Drug Discovery Research

Mechanism of Action of Taxols.

Image of taxol's structure retrieved from PubChem: https://pubchem.ncbi.nlm.nih.gov/compound/paclitaxel

What are taxols?

Taxols/Paclitaxels are drugs used in the treatment of cancer. They are antimictotubule plant alkaloids (gotten from plants). Because cancerous cells undergo uncontrolled cell division while evading self-programmed cell death, taxols are used to enforce apoptosis. They do this through the following three processes.

01.

They Bind Microtubules

Taxols are microtubule inhibitors. Microtubules are essential for cell division and replication. When taxols bind to microtubules, they disrupt this by affecting the microtubule dynamic instability.

02.

They Disrupt Dynamic Instability

Dynamic instability is the growing and shrinking of microtubules. Disrupting this would lead to mitotic arrest and cell death. Taxols suppress the rate and extent of microtubule shortening after it binds to the microtubule; this disrupts the microtubule dynamic instability.

03.

They Cause Cell Death/Apoptosis

By disrupting microtubule dynamics, taxols are able to enforce cell death or apoptosis by suppressing the functioning and assembly of the microtubule spindle. This inhibits cell cycle progression at the metaphase-anaphase checkpoint which causes the cell to die.

Microtubule Dynamic Instability

Microtubule Dynamics Animation

Microtubule Dynamics

What is microtubule dynamic instability?

Microtubule Dynamic Instability is the continuous shortening and growing of microtubules which is essential for intracellular transport as well as cell division. Microtubules are made of alpha and beta tubulins which form dimers that polymerize together to give the microtubule. Taxols bind to these polymers and inhibit depolymerization. I have made an animation to depict how these lengthening and shortening is observed in the laboratory.

Video Explanation

Action of Taxol on Microtubules

Taxol binds to microtubule polymers to inhibit spindle assembly and disrupt microtubule dynamic instability. This is the mechanism of action of the taxol. I have created a video to describe this process.

Taxol Resistance

Sometimes cells could be resistant to taxol. When a cell has an abnormally high instability, low doses of taxol can actually help these cells to survive because the cell could die under stress at really high microtubule instability. Taxols antimicrotubule effect would then bring this cell to a state of normalcy.

Action of Taxol

Taxol binds to microtubule polymers. When the rate of hydrolysis is greater than the rate at which tubulin dimers is added to the microtubule chain, the polymer begins to depolymerize. However in the presence of taxol, this depolymerization is slowed down or suppressed. The diagram below is extracted from the video to show this action.

LO's Applied (Slideshow).

Use the numbers at the end of this section to navigate to the LO explained.

This article shows the biochemical interactions that occur in microtubule dynamic instability. There is the breakdown of GTP to GDP and phosphate in the presence of water. This allows for the growing of the microtubule. When this hydrolysis exceeds the addition of tubulin dimers, then we begin to see the microtubule disintegrate. This is the shrinking.

— #molecularinteractions
Even further strengthening #molecularinteractions, we see here that taxols play an antimicrotubule inhibitory effect. Taxols inhibit the shortening or depolymerization of the microtubule after the bind to it. Hence, it has a regulatory function microtubule dynamics. This is what makes it a good drug for cancer treatment as the slowing down of cell cycle progression at the metaphase-anaphase stage eventually leads to cell death.

— #regulatoryfunction
We discuss taxol resistance in cell types that have mutated to have increased instability. In this case, without the presence of taxol, they might not be able to survive; however, they would have an increased fitness in the presence of low doses of taxol.

— #resistance

References

Goncalves, A., Braguer, D., Kamath, K., Martello, L., Briand, C., & Horwitz, S. et al. (2001). Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics. Proceedings Of The National Academy Of Sciences, 98(20), 11737-11742. doi: 10.1073/pnas.191388598

Paclitaxel. Retrieved from https://pubchem.ncbi.nlm.nih.gov/compound/paclitaxel

Taxol - Chemotherapy Drugs - Chemocare. Retrieved from http://chemocare.com/chemotherapy/drug-info/Taxol.aspx