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Bioproduction of Anticancer Podophyllotoxin and Related Aryltretralin-Lignans in Hairy Root Cultures of Linum Flavum L.

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Plant Cell and Tissue Differentiation and Secondary Metabolites

Part of the book series: Reference Series in Phytochemistry ((RSP))

Abstract

Podophyllotoxin (PPT) is the unique natural precursor of Etoposide, a topoisomerase II inhibitor drug, used in more than a dozen anticancer chemotherapy treatments. Etoposide is appearing on the list of essential medicines of the World Health Organization. PPT is still exclusively extracted from the rhizome of Podophyllum species, its main natural source. The supply of Podophyllum hexandrum plants is limited, since the occurrence of these plant species is scarce, collection is destructive, and the plants need a long regeneration period. As a consequence, this species is now endangered and listed on Appendix II of the Convention on International Trading of Endangered Species. Chemical synthesis of PPT is difficult due to the presence of four contiguous chiral centers and the presence of a base sensitive trans-lactone moiety. Alternatives are being actively searched, but so far, no wild plants have been described with similar PPT production capacity as compared to Podophyllum. However, several plants producing PPT or other related aryltetralin lignans (ATL) have been identified in recent decades, including the Linaceae. Given its high lignan accumulation capacity, Linum flavum is considered a promising alternative source of PPT and other related ATL. However, unlike the common flax L. usitatissimum, L. flavum has a low agricultural potential (e.g., slow growth and dehiscence of fruits). Therefore, in vitro cultures of plant cells and/or tissues provide an interesting alternative to whole L. flavum plants for the production of these valuable ATL. In particular, L. flavum hairy roots (HRs) accumulate high levels of ATL and it is also possible to further increase this ATL accumulation by the selection of the best genotype, optimization of cultures media and conditions and choice of carbon sources, use of plant growth regulators, elicitor treatments, or precursors’ addition. To date, the ATL accumulation levels can still be perceived insufficient for L. flavum HRs before being used as a commercially viable biotechnological production system. To reach this goal, a better knowledge of the mechanisms that regulate the metabolic flux of intermediates in the different branches of the ATL metabolic pathway will be an important prerequisite to direct the biosynthesis toward the production of a high amount of the desired PPT. In the future, metabolic engineering aiming at constructing the PPT pathway in a heterologous host is very appealing, but for that approach in-depth knowledge of the biosynthetic pathway toward PPT and other related ATL is necessary.

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Abbreviations

ATL:

Aryltetralin lignan

B5:

Gamborg B5

DPT:

Deoxypodophyllotoxin

DW:

Dry weight

FW:

Fresh weight

LS:

Linsmaier and Skoog

MPT:

Methoxypodophyllotoxin

MPTG:

Methoxypodophyllotoxin-β-D-glucoside

MS:

Murashige and Skoog

PPT:

Podophyllotoxin

PPTG:

Podophyllotoxin-β-D-glucoside

WPM:

Woody plant medium

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Acknowledgments

The authors are grateful for financial support from Ligue Contre le Cancer (IMPACT and Cell4LiFE grants).

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  1. Sara Mikac and Lucija Markulin contributed equally with all other contributors.

Authors and Affiliations

  1. Laboratoire de Biologie des Ligneux et des Grandes Cultures, INRA USC1328, Orleans University, Orléans Cedex 2, France

    Sara Mikac, Lucija Markulin, Samantha Drouet, Cyrielle Corbin, Duangjai Tungmunnithum, Bilal Haider Abbasi, Sullivan Renouard, Eric Lainé & Christophe Hano

  2. International Centre for Cancer Vaccine Science, University of Gdansk, Gdansk, Poland

    Sara Mikac

  3. Department of Molecular Biology, Faculty of Science, University of Zagreb, Zagreb, Croatia

    Lucija Markulin

  4. Department of Pharmaceutical Botany, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand

    Duangjai Tungmunnithum

  5. Department of Horticultural Sciences, College of Agriculture and Natural Resources, University of Tehran, Karaj, Iran

    Reza Kiani

  6. I.K. Gujral Punjab Technical University, Kapurthala, Punjab, India

    Atul Kabra

  7. Department of Biotechnology, Quaid-i-Azam University, Islamabad, Pakistan

    Bilal Haider Abbasi

  8. Institut de Chimie et de Biologie des Membranes et des Nano-objets, CNRS UMR 5248, Université de Bordeaux, Pessac, France

    Sullivan Renouard

  9. Faculty of Health and Life Sciences, De Montfort University, Leicester, UK

    Avninder Bhambra & Randolph R. J. Arroo

  10. Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, Germany

    Elisabeth Fuss

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  1. Department of Botany, M.L.Sukhadia university, Udaipur, Rajasthan, India

    Kishan Gopal Ramawat

  2. Department of Pharmaceutical Botany, Jagiellonian University, Medical College, Kraków, Poland

    Halina Maria Ekiert

  3. Amarillo, TX, USA

    Shaily Goyal

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Mikac, S. et al. (2020). Bioproduction of Anticancer Podophyllotoxin and Related Aryltretralin-Lignans in Hairy Root Cultures of Linum Flavum L.. In: Ramawat, K., Ekiert, H., Goyal, S. (eds) Plant Cell and Tissue Differentiation and Secondary Metabolites. Reference Series in Phytochemistry. Springer, Cham. https://doi.org/10.1007/978-3-030-11253-0_20-1

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