Paclitaxel: From yew tree to chemotherapy

The idea of looking to nature for curative properties is ancient. For thousands of years, humans have used natural medicine to treat both disease progression and symptoms. One such example is paclitaxel. Derived from the yew tree, this plant-based compound is now widely utilized in the treatment of many different cancers. 

History of paclitaxel 

In the 1960s, the US Department of Agriculture (USDA) and the National Cancer Institute (NCI) initiated a plant-based screening program to identify potential anticancer agents. During this program, over 115,000 extracts from 15,000 species of plants were tested and collected. However, palitaxel is the only compound from this program that made it to be an FDA approved chemotherapeutic.  

Paclitaxel has had a long journey to becoming an approved treatment, even in the early stages. As part of the program, USDA botanist Arthur Barclay collected samples from the Pacific yew tree, Taxus brevifolia, in 1962.  This included the bark, twigs, needles, and fruit. However, back in the laboratory, only the Pacific yew bark extracts were shown to have cytotoxic properties and killed cancer cells. It wasn’t until 1967 that scientists isolated the active compound, which was then named “taxol”. It wasn’t until 1971 that the structure was solved and the compound entered the official NCI drug development program. 

However,  even more challenges complicated the path. This included the compound's solubility in water, mixed results in preclinical trials, cost, and limited supply of the bark. Over the growing concern of manufacturing, the NCI decided to transfer taxol to a private company for commercialization. In 1992, 30 years after its initial discovery, the trademarked Taxol or its generic name “paclitaxel” was approved by the Food and Drug Administration (FDA) for the treatment of ovarian cancer. Today, paclitaxel is an FDA approved treatment for ovarian cancer, breast cancer, small lung cancer, and Kaposi sarcoma, a skin and mucous cancer found in AIDS patients. It is also used as an off-label, or non-FDA approved, treatment for a number of other cancers as well as approved treatment around the world.

How does paclitaxel work?

Cancer treatment is complicated as the disease involves the body’s own cells that have gained abnormalities and multiply uncontrollably. These abnormalities typically occur in the regulation of cell division, survival, and differentiation. Paclitaxel is an effective anticancer drug because it stops uncontrollable cell growth. 

In normal physiology, many cells in the body regularly divide following the cell cycle. The cell cycle stages include: 

• Cell growth (G1 phase)

• DNA synthesis (S phase)

• Cell Growth (G2 phase)

• Mitosis 

Because cancer cells rapidly divide, they spend more time in mitosis compared to normal cells. Paclitaxel is an effective anticancer drug because it halts mitosis, typically at the G₂/M and M checkpoints, killing the dividing cell. Specifically, paclitaxel acts on a cellular structure known as the microtubule, dynamic polymers that are indispensable for mitosis. Paclitaxel binds to the subunit of microtubules causing the microtubule to lose the capacity to be dynamic. The dynamicity is integral to mitosis and paclitaxel-treated cells commonly can not progress past mitotic checkpoints. However, if the cell does complete mitosis, it typically does so with an abnormal mitotic spindle, which is composed of microtubules. This can lead to defects in mitosis such as missegregation of chromosomes and eventually cell death. While cancer cells are more susceptible to paclitaxel due to their rapid division, normal calls can also be affected, leading to unwanted side effects. 

In addition to its effect on microtubules, other secondary cellular targets of paclitaxel during interphase have been proposed. Some studies suggest that paclitaxel activates proapoptotic signaling pathways to induce cell death by increasing endoplasmic reticulum (ER) stress while other research states that paclitaxel may also lead to mitochondrial damage. Paclitaxel has also been implicated in autophagy and pro-inflammatory pathways. These secondary targets may contribute to its anti-cancer properties. 

Treatment

In the clinic, cancer patients receive paclitaxel intravenously. However, many other treatment factors, such as dosage and duration, depend on the patient and disease progression. A single paclitaxel administration generally lasts a few hours but can continue for up to 24 hours and typically occurs once every couple weeks. Patients taking paclitaxel may be given other medications during treatment, such as those used to prevent an allergic reaction. A course of paclitaxel may be followed by treatment with other chemotherapy drugs such as cisplatin, another microtubule targeting agent.

Side effects

Like many cancer therapies, paclitaxel can cause adverse effects due to its impact on healthy cells. For paclitaxel, the most common side effects include: 

• Hair loss

• Allergic reactions 

• Neuropathy 

• Weakness 

• Vomiting 

• Low white blood cell count 

This is not an exhaustive list and side effects depend on many factors such as paclitaxel dosage, treatment regimen, the type of cancer, and individual patient factors.

Future of paclitaxel treatment 

Research exploring paclitaxel’s effectiveness as an anticancer agent is ongoing. Current clinical trials are comparing paclitaxel to new cancer therapies and exploring whether combining it with other drugs can enhance its effects. Researchers are also investigating ways to better target paclitaxel to cancer cells, reducing its off target impacts/impacts on healthy tissues. Cancer therapeutics are constantly advancing and with that so is paclitaxel treatment. It’s fair to say, the story of the Pacific yew bark compound as a treatment is not finished. 

Written by Alisa Cario PhD

Edited by Tiffany vanLieshout PhD

References 

1. Weaver, BA. How paclitaxel/Taxol kills cancer cells. MBoC. 2014; 25: 2677-2681. doi:  10.1091/mbc.E14-04-0916

2. Awosika AO, Farrar MC, Jacobs TF. Paclitaxel. . In: StatPearls . Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536917/

3. Sharifi-Rad, J. et al. Paclitaxel: Application in modern oncology and nanomedicine-based cancer therapy. Oxidative medicine and cellular longevity. 2021; 1-24. doi: 10.1155/2021/3687700 

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6. Fuchs, DA. Johnson, RK. Cytologic evidence that taxol,  an antineoplastic agent from Taxus brevifolia, acts as a mitotic spindle poison. Cancer treat rep. 1978; 62(8):1219-1222.