June 17, 2008 A novel small molecule inhibitor reduced both endogenous and drug-induced resistance to chemotherapy in a mouse model of melanoma.
The NF-κB pathway is often active in human cancers and promotes resistance to cytotoxic chemotherapy drugs. Some cytostatic drugs, such as doxorubicin, induce NF-κB pathway activity.
To determine if a new inhibitor of the pathway, called KINK-1, could overcome this resistance, Michael Schön, M.D., of the University Medical Center Göttingen in Germany and colleagues injected mice with melanoma cells and then treated them with doxorubicin and KINK-1.
They found that mice treated with a combination of the two drugs developed smaller lung metastases than mice treated with either agent alone.
"Based on our observation that the compound suppressed constitutive NF-κB activation and NF-κB activation induced by cytostatics or inflammatory agents, KINK-1 appears to be a universal inhibitor of NF-κB activation in melanoma cells, regardless of the mode of activation," the authors write.
In an accompanying editorial, John Kirkwood, M.D., of the University of Pittsburgh Medical Center and University of Pittsburgh Cancer Institute and colleagues review the biology of NF-κB and its impact on melanoma cells. Other inhibitors of the pathway have been tried in melanoma and did not prove successful. The KINK-1 inhibitor blocks the pathway in a different manner and may have a bigger impact on the disease, though that must be tested in a clinical trail. "These new agents may be most beneficially combined with chemotherapeutic agents to which melanoma has been refractory in the past," the editorialists conclude.
This research was recently published in the Journal of the National Cancer Institute.
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