, USA

    Ben Shen

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  1. Claudia Eva-Maria Unsin
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  2. Scott R. Rajski
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  3. Ben Shen
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Correspondence to Ben Shen .

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Editors and Affiliations

  1. , Natural Products/World Wide Medicinal Ch, Pfizer Inc, 445 Eastern Point Road, Groton, 06340, Connecticut, USA

    Frank E. Koehn

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Unsin, C.EM., Rajski, S.R., Shen, B. (2013). The Role of Genetic Engineering in Natural Product-Based Anticancer Drug Discovery. In: Koehn, F. (eds) Natural Products and Cancer Drug Discovery. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4654-5_7

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  • DOI: https://doi.org/10.1007/978-1-4614-4654-5_7

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