Scientists find Achilles' heel of cancer cells

November 05, 2012

Several substances inhibiting so-called HDAC enzymes have been studied in trials searching for new anti-cancer drugs in recent years. "Trials have shown that HDAC inhibitors are very effective in arresting growth of cultured cancer cells. But apart from a very rare type of lymphoma, these drugs unfortunately do not clinically affect malignant tumors," says Prof. Dr. Olaf Witt, who heads a research department at DKFZ and is pediatrician at the Center for Child and Adolescent Medicine of Heidelberg University Hospital.

In the cell, histone deacetylases (HDAC) are responsible for removing small chemical tags called acetyl groups from histone proteins. Histones serve as coils the genetic material wraps around in the nucleus. The presence or absence of acetyl tags determines where genetic material is accessible and can get transcribed.

Now this is where Witt and his colleagues suspect the reason for the problems in clinical application of HDAC inhibitors. Currently available substances equally block all members of the large family of HDAC enzymes. Thus, they interfere with vital cellular functions and also harm healthy cells. This can lead to severe side effects preventing their administration at a sufficient dosage.

Searching for a solution to this dilemma, Witt's team came across a member of the HDAC family, HDAC11, which was identified only recently. The researchers could show that many cancer cells, including cells of breast, liver and renal cancers, produce extraordinary high levels of HDAC11. This has not been observed in healthy cells, and hardly any specific functions of HDAC11 are known there. "It therefore seemed obvious that a specific HDAC11 inhibitor would specifically target tumor cells, where this enzyme appears to play a critical role," says Dr. Hedwig Deubzer, first author of the article.

As there are no specific HDAC11 inhibitors available yet, the team took a different approach to verify their hypothesis. Using molecular techniques, they turned off production of HDAC11 in breast, colon, prostate and ovarian cancer cell lines and likewise in control cells of healthy tissues. The result: Cancer cells without HDAC11 were impaired in viability and more often underwent cell death (apoptosis). By contrast, loss of HDAC11 did not cause any noticeable changes in normal cells.

"The result suggests that selective blocking of HDAC11 would act exclusively on tumor cells," says Hedwig Deubzer. Numerous highly specific inhibitors against various cancer-relevant enzymes have been developed in recent years, with some of them already approved as drugs. This encourages the Heidelberg research team, jointly with Bayer Healthcare, to look for a suitable substance that specifically targets HDAC11.

HDAC inhibitors belong to a group of drugs classified by researchers as "epigenetically effective" drugs. These agents influence the chemical tags that a cell attaches directly to the genetic material or to the packaging proteins of genetic material such as histones. These tags play a substantial role in regulating gene activity. In the past few years, evidence has been accumulating that epigenetic tagging defects promote cancer development. Novel agents such as HDAC inhibitors are intended to correct such defects.
-end-
Hedwig E. Deubzer, Marie C. Schier, Ina Oehme, Marco Lodrini, Bernard Haendler, Anette Sommer and Olaf Witt: HDAC11 is a novel drug target in carcinomas. International Journal of Cancer 2012, DOI:10.1002/ijc.27876

The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 2,500 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg where promising approaches from cancer research are translated into the clinic. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. The center is a member of the Helmholtz Association of National Research Centers. Ninety percent of its funding comes from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.

Dr. Stefanie Seltmann
Head of Press and Public Relations
German Cancer Research Center
Im Neuenheimer Feld 280
D-69120 Heidelberg
T: 49-622-142-2854
F: 49-622-142-2968

Helmholtz Association

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.