Pharmaceutically Active Natural Product Synthesis and Supply via Plant Cell Culture Technology
TL;DR: This review focuses on some of the key challenges in utilizing and commercializing plant cell culture suspension technology, with a focus on pharmaceutically active natural products.
Abstract: The chemical diversity of plant-derived natural products allows them to function in a multitude of ways including flavor enhancers, agricultural chemicals, and importantly, human medicinals Supply of pharmaceutically active natural products is often a challenge due to the slow growing nature of some species, low yields found in nature, and unpredictable variability in accumulation Several production options are available including natural harvestation, total chemical synthesis, semisynthesis from isolated precursors, and expression of plant pathways in microbial systems However, for some medicinal natural products, such as the anticancer agent paclitaxel, where low yields in nature, chemical complexity and lack of knowledge of the complete biosynthetic pathway, preclude many of these options, plant cell culture technology is an attractive alternative for supply Plant cell suspension cultures are amenable to scale-up, environmental optimization, and metabolic engineering This review focuses on some of the key challenges in utilizing and commercializing plant cell culture suspension technology, with a focus on pharmaceutically active natural products Recent research has been directed toward application of traditional strategies such as reactor design, cell immobilization, and enzyme elicitation as well as emerging strategies such as characterizing cellular heterogeneity and variability through flow cytometric techniques, metabolic engineering, and system-wide analysis
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TL;DR: While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs in the future.
1,760 citations
Cites background from "Pharmaceutically Active Natural Pro..."
...…since natural product-based drug discovery is associated with some intrinsic difficulties (discussed in more details in Section 2.1), pharmaceutical industry has shifted its main focus toward synthetic compound libraries and HTS for discovery of new drug leads (Beutler, 2009; David et al., 2015)....
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TL;DR: This work illustrates the high degree of innovation in the field of marine natural products, which in its view will lead to a new wave of drugs that flow into the market and pharmacies in the future.
Abstract: The largely unexplored marine world that presumably harbors the most biodiversity may be the vastest resource to discover novel ‘validated’ structures with novel modes of action that cover biologically relevant chemical space. Several challenges, including the supply problem and target identification, need to be met for successful drug development of these often complex molecules; however, approaches are available to overcome the hurdles. Advances in technologies such as sampling strategies, nanoscale NMR for structure determination, total chemical synthesis, fermentation and biotechnology are all crucial to the success of marine natural products as drug leads. We illustrate the high degree of innovation in the field of marine natural products, which in our view will lead to a new wave of drugs that flow into the market and pharmacies in the future.
363 citations
TL;DR: Recent advances in the production of taxol and related taxanes in Taxus baccata, the taxol-producing European yew, using cell suspension culture technology are focused on, giving particular emphasis to the optimization steps that have improved production and including the most recently developed new tools.
292 citations
TL;DR: This review summarizes the important bioactive compounds currently produced by plant tissue culture and the fundamental methods and plants employed for their production.
Abstract: Plant tissue culture as an important tool for the continuous production of active compounds including secondary metabolites and engineered molecules. Novel methods (gene editing, abiotic stress) can improve the technique. Humans have a long history of reliance on plants for a supply of food, shelter and, most importantly, medicine. Current-day pharmaceuticals are typically based on plant-derived metabolites, with new products being discovered constantly. Nevertheless, the consistent and uniform supply of plant pharmaceuticals has often been compromised. One alternative for the production of important plant active compounds is in vitro plant tissue culture, as it assures independence from geographical conditions by eliminating the need to rely on wild plants. Plant transformation also allows the further use of plants for the production of engineered compounds, such as vaccines and multiple pharmaceuticals. This review summarizes the important bioactive compounds currently produced by plant tissue culture and the fundamental methods and plants employed for their production.
281 citations
TL;DR: Recent advancements in plant cell culture processing technology are discussed, focusing on progress towards overcoming the problems associated with commercialization of these production systems and highlighting recent commercial successes.
