Alkaloids derived from tree bark destroy cancer cells

Tree bark acts as an important chemical defence mechanism against pests. When a plant comes under threat from bacteria or an insect, alkaloids secreted by the plant may, for example, inhibit cell division or the activity of DNA in the insect, preventing reproduction. This is the operating mechanism of paclitaxel and camptothecin, two compounds isolated from the bark of different trees and developed into effective anticancer drugs. Data analyses and databases have now become available to help identify bioactive compounds in trees and other plants.

There are half a million plants in the world, of which an estimated 7% are used for medicinal purposes. Around 25% of prescription medicines in use today are plant-based. This refers to medicines consisting of natural compounds isolated from plants and synthetic derivatives developed from them. Preserving biodiversity is also of paramount importance for pharmaceuticals, as new plant species are constantly being discovered and the chemical composition of even known plants is largely unknown.

Paclitaxel and camptothecin are examples of anticancer drugs that were discovered when samples from potential medicinal plants were systematically screened. The US National Cancer Institute (NCI) screened more than 35,000 plant samples in a research programme that started in 1956 and continued until 1981. The aim of the programme was to identify plant compounds that could be used to prevent or treat cancers.

The ambitious programme also drew on ethnobotany and history. Programme director Jonathan Hartwell compiled an extensive collection of ancient Chinese, Egyptian, Greek and Roman texts on the medicinal uses of plants. To find the samples and obtain accurate botanical information, Hartwell turned to the U.S. Department of Agriculture (USDA). USDA botanists began collecting plants from around the world to be analysed in laboratories.

Camptothecin and its derivatives

Research Triangle Institute’s  chemists Monroe E. Wall and Mansukh C. Wani received samples of Camptotheca acuminata for study. Known as the Happy Tree in China, Camptotheca acuminata grows naturally on wet banks of the Yangtze River. In traditional Chinese medicine, its leaves and bark have been used to treat various inflammations and infections.

Wall and Wani discovered that the compounds in C. acuminata were highly active in the L1210 mouse leukaemia cell line, meaning that its effects were seen in cancer cells.  The L1210 line is commonly used in cancer research and for testing new anticancer therapeutics. It was isolated from a mouse with lymphocytic leukaemia. Wall and Wani isolated an active compound from wood, which was named camptothecin. It was found to be highly effective against leukaemia cells.

Camptothecin binds to an important cellular enzyme, topoisomerase I, and to DNA complexes. This prevents cancer cells from replicating their DNA, resulting in cell death. Despite its effectiveness, camptothecin has serious side effects and poor solubility. A drug being soluble in water is important because it affects the absorption and distribution of the therapeutic agent in the body. Later, derivatives of camptothecin were developed that were water-soluble and better tolerated and retained their efficacy. These include topotecan and irinotecan. Topotecan (Hycamtin) is used for ovarian, lung and cervical cancer, while irinotecan (Camptosar) is used primarily for colon and rectal cancers.

Developing Irinotecan

Synthetic derivatives developed from a natural compound can be significantly more effective than the original compound. In the 1980s, the Japanese company Yakult Honsha developed irinotecan, a derivative of camptothecin. It was then discovered that its active form in the body is its metabolic product 7-ethyl-10-hydroxycamptothecin, which is about 100 to 1,000 times more active than irinotecan itself. The compound was given the name SN-38, which stands for the pharmaceutical company code “SmithKline Number 38”. It is not active as such, but acts as a prodrug. SN-38 is a potent anticancer agent that is produced in the body when irinotecan is converted to its active form. Conversion to SN-38 takes place in the liver and other tissues. It is therefore a modified version of naturally occurring camptothecin with added ethyl and hydroxyl groups. These changes resulted in a highly effective therapeutic agent. Some individuals carry the UGT1A1*28 mutation. A mutation in the UGT1A1 gene (such as UGT1A1*28) may reduce the activity of the enzyme and slow down the elimination of SN-38, thereby increasing its toxicity. This may increase the drug’s side effects. The Ensembl database can be used to study the UGT1A1 gene, its mutations and possible effects on SN-38 metabolism, for example.

