Curcumin derivatives: molecular basis of their anti-cancer activity

Valentina Basile , Erika Ferrari , Sandra Lazzari , Silvia Belluti , Francesca Pignedoli , Carol Imbriano

Curcumin, a phenolic compound from the plant , has shown a wide-spectrum of chemopreventive, anti-oxidant and anti-tumor 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 -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 p21- independent mitotic arrest, which is more stable and long-lasting for bDMC. A subsequent p53/p21- dependent inhibition of G1 to S transition is triggered by Curcumin and DAC as a consequence of the mitotic slippage, preventing postmitotic 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.

Mots clés: Natural compounds; Curcumin analogs; cell cycle regulation; p53; DNA damaging agents; bDMC; DAC; MIT; BrdU; PI; DMSO; DSB; FACS; ChIP; ATM; ATR

Valentina Basile, Erika Ferrari, Sandra Lazzari, Silvia Belluti, Francesca Pignedoli, et al.. Curcumin derivatives: molecular basis of their anti-cancer activity. Biochemical Pharmacology, 2009, 78 (10), pp.1305. ⟨10.1016/j.bcp.2009.06.105⟩. ⟨hal-00522545⟩