New drug combination has potential to significantly improve chemotherapy success

November 01, 2016

Athens, Ga. - University of Georgia researchers have found a way to enhance chemotherapy's cancer-killing powers, bringing science one step closer to a more complete cancer treatment.

Chemotherapy's ultimate goal is to destroy a person's cancer, but one common type of the treatment known as antimicrotubule chemotherapy has the tendency to let cancer cells slip through at the exact time that it's supposed to kill them--during the cell division phase known as mitosis.

These dividing cells leave through a process known as mitotic slippage. It's here that UGA researchers have targeted their studies--in understanding how mitotic slippage occurs and how to prevent it. According to the study published Oct. 24 in the Journal of Cell Biology, they found a drug combination that caused 100 percent mitotic cell death, thereby significantly improving the killing efficiency of antimicrotubule chemotherapy drugs.

The drug combination they discovered "could revolutionize chemotherapy by dramatically improving one of the main classes of chemotherapy drugs," said the study's senior author, Edward Kipreos, a professor in the Franklin College of Arts and Sciences department of cellular biology.

To get to that treatment, they first uncovered the cause of mitotic slippage: the action of the protein complex CRL2-ZYG11. Inactivating this protein complex can significantly improve antimicrotubule chemotherapy's ability to kill mitotic cells.

By combining conventional antimicrotubule drugs with a new drug called MLN4924 that targets all CRL complexes, the researchers were able to achieve complete mitotic cell death during testing. MLN4924 has undergone phase I clinical trials, meaning that MLN4924 has been evaluated for its safety, to determine a safe dosage range and to identify side effects.

"Because cancer arises from the unregulated division of cells, it follows that if a chemotherapy drug could kill all dividing cells, it would be able to effectively treat all cancers," Kipreos said.

The paper focuses on new insights into the regulation of mitosis, primarily on the inactivation of cyclin B1-CDK1, an enzyme complex that is essential for mitosis. Because cyclin B1-CDK1 activity promotes the mitotic program, cyclin B1 must be degraded during mitosis to allow cells to exit mitosis. Previously, the understanding was that cyclin B1 is targeted for degradation solely by the action of the anaphase-promoting complex/cyclosome, or APC/C, ubiquitin ligase.

The researchers identified a second ubiquitin ligase complex, CRL2-ZYG11, that also targets cyclin B1 for degradation. The study shows that this pathway is conserved in both humans and the small roundworm Caenorhabditis elegans. In human cells, inactivating CRL2-ZYG11 by itself does not have a large effect on a cell's passage through mitosis, because APC/C is able to handle the degradation of cyclin B1. However, when APC/C is inactivated or cyclin B1 is overexpressed, CRL2-ZYG11 becomes critical to allow cells to exit mitosis.

Antimicrotubule drugs used for chemotherapy work by preventing the formation of the mitotic spindle, which inhibits APC/C, thereby blocking APC/C's ability to degrade cyclin B1 and causing cells to arrest in mitosis. Many of the arrested mitotic cells die. However, because CRL2-ZYG11 can still degrade cyclin B1, a substantial fraction of the arrested cells are able to exit mitosis via mitotic slippage.

"Another negative aspect of mitotic slippage is that it leaves cells with twice the amount of DNA, making normal cells more susceptible to becoming cancerous," Kipreos said. "If MLN4924 in combination with antimicrotubule chemotherapy drugs is as effective in people as it is in vitro--without significant side effects--then it could be used to treat a broad range of cancers, by killing all dividing cells."
The study, "The ubiquitin ligase CRL2ZYG11 targets cyclin B1 for degradation in a conserved pathway that facilitates mitotic slippage," is available at

Co-authors on the study, all from the University of Georgia, include Riju S. Balachandran, Natalia G. Starostina, James W. Anderson, David L. Owen and Srividya Vasudevan from the department of cellular biology; and Cassandra S. Heighington of the department of genetics.

University of Georgia

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 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