MIT team found how melanoma evades chemotherapy

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.