Abstract: Plant cell culture systems were initially explored for use in commercial synthesis of several high-value secondary metabolites, allowing for sustainable production that was not limited by the low yields associated with natural harvest or the high cost associated with complex chemical synthesis. Although there have been some commercial successes, most notably paclitaxel production from Taxus sp., process limitations exist with regards to low product yields and inherent production variability. A variety of strategies are being developed to overcome these limitations including elicitation, in situ product removal and metabolic engineering with single genes and transcription factors. Recently, the plant cell culture production platform has been extended to pharmaceutically active heterologous proteins. Plant systems are beneficial because they are able to produce complex proteins that are properly glycosylated, folded and assembled without the risk of contamination by toxins that are associated with mammalian or microbial production systems. Additionally, plant cell culture isolates transgenic material from the environment, allows for more controllable conditions over field-grown crops and promotes secretion of proteins to the medium, reducing downstream purification costs. Despite these benefits, the increase in cost of heterologous protein synthesis in plant cell culture as opposed to field-grown crops is significant and therefore processes must be optimized with regard to maximizing secretion and enhancing protein stability in the cell culture media. This review discusses recent advancements in plant cell culture processing technology, focusing on progress towards overcoming the problems associated with commercialization of these production systems and highlighting recent commercial successes.
270 citations
Cites background from "Pharmaceutically Active Natural Pro..."
...Additionally, secondary metabolite accumulation over time within a single cell line and amongst cultures of the same cell line is often variable, which is likely related to cellular heterogeneity (Kolewe et al., 2008)....
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...Table 1 Products produced commercially via plant cell culture (Kolewe et al., 2008; Obembe et al., 2010)...
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...The existence of cell subpopulations necessitates the study of suspension cultures at the single cell level to fully understand and ultimately engineer cultures for optimal performance (Kolewe et al., 2008)....
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References
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TL;DR: A number of promising new agents are in clinical development based on selective activity against cancer-related molecular targets, including flavopiridol and combretastin A4 phosphate, while some agents which failed in earlier clinical studies are stimulating renewed interest.
1,794 citations
TL;DR: Localization of expression of more than 22,000 genes in the Arabidopsis root correlates groups of genes to specific cell fates and should serve to guide reverse genetics.
Abstract: A global map of gene expression within an organ can identify genes with coordinated expression in localized domains, thereby relating gene activity to cell fate and tissue specialization. Here, we present localization of expression of more than 22,000 genes in the Arabidopsis root. Gene expression was mapped to 15 different zones of the root that correspond to cell types and tissues at progressive developmental stages. Patterns of gene expression traverse traditional anatomical boundaries and show cassettes of hormonal response. Chromosomal clustering defined some coregulated genes. This expression map correlates groups of genes to specific cell fates and should serve to guide reverse genetics.
1,206 citations
TL;DR: It is shown that endogenous jasmonic acid and its methyl ester accumulate rapidly and transiently after treatment of plant cell suspension cultures of Rauvolfia canescens and Eschscholtzia californica with a yeast elicitor.
Abstract: To deter pathogenic microorganisms and herbivores, plants have developed an inducible chemical defense system It is known that the induced synthesis of low molecular weight compounds can be provoked by exposing cultured cells to fungal cell wall fragments In this study we show that endogenous jasmonic acid and its methyl ester accumulate rapidly and transiently after treatment of plant cell suspension cultures of Rauvolfia canescens and Eschscholtzia californica with a yeast elicitor Thirty-six plant species tested in cell suspension culture could be elicited with respect to the accumulation of secondary metabolites by exogenously supplied methyl jasmonate Addition of methyl jasmonate initiates de novo transcription of genes, such as phenylalanine ammonia lyase, that are known to be involved in the chemical defense mechanisms of plants These data demonstrate the integral role of jasmonic acid and its derivatives in the intracellular signal cascade that begins with interaction of an elicitor molecule with the plant cell surface and results, ultimately, in the accumulation of secondary compounds
1,093 citations
TL;DR: Plant cell culture technologies were introduced at the end of the 1960s as a possible tool for both studying and producing plant secondary metabolites, and it is now possible to manipulate the pathways that lead to secondary plant compounds.
978 citations
TL;DR: Orca3 overexpression resulted in enhanced expression of several metabolite biosynthetic genes and in increased accumulation of terpenoid indole alkaloids, which may link plant stress responses to changes in metabolism.
Abstract: Biosynthesis of many classes of secondary metabolites in plants is induced by the stress hormone jasmonate. The gene for ORCA3, a jasmonate-responsive APETALA2 (AP2)-domain transcription factor from Catharanthus roseus, was isolated by transferred DNA activation tagging. Orca3 overexpression resulted in enhanced expression of several metabolite biosynthetic genes and, consequently, in increased accumulation of terpenoid indole alkaloids. Regulation of metabolite biosynthetic genes by jasmonate-responsive AP2-domain transcription factors may link plant stress responses to changes in metabolism.
867 citations