ArticleProceedings of the National Academy of Sciences of the United States of America2008
Mutations in topoisomerase I as a self-resistance mechanism coevolved with the production of the anticancer alkaloid camptothecin in plants.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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45 citing papers in PubMed, 111 citations in OpenAlex.
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- Not only the top: Type I topoisomerases function in multiple tissues and organs development in plants.Journal of advanced research · 2025Review
- Machine learning reveals complex genetics of fungal resistance in sorghum grain mold.Heredity · 2025Article
- Development of phytochemical genomics: From decoding metabolome to functional genomics and biotechnology of plant metabolism.Proceedings of the Japan Academy. Series B, Physical and biological sciences · 2025Review
- Exploring the Evolvability of Plant Specialized Metabolism: Uniqueness Out Of Uniformity and Uniqueness Behind Uniformity.Plant & cell physiology · 2023Review
- Genomic and transcriptomic analysis of camptothecin producing novel fungal endophyte: Alternaria burnsii NCIM 1409.Scientific reports · 2023Article
- Fungal Drug Discovery for Chronic Disease: History, New Discoveries and New Approaches.Biomolecules · 2023Review
- Detecting macroevolutionary genotype-phenotype associations using error-corrected rates of protein convergence.Nature ecology & evolution · 2023Article
- Into a dilemma of plants: the antagonism between chemical defenses and growth.Plant molecular biology · 2022Review
- Analysis of Plant-Plant Interactions Reveals the Presence of Potent Antileukemic Compounds.Molecules (Basel, Switzerland) · 2022Article
- Identification of WRKY transcription factors involved in regulating the biosynthesis of the anti-cancer drug camptothecin inHorticulture research · 2022Article
- Divergent camptothecin biosynthetic pathway in Ophiorrhiza pumila.BMC biology · 2021Article
- The benzylisoquinoline alkaloids, berberine and coptisine, act against camptothecin-resistant topoisomerase I mutants.Scientific reports · 2021Article
- Chromosome-level genome assembly of Ophiorrhiza pumila reveals the evolution of camptothecin biosynthesis.Nature communications · 2021Article
- The transcription factor OpWRKY2 positively regulates the biosynthesis of the anticancer drug camptothecin in Ophiorrhiza pumila.Horticulture research · 2021Article
- Artemisinin Derivatives with Antimelanoma Activity Show Inhibitory Effect against Human DNA Topoisomerase 1.ACS medicinal chemistry letters · 2020Article
- Multifeature analyses of vascular cambial cells reveal longevity mechanisms in oldProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Nematophin, an Antimicrobial Dipeptide Compound FromFrontiers in microbiology · 2019Article
- Comparison of Strategies to Overcome Drug Resistance: Learning from Various Kingdoms.Molecules (Basel, Switzerland) · 2018Review
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Plants produce a variety of toxic compounds, which are often used as anticancer drugs. The self-resistance mechanism to these toxic metabolites in the producing plants, however, remains unclear. The plant-derived anticancer alkaloid camptothecin (CPT) induces cell death by targeting DNA topoisomerase I (Top1), the enzyme that catalyzes changes in DNA topology. We found that CPT-producing plants, including Camptotheca acuminata, Ophiorrhiza pumila, and Ophiorrhiza liukiuensis, have Top1s with point mutations that confer resistance to CPT, suggesting the effect of an endogenous toxic metabolite on the evolution of the target cellular component. Three amino acid substitutions that contribute to CPT resistance were identified: Asn421Lys, Leu530Ile, and Asn722Ser (numbered according to human Top1). The substitution at position 722 is identical to that found in CPT-resistant human cancer cells. The other mutations have not been found to date in CPT-resistant human cancer cells; this predicts the possibility of occurrence of these mutations in CPT-resistant human cancer patients in the future. Furthermore, comparative analysis of Top1s of CPT-producing and nonproducing plants suggested that the former were partially primed for CPT resistance before CPT biosynthesis evolved. Our results demonstrate the molecular mechanism of self-resistance to endogenously produced toxic compounds and the possibility of adaptive coevolution between the CPT production system and its target Top1 in the producing plants.
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