Anti-malaria drug chloroquine finding may lead to treatments for arthritis, cancer and other diseases

ScienceDaily (July 18, 2011) — In a study published recently in the journal Science Signaling, Van Andel Research Institute (VARI) scientists demonstrate on the molecular level how the anti-malaria drug chloroquine represses inflammation, which may provide a blueprint for new strategies for treating inflammation and a multitude of autoimmune diseases such as arthritis, multiple sclerosis, … Continue reading “Anti-malaria drug chloroquine finding may lead to treatments for arthritis, cancer and other diseases”

ScienceDaily (July 18, 2011) — In a study published recently in the journal Science Signaling, Van Andel Research Institute (VARI) scientists demonstrate on the molecular level how the anti-malaria drug chloroquine represses inflammation, which may provide a blueprint for new strategies for treating inflammation and a multitude of autoimmune diseases such as arthritis, multiple sclerosis, and certain cancers.

Chloroquine is a widely used anti-malaria drug that inhibits the growth of parasites. For decades, chloroquine and its derivative amodiaquine have also been used as anti-inflammation drugs to treat diseases such as rheumatoid arthritis, though the exact mechanism of how chloroquine affects the immune system has remained unclear.

By providing an understanding of these basic functions, researchers may now have the necessary tools to develop improved treatments for a myriad of common autoimmune disorders.

“The implications of this study are significant,” said Henry F. McFarland, Ph.D., former Chief of the Neuroimmunology Branch of the National Institute of Neurological Disorders and Stroke (NINDS). “These results provide a mechanistic basis for therapeutic strategies for treating inflammation and autoimmune diseases and should provide exciting new approaches which can be tested in clinical trials.”

Autoimmune diseases arise when the body’s immune system mistakes otherwise healthy cells, tissues, and organs for pathogens and attacks them. These diseases can afflict any part of the body, but one symptom common to most autoimmune diseases is that of inflammation.

The National Institutes of Health (NIH) lists more than 80 common autoimmune diseases including asthma, Crohn’s disease, Guillain-Barré syndrome, multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis, and some types of cancers among many others.

Dr. H. Eric Xu, Head of the VARI Center for Structural Biology and Drug Discovery, and his colleagues showed that chloroquine represses inflammation through synergistic activation of glucocorticoid signaling. Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor present in almost every vertebrate animal cell. They are among the most potent and effective agents for treating inflammation and autoimmune diseases.

Synthetic glucocorticoids are used for treating asthma, allergies, and rheumatoid arthritis. Since glucocorticoids also interfere with some of the abnormal mechanisms in cancer cells, they are also used in high doses to treat certain cancers such as leukemia and lymphoma. However, at therapeutic dosages, glucocorticoids can cause a range of debilitating side effects including diabetes, osteoporosis, skin atrophy, and growth retardation.

“The discovery and development of novel uses of glucocorticoids that retain their beneficial therapeutic effects but reduce undesired adverse side effects remains a major medical challenge,” said VARI Research Scientist Yuanzheng He, Ph.D., lead author of the study.

The VARI research revealed an unexpected regulation of glucocorticoid signaling by lysosomal functioning. Lysosomes are organelles found in animal cells that use enzymes to break down waste materials and cellular debris.

Researchers found that they could mimic the effect of chloroquine by inhibiting lysosomes in the cell. They believe that the development of new therapies for treating inflammation and autoimmune disease will involve strategies that combine both glucocorticoid and lysosomal inhibitors.

“We have known for some time that both steroids and lysosomes affect the immune system, but we didn’t know that they worked together,” said VARI President and Research Director Jeffrey Trent, Ph.D. “Researchers now have a clear path forward for undertaking projects to develop glucocorticoid and lysosomal inhibitors, and to improve the efficacy and potency of chloroquine as a therapeutic agent.”


Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Van Andel Research Institute.


Journal Reference:

  1. Y. He, Y. Xu, C. Zhang, X. Gao, K. J. Dykema, K. R. Martin, J. Ke, E. A. Hudson, S. K. Khoo, J. H. Resau, A. S. Alberts, J. P. MacKeigan, K. A. Furge, H. E. Xu. Identification of a Lysosomal Pathway That Modulates Glucocorticoid Signaling and the Inflammatory Response. Science Signaling, 2011; 4 (180): ra44 DOI: 10.1126/scisignal.2001450

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Esophageal cancer risk higher in medically treated GERD patients with fewest symptoms

ScienceDaily (July 18, 2011) — Medically treated patients with mild or no symptoms of gastroesophageal reflux disease (GERD) are at higher risk for developing esophageal cancer than those with severe GERD symptoms, according to a University of Pittsburgh study published in the current issue of Archives of Surgery.

Many patients who develop adenocarcinoma, a common form of esophageal cancer, are unaware that they have Barrett’s esophagus — a change in the cells lining the esophagus often due to repeated stomach acid exposure. In some cases, Barrett’s esophagus develops into esophageal cancer.

“Typically, patients with severe GERD symptoms are screened for Barrett’s esophagus, but those with mild or absent symptoms are not. Unfortunately, many patients who develop adenocarcinoma don’t know that they have Barrett’s esophagus until it has transformed into cancer and become advanced, leading to obstruction,” said principal investigator Blair A. Jobe, M.D., professor and director of esophageal research and esophageal diagnostics and therapeutic endoscopy, Department of Cardiothoracic Surgery, Pitt School of Medicine.

