Abstract
The NF-κB signaling pathway is activated in many colorectal cancer (CRC) cells and in the tumor microenvironment, which plays a critical role in cancer initiation, development, and response to therapies. We found in the present study that the widely used antimalarial drug mefloquine was a NF-κB inhibitor that blocked the activation of IκBα kinase, leading to the reduction of IκBα degradation, decrease of p65 phosphorylation, and suppressed expression of NF-κB target genes in colorectal cancer cells. We also found that mefloquine induced growth arrest and apoptosis of colorectal cancer cells harboring phosphorylated p65 in culture and mice. Furthermore, expression of constitutive active IKKβ kinase significantly attenuated the cytotoxic effect of the compound. These results demonstrated that mefloquine could exert anti-tumor action through inhibiting the NF-κB signaling pathway, and indicated that the antimalaria drug might be re-purposed for anti-CRC therapy in clinic as a single agent or in combination with other anti-cancer drugs.
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