New hope for cancer comes straight from the heart

January 06, 2009

Johns Hopkins researchers discover new use for digoxin

Digitalis-based drugs like digoxin have been used for centuries to treat patients with irregular heart rhythms and heart failure and are still in use today. In the Dec. 16 issue of the Proceedings of the National Academy of Sciences, researchers at the Johns Hopkins University School of Medicine now report that this same class of drugs may hold new promise as a treatment for cancer. This finding emerged through a search for existing drugs that might slow or stop cancer progression.

"This is really exciting, to find that a drug already deemed safe by the FDA also can inhibit a protein crucial for cancer cell survival," says Gregg L. Semenza, M.D., Ph.D., director of the vascular program at the Johns Hopkins Institute for Cell Engineering and a member of the McKusick-Nathans Institute of Genetic Medicine.

Semenza and his team have long studied the hypoxia-inducible factor, or HIF-1, protein, which controls genes that help cells survive under low-oxygen conditions. HIF-1 turns on genes that grow new blood vessels to help oxygen-starved cells survive. Regions of low oxygen are common within the environment of fast-growing solid tumors.

"Oxygen-deprived cancer cells increase their HIF-1 levels to survive in these unfavorable conditions," says Semenza. "So turning down or blocking HIF-1 may be key to slowing or stopping these cells from growing."

The researchers took advantage of the Johns Hopkins Drug Library, a collection of more than 3,000 drugs already FDA approved or currently being tested in phase II clinical trials, assembled by Hopkins pharmacology professor Jun O. Liu. In this study, the research team tested every drug in the library for its ability to turn down HIF-1in cancer cells. The top 20 candidates identified were able to reduce HIF-1 by more than 88 percent, and more than half of these 20 belong to a class of drugs already commonly used for treating heart failure, and included digoxin.

The researchers focused on digoxin because of its already well-established clinical use. They treated prostate cancer cells grown at normal and low-oxygen levels with digoxin for three days and counted the number of cells each day. They found that cells treated with digoxin significantly slowed their growth, with fewer total cells after three days and increased numbers of cells that had stopped growing when compared to untreated cells.

"Many drugs may appear promising when used to treat cancer cells in a dish in the lab, but may have little or no effect on tumors in living animals," says Huafeng Zhang, Ph.D., a research associate in the Department of Oncology and the Institute for Cell Engineering at Hopkins.

To see if digoxin had the same effect on cancer cells in the physiological context of a whole animal, the team administered daily injections of digoxin to mice with tumors. In untreated mice, tumors were large enough to be felt within nine days, but in treated mice, tumors could first be felt only after as long as 15 to 28 days. The team then examined tumors from the mice and found that HIF-1 levels were lower than tumors from untreated mice. The team then went on to show that it is digoxin specifically reducing HIF-1 that leads to the anti-tumor results they saw.

While Zhang thinks it is possible that drugs like digoxin could someday be used for treating cancer, she cautions that a great deal of work remains to be done to understand in detail how these drugs inhibit HIF-1 and slow or stop tumor growth. Also, since this class of drugs acts by both strengthening and slowing down the rhythm of the heart, she notes that patients can safely tolerate them in only a limited dosage range-a range that is lower than the concentrations of digoxin used in this study. "We're trying to kill a tumor," she says, "We don't want to stop a heart."

Johns Hopkins Medical Institutions

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	The Third Element: Actinidic Archaea, Digoxin and the Biological Universe by Ravikumar A. Kurup (Editor), Parameswara Achutha Kurup (Editor) An actinide dependent shadow biosphere of archaea and viroids in disease states is described with archaeal digoxin playing a pathological role. Archaeal digoxin can produce neuro-immuno-endocrine-genetic-metabolic integration. Archaeal digoxin by producing sodium-potassium ATPase inhibition can generate synchronised sustained burst activity in neuronal cells resulting in a electromagnetic field and a plasma state in the cell. This can generate cellular and molecular electromagnetic traces important in signal transduction and quantal perception. Metal actinides in beach sands have been postulated to play a role in abiogenesis. A hypothesis of cholesterol as the primal prebiotic molecule synthesised on actinide surfaces with all other biomolecules arising from it and a self replicating...
	Hypothalamic Digoxin, Cerebral Dominance and Brain Function in Health and Diseases (Nova Biomedical) by Ravikumar Kurup (Author), Parameswaran Achutha Kurup (Author) The human hypothalamus produces endogenous membrane, sodium potassium ATPase inhibitor digoxin. The isoprenoid pathway synthesizes digoxin. The other products of the isoprenoid pathway are - dolichol, ubiquinone and cholesterol. Hemispheric chemical dominance can be related to the isoprenoid pathway and digoxin synthesis. In right hemispheric chemical dominance there is an unregulated isoprenoid pathway and elevated digoxin synthesis. In left hemispheric chemical dominance there is a downregulated isoprenoid pathway and decreased digoxin synthesis. This book examines digoxin via its modulation of membrane, sodium potassium ATPase that can regulate neurotransmitter transport, immunity and all aspects of cellular organelle function - mitochondrial, golgi body, lysosomal and nuclear. It can...
	The Nurses Are Innocent: The Digoxin Poisoning Fallacy by Dundurn In 1980–81, 43 babies died at Toronto's Hospital for Sick Children from a supposed digoxin overdose. Serial murder was suspected, leading to the arrest of nurse Susan Nelles. In order to clear Nelles's name, an investigation was launched to find an alternate explanation. No one on the Grange Royal Commission of Inquiry had expertise in diagnosis. The post-mortem diagnosis of digoxin poisoning was based on a single biochemical test without knowledge of the normal values. Gavin Hamilton's extensive research shows that a toxin found in natural rubber, a digoxin-like substance, might well have been the culprit in the babies' deaths. He clearly demonstrates that explanations other than serial murder account for the cluster of infant deaths at HSC. What can be learned from this black stain...
	Digoxin's benefits in severe heart failure often overlooked: DIG trial 'constantly misquoted'. (Cardiovascular Medicine).(Digitalis Investigation Group): An article from: Internal Medicine News by Bruce Jancin (Author) This digital document is an article from Internal Medicine News, published by International Medical News Group on July 1, 2003. The length of the article is 509 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Digoxin's benefits in severe heart failure often overlooked: DIG trial 'constantly misquoted'. (Cardiovascular Medicine).(Digitalis Investigation Group) Author: Bruce Jancin Publication: Internal Medicine News (Magazine/Journal) Date: July 1, 2003 Publisher: International Medical News Group Volume: 36 Issue: 13 Page: 25(1) Distributed by Thomson...
	Standard digoxin nomogram can lead to deadly overdoses in HF.(Cardiovascular Medicinelimb ischemia.)(Heart failure): An article from: Internal Medicine News by Mitchel L. Zoler (Author) This digital document is an article from Internal Medicine News, published by International Medical News Group on March 1, 2005. The length of the article is 502 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Standard digoxin nomogram can lead to deadly overdoses in HF.(Cardiovascular Medicinelimb ischemia.)(Heart failure) Author: Mitchel L. Zoler Publication: Internal Medicine News (Magazine/Journal) Date: March 1, 2005 Publisher: International Medical News Group Volume: 38 Issue: 5 Page: 62(1) Distributed by Thomson...
	Using standard digoxin nomogram can lead to deadly overdoses.(Cardiovascular Medicine): An article from: Family Practice News by Mitchel L. Zoler (Author) This digital document is an article from Family Practice News, published by International Medical News Group on May 1, 2005. The length of the article is 484 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Using standard digoxin nomogram can lead to deadly overdoses.(Cardiovascular Medicine) Author: Mitchel L. Zoler Publication: Family Practice News (Magazine/Journal) Date: May 1, 2005 Publisher: International Medical News Group Volume: 35 Issue: 10 Page: 19(1) Distributed by Thomson...
	Combo of [beta]-blocker plus digoxin affirmed in atrial fibrillation.(Cardiovascular Medicine): An article from: Family Practice News by Bruce Jancin (Author) This digital document is an article from Family Practice News, published by Thomson Gale on September 15, 2005. The length of the article is 655 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Combo of [beta]-blocker plus digoxin affirmed in atrial fibrillation.(Cardiovascular Medicine) Author: Bruce Jancin Publication: Family Practice News (Magazine/Journal) Date: September 15, 2005 Publisher: Thomson Gale Volume: 35 Issue: 18 Page: 20(1) Distributed by Thomson...
	MI: physician overdosed patient on digoxin: court rules "discovery rule" applied.(Medical Law Cases of Note)(Dr. Harry Colfer and Cardiac professional ... An article from: Medical Law's Regan Report by A. David Tammelleo (Author) This digital document is an article from Medical Law's Regan Report, published by Thomson Gale on September 1, 2005. The length of the article is 611 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: MI: physician overdosed patient on digoxin: court rules "discovery rule" applied.(Medical Law Cases of Note)(Dr. Harry Colfer and Cardiac professional Group) Author: A. David Tammelleo Publication: Medical Law's Regan Report (Magazine/Journal) Date: September 1, 2005 Publisher: Thomson Gale Volume: 38 Issue: 9 Page: 3(1) Distributed by Thomson...
	Cochrane review finds use for digoxin in heart failure.(Cardiovascular Medicine): An article from: Family Practice News by Bruce Jancin (Author) This digital document is an article from Family Practice News, published by International Medical News Group on November 15, 2005. The length of the article is 436 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Cochrane review finds use for digoxin in heart failure.(Cardiovascular Medicine) Author: Bruce Jancin Publication: Family Practice News (Magazine/Journal) Date: November 15, 2005 Publisher: International Medical News Group Volume: 35 Issue: 22 Page: 13(1) Distributed by Thomson...
	Cochrane review finds role for digoxin in heart failure.(Cardiovascular Medicine): An article from: Internal Medicine News by Bruce Jancin (Author) This digital document is an article from Internal Medicine News, published by Thomson Gale on October 1, 2005. The length of the article is 470 words. The page length shown above is based on a typical 300-word page. The article is delivered in HTML format and is available in your Amazon.com Digital Locker immediately after purchase. You can view it with any web browser. Citation Details Title: Cochrane review finds role for digoxin in heart failure.(Cardiovascular Medicine) Author: Bruce Jancin Publication: Internal Medicine News (Magazine/Journal) Date: October 1, 2005 Publisher: Thomson Gale Volume: 38 Issue: 19 Page: 64(1) Distributed by Thomson...