The study included 769 GERD patients who presented for their first upper endoscopy, in which a flexible endoscopic camera is guided through the esophagus and stomach to look for tissue changes. Participants were separated into three groups: patients who were referred for upper endoscopy for any clinical indication regardless of symptoms; patients with typical GERD symptoms, such as heartburn, regurgitation and difficulty swallowing; and patients with atypical GERD symptoms, such as hoarseness, throat-clearing, mucus, coughing and a lump sensation in the throat.

All study participants underwent endoscopy and completed questionnaires and a detailed medication history. Endoscopy revealed that 122 of these patients, or 15.9 percent, had Barrett’s esophagus or adenocarcinoma. Patients who were adequately managing their GERD symptoms with proton pump inhibitors (PPIs) were 61 percent more likely to have Barrett’s esophagus or adenocarcinoma if they reported no severe GERD symptoms, compared to patients taking PPIs who reported severe symptoms. Patients with severe GERD symptoms often experienced irritation or swelling of the esophagus, but that was associated with decreased odds of having esophageal cancer.

“Our research indicates that even patients without severe symptoms may benefit from Barrett’s esophagus screening,” Dr. Jobe noted. “If GERD patients are screened early enough, there is a better chance that Barrett’s esophagus can be identified before it becomes cancerous,” he stated. “We are learning that the chronic and long-term use of PPIs may not be entirely without consequences and may lead to more insidious problems such as calcium malabsorption or cause one to be asymptomatic in the face of continued esophageal injury from GERD.”

Dr. Jobe and his Pitt colleagues have established the Barrett’s Esophagus Risk Consortium (BERC), in which primary care patients are being screened with in-office, small-caliber, unsedated endoscopy in an attempt to better understand risk factors for the condition as well as lower the threshold for screening. The multicenter effort is funded by the National Institutes of Health.

Study co-authors include Katie S. Nason, M.D., M.P.H., Omar Awais, M.D., Matthew J. Schuchert, M.D., and James D. Luketich, M.D., all from Pitt; and Promporn Paula Wichienkuer, M.D., M.P.H., Robert W. O’Rourke, M.D., John G. Hunter, M.D., and Cynthia D. Morris, Ph.D., M.P.H., all from Oregon Health and Science University.

The study was funded by the Robert Anthony McHugh Research Fund for the Prevention and Early Detection of Esophageal Cancer, David Gold and Irene Blumenkrantz Esophageal Cancer Research Fund, the Sampson Family Endowed Chair, the UPMC Heart, Lung and Esophageal Surgery Institute, the American Surgical Association Foundation Fellowship Award and grants from the National Institutes of Health.


Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Pittsburgh Schools of the Health Sciences, via EurekAlert!, a service of AAAS.


Journal Reference:

  1. Katie S. Nason; Promporn Paula Wichienkuer; Omar Awais; Matthew J. Schuchert; James D. Luketich; Robert W. O’Rourke; John G. Hunter; Cynthia D. Morris; Blair A. Jobe. Gastroesophageal Reflux Disease Symptom Severity, Proton Pump Inhibitor Use, and Esophageal Carcinogenesis. Archives of Surgery., 2011; 146 (7): 851-858 DOI: 10.1001/archsurg.2011.174

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Melanoma screening by physicians associated with finding more cancers than patient self-detection

ScienceDaily (July 18, 2011) — Physician-based screening for melanoma is associated with higher rates of physician-detected melanoma and detection of thinner melanoma, according to a report published Online First by Archives of Dermatology, one of the JAMA/Archives journals.

The disease-specific survival rate for advanced-stage melanoma is poor, so detecting the cancer in an earlier stage is the best means to ensure a favorable prognosis, according to background information in the article. Previous research has demonstrated that patients find most melanomas, and that those lesions tend to be thicker than physician-detected lesions. “Working on the premise that physician-based screening and patient self-screening are vital in the detection of early melanoma,” explain the authors, “we compared melanoma characteristics in patients new to our practice vs. established patients in the pigmented lesions clinic (PLC) at Memorial Sloan-Kettering Cancer Center” (MSKCC) in New York City.

Ivanka Kovalyshyn, D.O., from MSKCC, and colleagues conducted a retrospective review of patient records and biopsy logs from two MSKCC pigmented lesion specialists from January 1998 through December 2008. The institution’s PLC serves patients at high risk for developing melanoma, so each patient visit involves a total body skin examination, and patients are given brochures instructing them how to perform skin self-examination (SSE). Researchers divided the group into “established” patients, who had been treated at MSKCC’s PLC for three months or more, and “new” patients who were new to the practice.

A total of 527 melanomas were identified in 394 patients. Among the established group, lesions tended to be thinner, more often detected in the in situ phase and less likely to exhibit negative prognostic attributes. Physicians detected 82 percent of melanomas in established patients and 63 percent in new patients. The overall patient-detection rate was 18 percent, and most lesions found by patients were detected because of change in appearance.

“Although we recognized that high-risk patients may have more frequent physician skin examinations and may be more vigilant in performing SSE, we strongly believe that the PLC setting contributes to earlier detection of melanoma in our cohort,” the authors write. They do note that the patient’s role in melanoma recognition is important as well. “Therefore,” they conclude, “it is crucial to emphasize that a combined strategy of physician detection and patient participation must continue to be implemented to ensure early melanoma diagnosis.”


Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by JAMA and Archives Journals.


Journal Reference:

  1. Ivanka Kovalyshyn; Stephen W. Dusza; Katherine Siamas; Allan C. Halpern; Giuseppe Argenziano; Ashfaq A. Marghoob. The Impact of Physician Screening on Melanoma Detection. Archives of Dermatology, 2011; DOI: 10.1001/archdermatol.2011.181

Note: If no author is given, the source is cited instead.

Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.