Michael B. Kastan, MD, PhD

New way to reduce incidence of diabetes, heart disease

A drug commonly used to treat malaria shows significant potential as a treatment for one of the most common health problems of modern industrial society, according to researchers at St. Jude and Washington University.

The disease, called metabolic syndrome, afflicts up to one in four American adults and sharply increases their risk of developing type 2 diabetes and clogged arteries. The range of symptoms includes obesity, insulin resistance, high blood pressure, low levels of good cholesterol and high blood sugar levels. The occurrence of metabolic syndrome is increasing not only in industrialized countries, but also in developing countries such as India and China as people there adopt Western living standards, the researchers said.

The St. Jude/Washington University team demonstrated in mouse models of metabolic syndrome that the malaria drug chloroquine reduced blood pressure, decreased hardening and narrowing of the arteries and improved blood sugar tolerance. A report on these findings appears in the November issue of Cell Metabolism.

"There is already a great deal of information about the use of chloroquine in humans that shows it is safe and well-tolerated,” said Michael Kastan, MD, PhD, Cancer Center director and a co-author of the article. “The results of our mouse model studies suggest that we could provide people with the same benefits using very low and perhaps infrequent doses of such a drug.”
 
The key to chloroquine’s effectiveness arises from its link to a protein called ATM, which is known better among scientists for its role in the cell’s response to stress and repair of DNA.  ATM is mutated in the rare genetic disorder ataxia-telangiectasia (AT), and individuals with this disease have markedly increased risk of tumors, immunological problems and severe progressive deterioration of a part of their brain that controls muscle function and coordination. Kastan’s lab previously showed how ATM is activated following DNA damage; the recent metabolic syndrome studies were undertaken because of the researchers’ discoveries that insulin signals through the ATM enzyme and that chloroquine activates ATM.

St. Jude/Washington University team demonstrated that the ATM enzyme is important for many of the beneficial effects of insulin and that loss of ATM worsens blood sugar control, high blood pressure and atherosclerosis.

Following the studies in mice, a small pilot clinical trial of chloroquine use in patients with symptoms of metabolic syndrome at Washington University showed promising results; a larger trial will get underway soon. Melissa Hudson, MD, Cancer Survivorship director; Les Robison, PhD, Epidemiology and Cancer Control chair; and colleagues in the St. Jude Cancer Prevention and Control Program have also found that survivors of childhood cancer have a high frequency of metabolic syndrome when they get older. The study’s findings may also lead to a useful treatment option for these patients.

The paper’s other St. Jude authors are Kirsteen Maclean, PhD, Oncology, and former employee Masatoshi Takagi.

November 2006

St. Jude does both laboratory and clinical research in order to find cures for catastrophic diseases of children. Much of this research, especially in the laboratory, leads to discoveries of the basic workings of the body's cells. Therefore, some of our work has broader implications than childhood diseases and provides insights into adult diseases as well.

 


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