Paclitaxel - a “friendly” toxin that helps you with cancer

Few example species of this genus are Taxus baccata, Taxus brevifolia and Taxus Canadensis, between others. The distribution of this genus is widespread in the Northern Hemisphere, with different species in different continents such as North America, Europe and Asia. The genus is known as the source of the drug Paclitaxel, which was firstly isolated from Taxus brevifolia commonly known as Pacific yew. Paclitaxel is a taxine alkaloid present in berries, needles and bark of yew. This drug is used in chemotherapy to combat some kinds of cancer such as ovarian, breast or lung cancer. It is an inhibitor of cell division, therefore being widely used in treatments against cancer.

Berries of this plant are sometimes ingested confused with other non-toxic berries. The toxic part of the berry is the seed, while the meat around is edible. Moreover, the needles are brewed to make tea. The ingestion of this plant in several forms is a common intoxication pathway in humans. The lethal dose for adults is estimated to be around 50 g of yew needles (Piskac et al., 2015). Intoxication is specially common in children of small age after the ingestion of berries, consumed by accident.

Paclitaxel, is a taxine alkaloid composed by different types and isomers. Taxine alkaloids are those extracted from the genus Taxus. The commercialized drug is sold under the name of Taxol, being sold in vials of 30, 100 and 300 mg vials. The first pharmaceutical company able to produce it in large scale was Polysciences, Inc. The mechanisms was to isolate 10-deacetylbaccatin III, a precursor of the drug, which by synthesis procedures was converted to paclitaxel.

The isolation and production of this drug is very complex, as it only accounts to a minor part of the total taxoid content of the plant (0.001-0-05%). To put into perspective, the production of the drug needed to treat one cancer patient requires approximately eight 60-year old yew trees. CEC China Pharmaceuticals Ltd., other producer of this drug, stated that 10 000 kg of needles is needed to the production of 1 kg of pure paclitaxel. In yew has been identified two major types of taxine alkaloid, Taxine A and Taxine B. In total, Taxus produces 10 different alkaloids. Taxine B is the responsible of the cardiotoxicity of yew.

• Formula: C₄₇H₅₁NO₁₄
• CAS: 33069-62-4
• Molar mass: 853.906 g/mol
• Chemical name: 5β, 20-Epoxy-1,2α,4,7β,10β,13α- hexahydroxytax-11-en-9-one 4,10-diacetate 2-benzoate 13-ester with (2R,3S)-N-benzoyl-3- phenylisoserine
• SMILES: CC1=C2[C@@]([C@]([C@H]([C@@H]3[C@]4([C@H](OC4)C[C@@H]([C@]3(C(=O) [C@@H]2OC(=O)C)C)O)OC(=O)C)OC(=O)c5ccccc5)(C[C@@H]1OC(=O)[C@H](O)[C@@H](NC(=O)c6ccccc6)c7ccccc7)O)(C)C
• Physico-chemical characteristics: lipophilic and insoluble in water, with a melting point of 216 ⁰C. It is colorless and odorless.
• Mechanism of action of drug: inhibition of cellular mitosis by binding and stabilization of microtubules in their polymerized form, inducing cell death by blocking the apoptosis inhibitor protein Bcl-2 (B-cell Leukemia 2)
• Toxicity: by accidental intoxication of the plant, the taxine alkaloids interfere with the sodium and calcium channels of the myocardial cells, increasing cytoplasmic calcium concentrations. Its cardiotoxicity leads to bradycardia, hypotension and arrhythmias.

References:

• Piskač, O., Stříbrný, J., Rakovcová, H., & Malý, M. (2015). Cardiotoxicity of yew. Cor et Vasa, 57(3), e234-e238.

• Pietsch, J., Schulz, K., Schmidt, U., Andresen, H., Schwarze, B., & Dreβler, J. (2007). A comparative study of five fatal cases of Taxus poisoning. International journal of legal medicine, 121(5), 417-422.

• Sinn, L. E., & Porterfield, J. F. (1991). Fatal taxine poisoning from yew leaf ingestion. Journal of Forensic Science, 36(2), 599-601.

• Grobosch, T., Schwarze, B., Felgenhauer, N., Riesselmann, B., Roscher, S., & Binscheck, T. (2013). Eight cases of fatal and non-fatal poisoning with Taxus baccata. Forensic science international, 227(1-3), 118-126.

• [US Natl Inst Health; DailyMed. Current Medication Information. Paclitaxel Solution. Sept 2007. Available from, as of May 21, 2008

Figure sources:

• Taxus baccata: www.treeseedonline.com
• Taxus baccata toxicity sign: www.Horsedvm.co.uk
• Taxus seed and berries: www.wikipedia.org