Abstract 2283: Potent curcumin analog FLLL-12 targets both intrinsic and extrinsic signaling pathways to induce apoptosis in lung cancers

Abstract

Abstract Background: Curcumin is the major bioactive compound isolated from the rhizome of Curcuma longa (turmeric). Despite its high margin of safety 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 developed. In the current study, we investigated the mechanism of apoptosis of one such synthetic analogue, FLLL-12, against lung cancers. This compound was reported to exhibit potent anti-tumor activity against prostate, colon and breast cancer cell lines. However, its mechanism of growth inhibition has yet to be elucidated. Methods: Multiple premalignant and fully transformed lung cancer cell lines were used throughout the study. SRB assay was used to measure cell growth inhibition. Annexin V staining was conducted for apoptosis assay. Expression of mRNAs and proteins were measured by RT-PCR and Western blotting, respectively. Gene overexpression and knockdown strategies were used to activate or shut down of specific proteins. Results: IC50 values and apoptosis assay results showed that FLLL-12 was ∼10-fold more potent than the natural parent compound, curcumin, against lung cancer cells. Further mechanistic studies revealed that FLLL-12 induced the expression of DR5, inhibited the protein expression of EGFR, p-AKT, AKT and Bcl-2 and increased the expression of BIM. Analysis of mRNA expression suggested that FLLL-12 strongly inhibited the mRNA expression of EGFR and AKT, whereas the expression of Bcl-2 and Bim mRNAs remained unchanged. FLLL-12 also induced the expression of p53 and p73. However, inactivation of these proteins with their dominant negative construct or siRNA had no significant effects on apoptosis induction. Conclusions: Our results strongly suggest that FLLL-12 is a potent curcumin analog that induces apoptosis of lung cancer cell lines by targeting: (1) intrinsic pathways via transcriptional inhibition of EGFR and AKT and induction of BIM, and (2) extrinsic pathway via induction of DR5. Future in vivo studies using appropriate animal models are warranted for further development of this promising compound for cancer prevention and/or treatment for lung cancer. (Supported by R03CA171663, P50CA128613 and Robbins Scholar Award of Winship Cancer Institute of Emory University). Citation Format: A.R.M. Ruhul Amin, Abedul Haque, Mohammad A. Rahman, James R. Fuchs, Zhuo G. Chen, Dong M. Shin. Potent curcumin analog FLLL-12 targets both intrinsic and extrinsic signaling pathways to induce apoptosis in lung cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2283. doi:10.1158/1538-7445.AM2014-2283