Doxorubicin, a 50-year-old chemotherapy drug still in widespread use against a variety of cancers, has long been known to destroy heart tissue, as well as tumors, in some patients.
Scientists have identified an unexpected mechanism via the enzyme Top2b that drives the drug's attack on heart muscle, providing a new approach for identifying patients who can safely tolerate doxorubicin and for developing new drugs. A team led by scientists at The University of Texas MD Anderson Cancer Center reports its findings about the general DNA-damaging drug today in the journal Nature Medicine.
"Even in this age of targeted therapies, doxorubicin remains an effective agent used mainly in combination with other drugs against a variety of malignancies, including breast, lung, ovarian and bladder cancers, as well as leukemia and lymphoma," said Edward T.H. Yeh, M.D., professor and chair of MD Anderson's Department of Cardiology and senior author of the study.
"However, its use is limited by its cardiotoxicity, which can lead to heart failure," Yeh said. "We're excited because we've identified the molecular basis for doxorubicin's damage to the heart."
A tale of two enzymes
Doxorubicin binds to topoisomerase2 (Top2), an enzyme that controls the unwinding of DNA necessary for cell division.
There are two types of Top2, Yeh said. Top2a is overproduced in cancer cells but largely absent in normal cells. The reverse is true for Top2b, virtually absent in cancer cells but present in normal cells.
Doxorubicin destroys cancer cells by binding to Top2a and to DNA, causing irreparable damage in the form of double-strand DNA breaks. This triggers apoptosis, a cellular suicide mechanism designed to prevent the growth of defective cells.
Yeh and colleagues found that the drug binds to Top2b in cardiomyocytes - heart muscle cells - but it inflicts its damage in a different manner from its attack on cancer cells, yet consistent with longstanding belief about the heart-damaging culprit.
Old suspect: reactive oxygen species
Increases in reactive oxygen species (ROS), highly reactive molecules that contain oxygen, have been observed after doxorubicin treatment. ROS are a normal byproduct of metabolism and play other roles, but at high levels cause cellular damage, a condition called oxidative stress.
ROS damage to cardiomyocytes via the redox cycle - a swapping of electrons to cause either oxidation or reduction of molecules - was hypothesized as the cause of doxorubicin-driven cardiotoxicity. Yet, therapies to directly reduce ROS levels did not prevent heart damage.
"We provide an explanation for the classic observation that doxorubicin generates major ROS, but we show that the entire cardiotoxicity cascade depends on Top2b," Yeh said.
The experimentsThe team developed an inducible mouse model in which treatment with the drug tamoxifen would knock out the Top2b gene only in heart muscle. They found:
Thus, doxorubicin causes heart damage both by inducing DNA double strand breaks and by affecting the heart muscle's metabolism. Both factors are entirely dependent on Top2b.
Clinical study launched to test biomarker potential
The team's mouse model experiments led to a clinical study now under way among two types of cancer patients - those who have received small amounts of doxorubicin and developed heart problems, and those who received large amounts of the drug yet without apparent heart damage.
The study aims to find whether patients' blood levels of Top2b indicate their sensitivity to doxorubicin-induced heart damage. It's funded by a $1.84 million, 5-year grant from the Cancer Prevention and Research Institute of Texas.
If the outcome of the clinical study is as predicted, a simple blood test could indicate who will be sensitive to doxorubicin, Yeh said. Protective measures, such as using cardiac protective drugs or close monitoring, could be taken early in treatment or the drug could be avoided altogether.
Another exciting alternative to avoid doxorubicin-induced cardiotoxicity is to develop drugs that only target Top2a, Yeh said.
"We want to make sure that cancer patients will have healthy hearts to enjoy their life after successful cancer treatment," Yeh said.
Co-authors with Yeh are first author Sui Zhang, M.D., Ph.D., and Tasneem Bawa-Khalfe, Ph.D., both of MD Anderson's Department of Cardiology; Xiaobing Liu, M.D., and Long-Sheng Lu, M.D., Ph.D., of the Texas Heart Institute/St. Luke's Episcopal Hospital in Houston; and Yi Lisa Lyu, Ph.D., and Leroy Liu, Ph.D., of the Robert Wood Johnson Medical School at the University of Dentistry and Medicine of New Jersey. Xiaobing Liu also is affiliated with the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine in Shanghai.
The project was funded by grants from The National Institutes of Health National Cancer Institute (CA102463), the Cancer Prevention and Research Institute of Texas, the Robert and Janice McNair Foundation, the New Jersey Commission on Cancer Research, and the U.S. Department of Defense.
About MD Anderson
The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. MD Anderson is one of only 41 comprehensive cancer centers designated by the National Cancer Institute. For nine of the past 11 years, including 2012, MD Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.
Scott Merville | EurekAlert!
Biofilm discovery suggests new way to prevent dangerous infections
23.05.2017 | University of Texas at Austin
Another reason to exercise: Burning bone fat -- a key to better bone health
19.05.2017 | University of North Carolina Health Care
Staphylococcus aureus is a feared pathogen (MRSA, multi-resistant S. aureus) due to frequent resistances against many antibiotics, especially in hospital infections. Researchers at the Paul-Ehrlich-Institut have identified immunological processes that prevent a successful immune response directed against the pathogenic agent. The delivery of bacterial proteins with RNA adjuvant or messenger RNA (mRNA) into immune cells allows the re-direction of the immune response towards an active defense against S. aureus. This could be of significant importance for the development of an effective vaccine. PLOS Pathogens has published these research results online on 25 May 2017.
Staphylococcus aureus (S. aureus) is a bacterium that colonizes by far more than half of the skin and the mucosa of adults, usually without causing infections....
Physicists from the University of Würzburg are capable of generating identical looking single light particles at the push of a button. Two new studies now demonstrate the potential this method holds.
The quantum computer has fuelled the imagination of scientists for decades: It is based on fundamentally different phenomena than a conventional computer....
An international team of physicists has monitored the scattering behaviour of electrons in a non-conducting material in real-time. Their insights could be beneficial for radiotherapy.
We can refer to electrons in non-conducting materials as ‘sluggish’. Typically, they remain fixed in a location, deep inside an atomic composite. It is hence...
Two-dimensional magnetic structures are regarded as a promising material for new types of data storage, since the magnetic properties of individual molecular building blocks can be investigated and modified. For the first time, researchers have now produced a wafer-thin ferrimagnet, in which molecules with different magnetic centers arrange themselves on a gold surface to form a checkerboard pattern. Scientists at the Swiss Nanoscience Institute at the University of Basel and the Paul Scherrer Institute published their findings in the journal Nature Communications.
Ferrimagnets are composed of two centers which are magnetized at different strengths and point in opposing directions. Two-dimensional, quasi-flat ferrimagnets...
An Australian-Chinese research team has created the world's thinnest hologram, paving the way towards the integration of 3D holography into everyday...
24.05.2017 | Event News
23.05.2017 | Event News
22.05.2017 | Event News
26.05.2017 | Life Sciences
26.05.2017 | Life Sciences
26.05.2017 | Physics and Astronomy