Abstract 3556: New curcumin analogues are cytotoxic towards estrogen receptor negative human breast cancer cell lines

Abstract

Abstract There is an urgent need for the development of a safe and efficacious drug therapy for the treatment of estrogen receptor negative breast cancers due to their high malignant nature and poor prognosis. In this study, a series of new heterocyclic monoketo curcumin analogues were synthesized and screened for anticancer activity. Among twenty eight analogues screened in estrogen receptor negative human breast cancer cell-lines MDA-MB-231 (ER-/HER2-), MDA-MB-468 (ER-/HER2-) and SKBr3(ER-/HER2+), the two most potent compounds were designated as RL-71 and RL-66. Cytotoxicity was assessed by sulforhodamine B (SRB) assay. Furthermore, the compounds were studied for their ability to modulate cell cycle progression and induce apoptosis. The mechanism of these drugs was also examined by determining protein expression by Western blot analysis. The results showed that RL-71 and RL-66 had sub micromolar EC50 values in all the cell lines and the cytotoxicity was concentration and time dependent. Mechanistic analyses demonstrated that RL-71 at 1µM and RL-66 at 2µM increased the proportion of MDA-MB-231 cells in G2/M-phase by 162.02 ± 1.53% and 134.12 ± 2.17% over control (P<0.001) respectively. In addition, the treatment with RL-71 (1µM) and RL-66 (2µM) increased the proportion of apoptotic MDA-MB-231 cells by 10-fold and 4-fold over control (p<0.001), respectively. Similar results were also produced in SKBr3 and MDA-MB-468 cells. Furthermore, Western blot analysis confirmed the effect of drugs on different cancer related genes involved in cell proliferation and apoptosis. Thus, these data suggest that the novel curcumin analogues RL-71 and RL-66 are potent antitumor drugs and have significant potential for further drug development for estrogen receptor negative breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3556.