Nitric oxide is a gas with many biological functions
in a healthy cells, and can also help some cancer cells survive chemotherapy. A
new study from MIT reveals one way in which this resistance may arise, and
raises the possibility of weakening cancer cells by cutting off their supply of
NO.
The findings of the research are presented this week
at the annual meeting of the American Association for Cancer Research, focus on
melanoma. The melanoma is a cancer that is difficult to treat, especially in
its later stages. The prognosis is generally worse for patients whose tumors
have high levels of NO.
According to Luiz Gody, an MIT research associate, he
and his colleagues have unraveled the mechanism behind the melanoma's
resistance to cisplatin. The Cisplatin is a commonly used chemotherapy drug,
and, in ongoing studies, have found that Cisplatin treatment also increases NO
levels in breast and colon cancers. The conclusion of the team is that this
could be an mechanism that is widley shared in different cancers, and if you
use the druges that are already used to treat cancer, along with other drugs
that could scavange or decrease the production of NO, you may have synergistic
effect.
NO gas has many roles in living cells. At low
concentrations it helps regulate processes such as a cell death and muscle
contraction. NO, which is a free radical is very important for immune system
function. Immune cells, such as macrophages produce large amounts of NO during
infection and in that way helping to kill invading microbes by damiging thir DN
or other cell components.
Lowering the concentration of NO
In the MIT study, the researchers treated melanoma
cells, which are grown in lab, with drugs that capture NO before it can act.
Once they got rid of NO they treated cells of melanoma with Cisplatin and
tracked cell death rates. The melanoma cells without NO became much more
sensitive to the drug.
The next step in MIT research was to investigate how
NO confers its survival benefits. It's already known that NO can alter protein
function through a process known as S-nitrostation, which involves attaching NO
to the target protein. S- nitrostation can affect many proteins, but in this
study the researchers focused on two that are strongly linked with cell death
and survival, known as capase-3 and PHD2. The role of caspase-3 is to stimulate
cell suicide, under the appropriate conditions, but adding NO to the protein
deactivates it. This prevents the cell from dying even when treated with
cisplatin, a drug that produces massive DNA damage. PHD2 is also involved in cell death; its role
is to help break down another protein called HIF-1 alpha, which is a
pro-survival protein. When NO inactivates PHD2, HIF-1 alpha stays intact and
keeps the cell alive.
The MIT researchers also found in some cancer cells,
NO levels were five times higher than normal following cisplatin treatment.
Godoy is now investigating how cisplatin stimulates that NO boost, and is also
looking for other proteins that NO may be targeting. Researchers in Wogan’s lab
also plan to start testing cisplatin in combination with drugs that block NO
production in animals.The research was funded by the National Cancer Institute
and the National Institute of Environmental Health Sciences. The research team
also published its findings in a November 2012 article in the Proceedings of
the National Academy of Sciences.
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