Paclitaxel: one of the most important cytostatic agents globally

Wall and Wani continued to study the plant samples after the discovery of camptothecin. They were asked to analyse samples of Pacific yew (Taxus brevifolia).

The Pacific yew is one of five genera in the Taxaceae family. It is a slow-growing tree native to North America, where it is found in the shade of giant conifers on the banks of streams, in deep ravines and in wet passes. Its wood is hard but of limited use. The tree has few natural pests because most parts of it are poisonous. In 1971, Wall, Wani and their colleagues published a study in which they presented a compound isolated from the bark of the yew tree. It prevents microtubules from breaking down, stopping cancer cells from dividing. The compound was named paclitaxel (Taxol).

Paclitaxel was an effective cancer drug, but there were environmental concerns. The extraction of the compound from the yew tree killed the rare tree. As the natural source (yew tree bark) was not sufficient for large-scale production of the drug, a semi-synthetic method was developed in the 1990s using 10-deacetylbaccatin from the needle of the yew tree as the raw material. The compound (10-DAB) is a precursor to paclitaxel, and by adding benzylamine to it, pure and ecologically sustainable paclitaxel can be produced.  Paclitaxel is one of the most commonly used medicines for breast and ovarian cancers.

ELIXIR Core Data Resources: Critical Databases and Services for Bioscience

The ELIXIR Core Data Resources (CDRs) have been selected based on their quality, wide usage, and long-term significance. They are essential to many fields of research, including genomics, proteomics, and drug development. ELIXIR Core Data Resources provide researchers with open and reliable access to biological datasets, promoting new discoveries and accelerating, for example, the development of new drugs, the understanding of diseases, and the identification of biomarkers.

The data analysis services and machine learning models provided by the ELIXIR infrastructure can help identify new drug candidates from large datasets. These resources and databases allow natural compounds to be analysed more quickly and accurately, supporting their development into safe and effective pharmaceuticals.

ENA: Genetic Data from Various Organisms

ENA (European Nucleotide Archive) is a database maintained by the European Bioinformatics Institute (EMBL-EBI) that stores and shares sequencing data from various organisms, including microbes, plants, animals, and humans.

Since ENA contains genomic and sequencing data from all forms of life, it is a key resource for biodiversity researchers analysing species’ genetic diversity, population genetics, and evolution. It aids in the identification of new species (via DNA barcoding and metagenomics) and the study of relationships between species (through phylogenetic analyses).

The genetic databases included in ENA enable large-scale meta-analyses and comparisons of genetic information across different populations or species. This supports progress in a wide range of research areas such as evolutionary biology, disease research, and medicine. ENA is openly accessible to researchers worldwide.

ChEBI: Small-Molecule Compounds

ChEBI (Chemical Entities of Biological Interest) is a curated biochemical database that contains information about biologically relevant small-molecule compounds. It provides accurate chemical and biological data on compounds such as drugs, metabolites, and natural products.

ChEBI includes precise information on chemical structure, molecular formula, mass, and isomeric details, which helps researchers analyze the chemical properties of pharmaceutical compounds.

Search example: The database can be used to look up the biological effects of paclitaxel and its target molecules.

Ensembl: Genomic Data from Organisms

Ensembl is a genomics and bioinformatics database that provides analysed genomic data from a range of organisms, including humans, animals, plants, and microbes.

Search example: The main molecular target of paclitaxel is the tubulin protein. Ensembl provides genetic and protein structure data on tubulin and related genes, aiding research into drug resistance and the effects of mutations.

Ensembl includes information on genetic variations that may affect the efficacy and side effects of Taxol. For instance, the enzymes CYP3A4 and CYP2C8, which metabolize Taxol, can carry mutations that impact the drug’s effectiveness.

Ari Turunen

8.5.2025

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