An elevated level of
copper (Cu), which is necessary for the growth and
metastasis of
tumor cells, has been found in many types of
cancer, including breast, prostate, lung and brain. Although its molecular basis is unclear, this
tumor-specific Cu elevation has been proposed to be a novel target for developing selective anti-
cancer therapies. We previously reported that
8-hydroxylquinoline (8-OHQ) is able to form a Cu complex that inhibits the
proteasome and induces apoptosis in cultured
cancer cells. Toward the goal of discovering novel 8-OHQ analogs as potential anti-
copper and anti-
cancer drugs, in the current study we synthesized several 8-OHQ analogs and their
copper complexes and evaluated their biological activities in human
breast cancer cells. We report that when substitutions are made on the
hydroxyl group of 8-OHQ, their
copper mixtures have profound effects on the
proteasome-inhibitory and apoptosis-inducing abilities in
breast cancer MDA-MB-231 cells. In addition, the
proteasome-inhibitory and apoptosis-inducing activities of 8-OHQ analog-
copper mixtures are determined by both the polarity and position of the substituents. Finally, a synthetic complex of 8-OHQ analog-
copper was able to inhibit the
proteasome activity, induce cell death and suppress the growth selectively in
breast cancer MDA-MB-231 cells, but not in normal immortalized human breast MCF-10A cells. Our results support the concept that human
cancer cells and tissues, which contain an elevated
copper level and are highly dependent on
proteasome activity for their survival, should be sensitive to treatment with anti-
copper drugs such as the novel 8-OHQ analogs described here.