Potent anticancer drug increases function of axons in mouse model of neurodegeneration

December 20, 2004

(Philadelphia, PA) - In a preclinical efficacy trial, the cancer drug paclitaxel (Paxceed)-which exerts its effects by binding to and stabilizing microtubules inside cells-reduced the adverse effects of Alzheimer's disease (AD)-like pathology in a mouse model. Researchers from the University of Pennsylvania School of Medicine showed that the microtubule-stabilizing drug Paxceed helps correct the problems caused by clumped tau proteins in the nerve cells of mice. "Our hope is that microtubule-stabilizing drugs could be used to treat Alzheimer's and other related diseases," says John Q. Trojanowski, MD, PhD, Director of the Institute on Aging and Co-director of the Center for Neurodegenerative Disease Research and the Marian S. Ware Alzheimer Program at Penn. This research appears in the December 20 early online edition of the Proceedings of the National Academy of Sciences.

Tau amyloids are misshapened, insoluble proteins that clump in the brain and elsewhere and cause a host of debilitating diseases. Since many neurodegenerative diseases share or contribute to this pathology, the focus of therapy has been on drugs that break up these aggregates. Virginia M.-Y. Lee, PhD, Director of the Center for Neurodegenerative Disease Research, and Trojanowski introduced the concept of using microtubule-stabilizing drugs over a decade ago, and this is the first study to confirm their potential as a new class of drug for neurodegenerative disorders. "Now everyone is focused on drugs that disrupt the aggregated protein," says Trojanowski. "We're working on that too, but we also wanted to find a drug that replaces the clumped tau in sick neurons."

Microtubule-binding drugs derived from plants (taxol) and other biological organisms such as sponges (discodermolides) have been used as anti-cancer drugs because they prevent cells from dividing. They do this by keeping microtubules stabilized, which blocks cell division and causes cell death. Microtubules are protein structures found within cells.

Since neurons do not divide, Paxceed does not affect them in the same way as normally dividing cells and tumor cells. Instead, microtubule-binding drugs have other effects in nerve cells similar to the function of the protein tau.

Tau binds microtubules, the highway system of axons in nerve cells. Mutations in the tau gene cause neurons to lose their ability to send and carry signals over time. "These are proteins that we all have in our brains and, as long as they stay soluble and properly folded, there's no disease," says Trojanowski. "When these misfolded proteins aggregate and form sheets called fibrils that accumulate in different parts of the brain, that's when things go awry." This happens when the cell's garbage disposal-the proteosome-isn't working properly or is overwhelmed, causing such affects as cell death, oxidative stress, and in this case impaired axonal transport, which is linked to many neurodegenerative diseases. Impaired axonal transport of proteins and other cargoes needed to maintain synapses can cause nerve cell loss with subsequent dementia, parkinsonism or weakened motor skills in peripheral muscles, and later muscle atrophy.

The protein tau, like Paxceed (or other natural products such as taxanes and discodermolides), is required to stabilize the microtubule. "Think of tau as the cross-tie of the microtubule train track," says Trojanowski. "The tracks will handle the traffic as long as they are parallel and there are substrates for transport. If the cross-ties are missing, the tracks will wobble and the train will run off the tracks."

In a sick neuron, tau is clumped into aggregates, so the microtubule cross-ties are missing, the tracks break, and transmission of nerve signals fails. In the hopes of restoring the microtubule tracks to their original supportive structure, the researchers gave mice Paxceed to replace the now unavailable tau. The team, led by Bin Zhang, PhD, a Senior Research Investigator in Trojanowski's and Lee's laboratory, gave the tau transgenic mice weekly injections of Paxceed at a high and low dose for 12 weeks. At both doses, more protein traveled down the spinal axon and the density of microtubules was greater in the Paxceed-treated mice. The drugs also reduced motor impairment in the tau transgenic mice.

Because microtubule-binding drugs such as Paxceed are approved for treating patients with cancer and a limited number of other diseases, it might be possible to move quickly to clinical trials of these types of compounds, say the researchers. However, it will be necessary to find microtubule-binding drugs that can cross the blood-brain barrier, where they can exert their beneficial effects on nerve cells inside the brain.

Penn coauthors are: Sharon Shively, Jennifer Bruce, Edward B. Lee, Sharon X. Xie, Sonali Joyce, Chi Li, along with Angiotech Pharmaceticals, Inc. (Vancouver, BC) colleagues Arpita Maiti, Fara Lakhani, Gaye McDonald-Jones, and Philip M. Toleikis. The research was funded by the National Institutes of Health, the Oxford Foundation, the Marian S. Ware Alzheimer Program, and Angiotech. Drs. Trojanowski and Lee hold no financial interests in Angiotech.
-end-
This release can also be found at: www.uphs.upenn.edu/news

PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation's first integrated academic health system).

Penn's School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

The University of Pennsylvania Health System includes three owned hospitals [Hospital of the University of Pennsylvania, which is consistently ranked one of the nation's few "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.

University of Pennsylvania School of Medicine

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.