Although
curcumin suppresses the growth of a variety of
cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an
anticancer agent. In this study, we show that
dimethoxycurcumin (DMC), a methylated, more stable analog of
curcumin, is significantly more potent than
curcumin in inducing cell death and reducing the clonogenicity of malignant
breast cancer cells. Furthermore, DMC reduces the
tumor growth of xenografted MDA-MB 435S cells more strongly than
curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to
curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than
curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the
protein levels of
CCAAT-enhancer-binding protein homologous
protein (CHOP) and Noxa, and the
small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP
protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in
breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger
proteasome inhibition and higher induction of CHOP compared with
curcumin, giving it more potent anticancer effects on malignant
breast cancer cells.