Abstract 5425: Potent curcumin analogue FLLL-22, but not natural curcumin, targets the DNA damage pathway for apoptosis in lung and head and neck cancer cells

Curcumin, 1, 7-bis (4-hydroxy-3-methoxyphenyl)-1, 6-heptadien-3, 5-dione, is the major bioactive compound isolated from the rhizome of Curcuma longa (turmeric). Despite its high margin of safety (no dose-limiting toxicity at doses up to 10 g/day in human) and efficacy against various types of cancers, the potential utility of curcumin as a chemopreventive/chemotherapeutic drug is compromised by its low bioavailability and poor selectivity. To circumvent these problems, more potent and selective curcumin analogues have been introduced. In the current study, we investigated one such synthetic analogue, (1E, 4E)-1, 5-bis (2, 4, 6-trimethoxyphenyl) penta-1, 4-dien-3-one (FLLL-22), against the head and neck cancer cell line Tu212 and lung cancer cell line H460. We conducted an SRB assay to determine IC50 values which showed that FLLL-12 was 24.6-fold and 31.6-fold more potent than natural curcumin against Tu212 and H460 cells, respectively. FLLL-22 also more strongly inhibited colony formation in both cell lines than that of natural curcumin. FLLL-22 at 1 μM was sufficient to completely inhibit colony formation, whereas up to 5 μM of curcumin had only minimal effects on colony formation. FLLL-22 also induced apoptosis more strongly (∼10-fold) than natural curcumin as evidenced by annexin V-PE staining and cleavage of PARP. Interestingly, FLLL-22, but not natural curcumin, activates DNA double strand breaks as evidenced by phosphorylation of H2AX and activation of p53 pathway. Although FLLL-22 strongly phosphorylated H2AX at doses of 3 and 5 μM, no H2AX phosphorylation was observed after curcumin treatment with doses 20 and 30 μM. At these doses, both compounds induced comparable apoptosis. FLLL-22 increased the protein level of p53, its phosphorylation at Ser15 and Ser392, and downstream target p21. A slight increase in p53 expression was observed with 20 μM curcumin, but not with 30 μM. Ablation of p53 by shRNA inhibited FLLL-22-induced p21, suggesting that FLLL-22 activates p53-dependent transcription. We also found that treatment with both FLLL-22 and curcumin inhibited phosphorylation of AKT, S6 and expression of Bcl-2. Taken together, our data strongly suggest that FLLL-22 is a potent curcumin analogue which activates the DNA damage pathway to induce apoptosis and might be a suitable anti-cancer drug for further preclinical and clinical development (supported by U01CA101244, R01CA112643, and P50CA128613 to DMS).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5425. doi:10.1158/1538-7445.AM2011-5425