Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Discovery of How Taxol Works Could Lead to Better Anticancer Drugs

Published: Saturday, May 24, 2014
Last Updated: Saturday, May 24, 2014
Bookmark and Share
The drug’s interference with the normal function of microtubules could help in designing better anticancer drugs.

UC Berkeley scientists have discovered the extremely subtle effect that the prescription drug Taxol has inside cells that makes it one of the most widely used anticancer agents in the world.

The details, involving the drug’s interference with the normal function of microtubules, part of the cell’s skeleton, could help in designing better anticancer drugs, or in improving Taxol and other drugs already known to disrupt the workings of microtubules.

“Efforts towards understanding these chemotherapeutics better are very important, because there are some microtubule differences in cancer cells versus normal cells that maybe we can exploit,” said principal author Eva Nogales, a biophysicist, UC Berkeley professor of molecular and cell biology and senior faculty scientist at Lawrence Berkeley National Laboratory (LBNL). “We are not there yet, but this is the kind of analysis we need to get there.”

Taxol, originally extracted from the bark of the Pacific yew tree, is one of the mostly commonly used drugs against solid tumors, and is a front-line drug for treating ovarian and advanced breast cancer. The drug is known to bind to microtubules and essentially freeze them in place, which prevents them from separating the chromosomes when a cell divides. This kills dividing cells, in particular cancer cells, which are known for rapid proliferation.

Nogales, a Howard Hughes Medical Institute investigator, has worked on microtubules since she was a doctoral student in England in the early ’90s, using techniques such as X-ray scattering and cryoelectron microscopy to study how Taxol and other anticancer agents affect microtubules. Later, during her postdoctoral work at LBNL with Ken Downing, she was the first to discover exactly where Taxol binds the basic building block, called tubulin, of the microtubule polymer.

Microtubules are the cell’s skeleton

Work by many scientists around the world has shown the microtubule network inside cells, called the cytoskeleton, to be very different from rigid animal skeletons. Microtubules are polymer filaments that constantly grow and shrink, and in doing so push and pull things around the cell, including the chromosomes. Scientists call this dynamic instability. The microtubules also provide a highway for transporting the cell’s organelles and other packages around the cell.

Tubulin, the basic structural unit of the microtubule, is a complex of two proteins - alpha and beta tubulin. Tubulin units stack one atop another to form strips that align with other strips and then zip up to form a hollow tube, the microtubule.

“Tubulin, the cytoskeletal protein that self-assembles into microtubules, is absolutely essential for the life of every eukaryotic cell, which is why it has become a major target of anticancer agents,” Nogales said. “It’s amazing how microtubules probe and try new things almost at random, but there is a level of control built into the cell that ultimately makes sense of this chaos, and the cell survives and prospers.”

Microtubules grow from their free end at about 1 micron per minute by continually adding more tubulin (around 20 tubulin molecules per second). But if they stop growing, they rapidly peel apart like the skin of a banana, releasing tubulin for recycling into other microtubules. This peeling, or depolymerization, takes place at up to 15 microns per minute, or about 300 tubulin molecules falling off per second, Nogales said.

Microtubules are like compressed springs

Nogales has now discovered why microtubules peel apart so rapidly. When they assemble, the strips of tubulin are put under intense strain, but prevented from bending and pulling apart by the growing cap of tubulin on the end. Once growing stops and that cap disappears, the restrained tension rips the microtubule apart.

The tension is created when the tubulin complex, which has a small energy molecule called GTP (guanosine triphosphate) attached, becomes hydrolyzed and the GTP turns into GDP (guanosine diphosphate). This chemical reaction compacts the alpha and beta subunits, much like compacted vertebrae, keeping the tubulin stack under tension as long as the microtubule is growing at its end.

“It had been proposed that tubulin had to be constrained, but no one had proved it,” Nogales said. “What we have seen is that as GTP hydrolysis happens, the tubulin structure gets stuck in a strained state, like a compressed spring. The end subunits are holding the whole thing together.”

When growth stops, the tension is unleashed, and the strips peel apart rapidly.

