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

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The Role of Genetic Engineering in Natural Product-Based Anticancer Drug Discovery Chapter 7 The Role of Genetic Engineering in Natural Product-Based Anticancer Drug Discovery Claudia Eva-Maria Unsin , Scott R. Rajski, and Ben Shen 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 signi fi cant antitumor compounds. Genes can be introduced into the microbial producer of medicinally relevant secondary metabolites or inactivated to achieve changes in the metabolic pro fi le. The pharma- ceutical 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 dif fi culties 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. C. Eva-Maria Unsin • S. R. Rajski School of Pharmacy, Division of Pharmaceutical Sciences , University of Wisconsin , 777 Highland Avenue , Madison , WI 53705-2222 , USA e-mail: [email protected] ; [email protected] B. Shen (*) 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 e-mail: [email protected] F.E. Koehn (ed.), Natural Products and Cancer Drug Discovery, Cancer Drug Discovery 175 and Development, DOI 10.1007/978-1-4614-4654-5_7, © Springer Science+Business Media New York 2013 176 C. Eva-Maria Unsin et al. 7.1 Introduction Actinomycetes are a major source of bioactive natural products. More than 10,000 substances with bioactivity have been isolated so far from terrestrial and marine actinomycetes (Berdy 2005, 2012 ) and many are clinically used as antitumor agents, antibiotics, or immunosuppressants. Natural products such as bleomycin, doxorubicin, rapamycin, mithramycin, and C-1027 constitute, or have inspired, important anticancer therapeutics. The signi fi cance of natural product to human health is by no means, however, restricted to anticancer agents. Regardless of their uses, drug intolerance, severe organ toxicity, and pathogen resistance often provide signi fi cant driving forces for analog design efforts. Genetic engineering is an impor- tant approach to devise new compounds that lack the aforementioned undesirable characteristics. Under the umbrella of genetic engineering, combinatorial biosyn- thesis is applied to “mix and match” biosynthetic genes from different gene clusters or gene environments. The resultant gene products often catalyze the production of hybrid substances possessing novel features relating to structure, activity, and/or solubility. Mutagenesis is another means of producing novel natural products via genetic manipulation although mutagenesis does not generally permit the precision of engineering approaches. Inactivation of enzymes from a biosynthetic pathway through genetic ablation of speci fi c genes leads in many cases to the generation of a drug derivative, especially if the respective enzyme acts at the end of the biosyn- thetic pathway. Titers can be elevated by heterologous expression of the biosynthetic genes in a suitable host or by manipulation of the producer’s genetic system. Regulatory genes can be altered to optimize expression levels. Most often, the over- expression of biosynthetic genes leads to profound increases in natural product titer. Alternatively, the expression of resistance factors or exporters can help stimulate production or increase natural product export from the producing cells (Fig. 7.1 ). 7.2 Titer Improvement Some antitumor substances are highly active but are produced in quantities insuf fi cient to support necessary development efforts. Exacerbating this dif fi culty is that, in many cases, the structural complexity of these natural products vastly complicates or prohibits their practical construction via total synthesis. It is therefore highly desirable to enhance the ability of the producing organism to produce such compounds in substantially greater quantities. 7.2.1 Titer Improvement in Native Producing Strains An organism’s primary and secondary metabolic pathways are linked via the metabolic burden that each places on the other. Although antitumor natural products result 7 Anticancer Drug Discovery via Genetic Engineering 177 Fig. 7.1 Important steps targeted by genetic engineering approaches to improve production titers of natural antitumor substances. (a ) Derepression or activation of regulatory genes leads to over- expression of structural genes; ampli fi cation of genes for ( b ) precursor supply or ( c ) structural genes overcomes pathway bottlenecks; ( d ) enhancement of self-resistance increases production levels; ( e ) enhanced expression of exporter proteins and ef fl ux pumps increases the cell’s ability to produce more compound by circumventing possible cell death and/or feedback mechanisms ordi- narily used to limit compound production from an organisms’ secondary metabolic machinery there remains an inextricable link between natural product titers and the absolute metabolic burden with which the producing organism needs to cope. As the principal producer of anticancer natu- ral products, the actinomycetes have therefore evolved strict regulatory mechanisms crucial to the maintenance of primary metabolism but that often limit natural prod- uct titers. Indeed, these regulatory mechanisms are at the root of many obstacles encountered in the industrial production of anticancer drugs. Such obstacles have been largely addressed through a combination of approaches based on genetic engi- neering (Fig. 7.1 ). Targeted inactivation of repressor genes and overexpression of transcriptional activators both constitute strategies that have been very effective in increasing natural product titers from their wild-type strains (Fig. 7.1a ). The overexpression of structural genes has also served as a useful approach to overcome natural product-based feedback inhibition (Fig. 7.1b, c ). Additionally, gene dosage plays an important role in the improvement of production titers. Relevant genes are multiplied or overexpressed in order to increase natural product production. Self-resistance can also contribute signi fi cantly to low titers. Increased resistance of the producer and ampli fi ed expression of structural genes can both lead to improved natural product titers (Fig. 7.1d ). Additionally, exporters, either as part of the self- defense system or simply to transport the drug outside the cell, can be overexpressed to enhance natural product synthesis (Fig. 7.1e ). Importantly, these strategies can be used individually or in combination to circumvent the problem of development- and production-limiting natural product titers. 178 C. Eva-Maria Unsin et al. 7.2.1.1 Regulation Pathway-speci fi c regulators in fl uence the transcription of structural genes and these can have either positive (activator) or negative (repressor) effects on the expression of biosynthetic genes. The identi fi cation of such elements is generally straightfor- ward as biosynthetic genes for a given natural product are typically clustered together in speci fi c regions of the chromosome. This is in contrast to pleiotropic regulators that control structural genes, pathway-speci fi c regulator genes, and others such as morphological genes or genes involved in regulating precursor and cofactor supply. Furthermore, feedback regulation mechanisms limit the amount of drug produced inside the cell. Manipulation of the regulatory system can change the production pro fi le signi fi cantly and there are clearly numerous opportunities for such engineering efforts. The often dramatic success of titer enhancement strategies has been recently reviewed (Chen et al. 2010 ) . In the context of anticancer drug discovery and development an extensively investigated example of regulatory system manipulation involves biosynthesis of the anthracycline-type antitumor antibiotic doxorubicin (Fig. 7.2 ), the production of which is tightly regulated in Streptomyces peucetius . Overexpression of transcrip- tional activators has been shown to increase doxorubicin production up to 4.3-fold relative to the wild-type strain (Malla et al. 2010a ) . S. peucetius strains bearing plasmids with an increasingly larger number of the regulatory genes dnrN , dnrI , afsR , and metK1-sp produced increasingly greater amounts of doxorubicin. Consistent with this work, when the global regulatory gene afsR , an established transcriptional activator, was overexpressed in S. peucetius , doxorubicin production was enhanced up to eightfold (Maharjan et al. 2009 ) . Similar experiments with the pikromycin producer Streptomyces venezuelae and the actinorhodin producer Streptomyces lividans yielded similar results; afsR overexpression in S. venezuelae led to a ~5-fold improvement in pikromycin (Fig. 7.2 ) production relative to the wild-type strain and afsR overexpression in S. lividans led to a 1.5-fold improve- ment in actinorhodin (Fig. 7.2 ) production relative to wild-type. Similar titer improvements have been achieved
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