Taxanes: natural chemotherapeutics

Plants, through their outstanding genetic diversity, are capable of producing a wide range of unique metabolites. As we discussed in a previous article, these metabolites are often referred to as secondary metabolites. These compounds are not vitally required by the plant for its survival, but grant it with enhanced resistance to pests, pathogens, or adverse environmental conditions.

Throughout history, human beings have exploited several plant secondary metabolites for medicinal purposes. Although the use of medicinal plants may appear strange in today's world, where we have access to powerful and reliable synthetic methodologies for the production of artificially designed pharmaceuticals, some plant-extracted pharmaceuticals remain the best option for the treatment of certain diseases. In this regard, there is probably no better example than the chemotherapeutical drugs of the taxane family.

An intricate molecular design

Taxanes are highly complex chemical compounds that occur among the different species of the slow-growing evergreen shrubs in the genus Taxus. They belong to a subtype of secondary metabolites known as ‘terpenes’, which all chemically derive from a molecule called ‘isoprenyl diphosphate’ (IPP).

Several molecules of IPP can react with one another to create different kinds of terpenes. They differentiate from other related terpenes with one key feature, that is, their core chemical structure. This feature is not universal among all members of the taxane family, but is shared by many of its members. Each specific taxane then has different chemical groups attached to their cyclic structure that determines its specific function and clinical capabilities.

Could plants hold the key?

The discovery of the first member of the taxane family started in 1955 when the National Cancer Institute of the United States (NCI) created the Cancer Chemotherapy National Service Center or CCNSC for short. This center was meant to serve as a research facility that could provide new chemotherapeutic options for cancer treatment through the screening of different readily available, and mostly synthetic, chemical compounds. In 1962, the NCI decided to change direction and commissioned a team of researchers from the U.S. Department of Agriculture (USDA) with an ambitious mission. These researchers were given the task of finding natural products that could have chemotherapeutical characteristics. In other words, naturally occurring chemical compounds that could be used to inhibit the uncontrolled growth and proliferation of cancer cells directly or indirectly.

After two years of research, they found some promising leads. It was discovered that extracts from the Pacific yew’s bark (Taxus brevifolia) could trigger cell death under in vitro conditions. A few years later other researchers at the Research Triangle Institute successfully isolated the most active component of the extract which proved promising as a chemotherapeutical agent. This compound was named ‘paclitaxel’, after the Pacific yew and the genus Taxus where it belongs.

In 1977, the NCI finally confirmed the antitumor activity of paclitaxel in several animal models. It was found that paclitaxel showed serious chemotherapeutical promise for several types of cancers such as melanoma, mammary, lung and colon tumors. Since then, more than 500 members of the taxane family have been isolated.

The key importance of taxanes in modern medicine

Compounds belonging to the taxane class have been referred by researchers at the Institute for Drug Development at San Antonio, Texas as “the most important addition to the chemotherapeutic armamentarium against cancer over the past several decades”, highlighting the critical role that these compounds play nowadays in the field of oncology.

Some key advantages of taxanes are:

• The key ability of taxanes comes from the fact that they can be used at different stages of cancer development.
• Taxanes not only palliate the symptoms of many types of advanced cancers, including ovary, breast, lung, bladder, and esophagus cancers, but are also very effective chemotherapeutical in the earlier stages of those types of cancers.
• Taxanes act by inhibiting cell proliferation as they block the cell from dividing at the stage of cell reproduction, mitosis. The process of division is even more critical in cancerous cells, which reproduce at an abnormally high pace. Therefore, paclitaxel’s effect is exacerbated in rapidly reproducing cells and is able to function as a chemotherapeutical.

Paclitaxel and plant tissue culture

Paclitaxel is still difficult to get naturally, despite its high therapeutic value and extensive research. When paclitaxel was first identified, it was isolated by extracting it from the Taxus species in which it was found. This method proved inefficient and expensive. Taxus shrubs, as previously noted, are typically slow-growing plants that take decades to mature. Paclitaxel is exclusively found in the bark of these plants and at extremely low amounts, ranging from 0.0001 to 0.005% of the total bark weight in Taxus brevifolia. As a result, different chemical and biotechnological sources have been investigated to generate paclitaxel in commercial amounts ever since.

Paclitaxel's very complicated molecular structure makes chemical synthesis difficult, resulting in poor yields of the final product after many reaction stages. In this context, biotechnological procedures have shown to be the most feasible methodology for producing paclitaxel, with a considerable portion of it now produced from the tissue culture of Taxus brevifolia cells in massive bioreactors.

We hope that this essay has taught you a lot about taxane and its use in plant-based medicines. Keep an eye on this space for additional intriguing articles on various facets of plant-based pharmaceuticals.

By David Alzuria Rodríguez | 2 August 2022

David Alzuria Rodrguez is a Spaniard from Barcelona. He holds a master's degree in plant biotechnology. He recently began performing plant science communication for Lab Associates in the form of short articles about plant-based cosmetics and pharmaceuticals. He has always been fascinated by nature and how it interacts with human societies. As a result, he decided to create an Instagram page, @plant_chem, dedicated to plant secondary metabolites as well as their properties and applications. He enjoys spending his spare time with friends and family, gardening, and hiking in the mountains.

References:

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• F. Schneider, K. Samarin, S. Zanella, and T. Gaich, “Total synthesis of the complex taxane diterpene canataxpropellane,” Science (80-. )., vol. 367, no. 6478, pp. 676–681, 2020, doi: 10.1126/science.aay9173.
• S. Howat, B. Park, I. S. Oh, Y. W. Jin, E. K. Lee, and G. J. Loake, “Paclitaxel: Biosynthesis, production and future prospects,” N. Biotechnol., vol. 31, no. 3, pp. 242–245, 2014, doi: 10.1016/j.nbt.2014.02.010.
• National Cancer Institute of the U.S. (NCI) available at https://dtp.cancer.gov/timeline/flash/success_stories/S2_taxol.htm. Last consulted at 11/03/22.