“This work represents a major step forward on a problem with a long history,” wrote Tim Mitchison in a commentary in the same issue of Cell. Mitchison, a Harvard University professor of systems biology, was the first to show the importance of GTP hydrolysis in destabilizing microtubules. The model proposed by Nogales and her team, he added, “provides our first glimpse into (the) destabilization mechanism.”

Nogales also found that Taxol inserts itself into the tubulin protein and prevents compaction of the alpha and beta subunits, so that no tension builds up. As a result, even if the microtubule stops growing, it remains intact, basically frozen in place, unable to peel apart, or depolymerize, and carry out its normal function.

“Taxol reverses the effects of GTP hydrolysis,” she said.

Pushing the limits of cryoelecton microscopy

Nogales and her team discovered these structural changes by pushing the limits of cryoelectron microscopy, a technique in which samples are frozen and probed with a high-powered electron beam. They have now achieved a resolution sufficient to see details smaller than 5 angstroms (one-tenth of a nanometer) across, which is about the size of five hydrogen atoms. While most information to date about the structure of tubulin inside the microtubule has come from the study of artificial, flat sheets of aligned strips of tubulin, Nogales was able to probe three-dimensional microtubules frozen into their natural state, with and without Taxol bound to tubulin. This comparison clearly showed the effect Taxol has on microtubule structure.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More Than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Engineered Hot Fat Implants Reduce Weight Gain
Scientists at UC Berkeley have developed a novel way to engineer the growth and expansion of energy-burning “good” fat, and then found that this fat helped reduce weight gain and lower blood glucose levels in mice.
Monday, August 24, 2015
Geographic Variation of Human Gut Microbes Tied to Obesity
People living in cold, northern latitudes have bacteria in their guts that may predispose them to obesity.
Monday, February 17, 2014
Unraveling Genetic Mysteries
A UC Berkeley researcher has been awarded $1.3 million of a $3.4 million shared grant to answer some basic scientific questions about inheritance in plants.
Tuesday, August 14, 2012
Scientific News
High Throughput Mass Spectrometry-Based Screening Assay Trends
Dr John Comley provides an insight into HT MS-based screening with a focus on future user requirements and preferences.
Promising Drug Combination for Advanced Prostate Cancer
A new drug combination may be effective in treating men with metastatic prostate cancer. Preliminary results of this new approach are encouraging and have led to an ongoing international study being conducted in 196 hospitals worldwide.
A Cellular Symphony Responsible for Autoimmune Disease
Broad Institute researchers have used a novel approach to increase our understanding of the immune system as a whole.
When it Comes to Breast Cancer, Common Pigeon is No Bird Brain
If pigeons went to medical school and specialized in pathology or radiology, they’d be pretty good at distinguishing digitized microscope slides and mammograms of normal vs. cancerous breast tissue, a new study has found.
Editing of LIMS Data Made Faster and More Efficient in Matrix Gemini
The latest version of the Matrix Gemini LIMS (Laboratory Information Management System) from Autoscribe Informatics now provides faster and more efficient editing of LIMS data by eliminating the need for a second editing screen.
How a Genetic Locus Protects Adult Blood-Forming Stem Cells
Mammalian imprinted Gtl2 protects adult hematopoietic stem cells by restricting metabolic activity in the cells' mitochondria.
Genetic Basis of Fatal Flu Side Effect Discovered
A group of people with fatal H1N1 flu died after their viral infections triggered a deadly hyperinflammatory disorder in susceptible individuals with gene mutations linked to the overactive immune response, according to a recent study.
New Tech Vastly Improves CRISPR/Cas9 Accuracy
A new CRISPR/Cas9 technology developed by scientists at UMass Medical School is precise enough to surgically edit DNA at nearly any genomic location, while avoiding potentially harmful off-target changes typically seen in standard CRISPR gene editing techniques.
The MaxSignal Colistin ELISA Test Kit from Bioo Scientific
Kit can help prevent the antibiotic apocalypse by keeping last resort drugs out of the food supply.
"Good" Mozzie Virus Might Hold Key to Fighting Human Disease
Australian scientists have discovered a new virus carried by one of the country’s most common pest mosquitoes.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos