The notorious poison arsenic does have some medical applications. Specifically, a form called arsenic trioxide has been used as a therapy for a particular type of leukemia for more than 10 years. Now researchers at the Stanford University School of Medicine have shown that it may be useful in treating a variety of other cancers.
Over ago Chinese researchers reported that low doses of a compound of the poison – arsenic trioxide – could aid the recovery of patients with acute promyelocytic leukaemia (APL).
APL is a potentially fatal type of cancer that affects the blood and bone marrow.
Combining arsenic with other therapies may give doctors a two-pronged approach to beating back forms of the disease caused by a malfunction in a critical cellular signaling cascade called the Hedgehog pathway. The U.S. Food and Drug Administration has already approved arsenic trioxide for use in humans, which could pave the way for clinical trials of this approach.
“Many pharmaceutical companies are developing anticancer drugs to inhibit the Hedgehog pathway,” said Philip Beachy, PhD, professor of developmental biology and the Ernest and Amelia Gallo Professor in the School of Medicine. In addition, Beachy recently identified an antifungal drug commonly used in humans, itraconazole, as a Hedgehog pathway inhibitor. “However, these compounds target a component of the pathway that can be mutated with patients then becoming resistant to the therapy. Arsenic blocks a different step of the cascade.”
Arsenic trioxide works in relatively low quantities by blocking one of the final steps in the Hedgehog pathway, preventing a few of the cell’s genes being expressed that would otherwise cause runaway, cancerous growth. Other treatments currently on the market also target the Hedgehog pathway, but they do so at much earlier points in the signaling cascade. That gives the malfunctioning pathway many more opportunities to mutate around the drug and relay its self-destructive messages to the cells. The arsenic treatment takes effect so late in the pathway that’s there is nearly no chance for the cancer to mutate around it.
Researchers Philip Beachy and Jynho Kim at the Stanford medical school first became interested in arsenic as a treatment for cancer when they noticed that birth defects brought on by arsenic exposure are very similar to the physical effects of not having an active Hedgehog pathway. They found that the same small amounts of arsenic trioxide that treated leukemia patients could also shut off the Hedgehog pathway, providing a potential treatment for sufferers of many other kinds of cancer.
Arsenic trioxide works by inhibiting a protein called Gli2 from causing gene transcription in the cell nucleus. Without Gli2, the Hedgehog pathway comes to a sudden, ineffectual end. Early tests of this treatment on mice found that most tumors either slowed down or stopped growing completely. Best of all, this works even in cells that have already proven resistant to other drugs that target the Hedgehog pathway.
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September 20th, 2010 at 7:56 pm
In a study on how the body responds to toxins in snake venom, Japanese scientists have reported that their findings could help in the development of therapies for heart disease and cancer.
The researchers claimed that inhibiting a protein found on the surface of blood cells known as platelets may combat both irregular blood clotting and the spread of certain cancers throughout the body.
“The finding that platelets not only play a role in blood clotting but also in the development of vessels that allow tumors to flourish was quite unexpected and paves the way for new research on the role or roles of platelets,” said Katsue Suzuki-Inoue, the associate professor at the University of Yamanashi.
“When a blood clot, or thrombus, forms during the body””s normal repair process, it””s doing its job. But, thrombotic diseases, such as heart attack and stroke, are leading causes of death in developed countries. Understanding and manipulating the underlying chemical reactions could help us save many lives,” said Suzuki-Inoue.
“Snake venom contains a vast number of toxins that target proteins in platelets. Some of those toxins prevent platelets from clotting, which can lead to profuse bleeding in snake bite victims. Others, like the one we””ve focused this research on, potently activate platelets, which results in blood clots. Identification of the molecular targets of many of these toxins has made an enormous contribution to our understanding of platelet activation and related diseases,” said Yonchol Shin, an associate professor at Kogakuin University who specializes in snake toxins.
Intrigued by the then-recent discovery that elements in snake venom can promote irregular aggregation of platelets – the kind that leads to clots and stroke – the researchers set out in 1997 to understand better the molecular underpinnings of those chemical reactions.
In 2000, another set of investigators came across a protein on the surface of platelets and dubbed it C-type lectin-like receptor 2, or CLEC-2.
After six years of research and collaborations with British investigators, the team in 2006 discovered how rhodocytin — a molecule purified from the venom of the Southeast Asia pit viper Calloselasma rhodastoma — binds to the CLEC-2 receptor protein on the platelet surface, spurring the platelet to clot with others like it.
Then, in 2007, the researchers reported how a separate molecule, called podoplanin, binds to the CLEC-2 platelet receptor protein very much like the venom molecule does.
Using a mouse model, the team in 2008 showed that blocking the tumour protein podoplanin from binding with the platelet receptor protein CLEC-2 could prevent tumours from metastasizing to the lung.
The recent investigations hinged on the generation and study of genetically engineered mouse embryos that lacked the platelet receptor protein CLEC-2.
In the end, the experiments showed that CLEC-2 is not only necessary for blood clotting but also necessary for the development of a different type of vessel, specifically lymphatic vessels that carry fluid away from tissues and prevent swelling, or edema.
“During fetal development, the CLEC-2 deficiency disturbed the normal process of blood clotting and, in fact, the normal development and differentiation of blood and lymphatic vessels. They had disorganized and blood-filled lymphatic vessels and severe swelling,” said Masanori Hirashima, an associate professor at Kobe University. ”
Podoplanin is also expressed on the surface of certain types of lymphatic cells and is known to play a role in the development of lymphatic vessels, explained Hirashima.
“These findings suggest that the interaction between CLEC-2 and podoplanin in lymphatic vessels is necessary for the separation between blood vessels and lymphatic vessels,” added Hirashima.
“We speculate that the interaction between the platelet””s CLEC-2 protein and the podoplanin molecule in lymphatic cells plays an essential role in the creation of lymphatic vessels, thereby facilitating tumour growth. If this is the case, a drug that blocks that interaction would prevent the spread of tumours through lymphatic vessels,” said Osamu Inoue, an assistant professor at the University of Yamanashi.
The study has been published in the Journal of Biological Chemistry.