Curcumin derivatives: Molecular basis of their anti-cancer activity |
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Authors: | Valentina Basile Sandra Lazzari Francesca Pignedoli |
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Institution: | a Dipartimento di Biologia Animale, Università di Modena e Reggio Emilia, via Campi 213/D, 41100 Modena, Italy b Dipartimento di Chimica, Università di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy |
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Abstract: | Curcumin, a phenolic compound from the plant Curcuma longa L., has shown a wide-spectrum of chemopreventive, antioxidant and antitumor properties. Although its promising chemotherapeutic activity, preclinical and clinical studies highlight Curcumin limited therapeutic application due to its instability in physiological conditions. To improve its stability and activity, many derivatives have been synthesized and studied, among which bis-DemethoxyCurcumin (bDMC) and diAcetylCurcumin (DAC). In this report, we show that both bDMC and DAC are more stable than Curcumin in physiological medium. To explore the mechanism of their chemotherapeutic effect, we studied their role in proliferation in the HCT116 human colon cancer cells. We correlated kinetic stability and cellular uptake data to their biological effects. Both bDMC and DAC impair correct spindles formation and induce a p53- and p21CIP1/WAF1-independent mitotic arrest, which is more stable and long-lasting for bDMC. A subsequent p53/p21CIP1/WAF1-dependent inhibition of G1 to S transition is triggered by Curcumin and DAC as a consequence of the mitotic slippage, preventing post-mitotic cells from re-entering the cell cycle. Conversely, the G1/S arrest induced by bDMC is a direct effect of the drug and concomitant to the mitotic block. Finally, we demonstrate that bDMC induces rapid DNA double-strand breaks, moving for its possible development in anti-cancer clinical applications. |
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Keywords: | bDMC bis-DemethoxyCurcumin DAC diAcetylCurcumin MIT microtubule-targeting agents BrdU bromodeoxyuridine PI propidium iodide DMSO dimethylsulfoxide DSB double-strand break FACS Fluorescence Activated Cell Sorter ChIP Chromatin immunoprecipitation ATM Ataxia Telangiectasia Mutated ATR ATM and Rad3-related |
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