Abstract
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.
Highlights
Curcumin has demonstrated selective killing of various cancer cell types, while sparing normal cells.[2,3,4] Despite the cancer-selective cytotoxic effects of curcumin, its clinical use has been limited by poor systemic bioavailability, poor absorption, rapid metabolism and conjugation in the gastrointestinal tract.[5]
We provide evidence suggesting that the ability of DMC to effectively induce paraptosis via potent proteasomal inhibition and CCAAT-enhancer-binding protein homologous protein (CHOP) upregulation may be responsible for its improved anticancer effects on malignant breast cancer cells, compared with curcumin
These results indicate that DMC demonstrates more potent anticancer effects than curcumin when tested on breast cancer cells in vitro and in vivo
Summary
Curcumin has demonstrated selective killing of various cancer cell types, while sparing normal cells.[2,3,4] Despite the cancer-selective cytotoxic effects of curcumin, its clinical use has been limited by poor systemic bioavailability, poor absorption, rapid metabolism and conjugation in the gastrointestinal tract.[5]. ALG-2-interacting protein X (Alix) has been identified as an inhibitor of paraptosis.[3,14,21,22,23] In addition, mitogenactivated protein (MAP) kinase activation has been associated with paraptosis induced by insulin-like growth factor I receptor,14 1-nitropyrene,[23] paclitaxel,[24] curcumin,[3,19] celastrol[25] and yessotoxin,[26] the importance of the respective MAP kinase differs depending on the stimulus.[3,14,20,23,24,25,26] We recently showed that proteasomal dysfunction and the generation of mitochondrial superoxide are critical for the curcumin-induced dilation of mitochondria and/or the ER and subsequent paraptotic cell death in breast cancer cells.[3] In this study, we provide evidence suggesting that the ability of DMC to effectively induce paraptosis via potent proteasomal inhibition and CCAAT-enhancer-binding protein homologous protein (CHOP) upregulation may be responsible for its improved anticancer effects on malignant breast cancer cells, compared with curcumin
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