Garcinol Enhances TRAIL-Induced Apoptotic Cell Death through Up-Regulation of DR5 and Down-Regulation of c-FLIP Expression

Abstract

Garcinol is a polyisoprenylated benzophenone derived from the Garcinia indica fruit that possess potential therapeutic effects such as inhibition of inflammation and tumor expansion. Here, we investigated whether garcinol induces TRAIL sensitization in renal carcinoma cells. Single treatment with garcinol or TRAIL did not effect on apoptosis. However, combined treatment with garcinol plus TRAIL significantly induced apoptosis in renal carcinoma (Caki, ACHN and A498), lung carcinoma (A549), and hepatoma (SK-Hep1) cells. In contrast, garcinol plus TRAIL did not alter cell viability in normal cells. Garcinol plus TRAIL induced up-regulation of DR5 and down-regulation of c-FLIP expression at post-translational levels. Furthermore, knock-down of DR5 by siRNA and ectopic expression of c-FLIP blocked apoptotic cell death induced by garcinol plus TRAIL. Overall, our study provides evidence that garcinol can be exploited as a potential TRAIL sensitizer.

Chemical and Biological Aspects of Garcinol and Isogarcinol: Recent Developments

“…Sensitization to cisplatin and erlotinib (garcinol), suppression of cancer stem cells (garcinol), increased TRAIL‐based apoptosis (garcinol)…”

“…Upregulation of let‐7c and miR‐200c (garcinol), suppression of Wnt/ β ‐catenin/STAT3 and ALDH1 A1 (garcinol), activation of DDIT3, induction of DR5 (garcinol), suppression of c‐FLIP (garcinol)…”

“…Suppression MMP2 and MMP9 (gallbladder carcinoma) (garcinol), synergism with STAT5 inhibition via HAT inhibition (leukemia, garcinol), increased TRAIL‐based apoptosis by induction of DR5 and suppression of c‐FLIP (hepatoma, renal cancer, garcinol), LC‐3 shift (osteosarcoma, garcinol)…”

“…New discoveries concerning mechanisms of action of garcinol and isogarcinol in tumor models were disclosed. In hepatoma (SK‐Hep1), lung (A549) and renal carcinoma cells (Caki, ACHN, A498) garcinol increased TRAIL‐based apoptosis by induction of DR5 and suppression of c‐FLIP . The HAT inhibitor garcinol also led to proteasome‐based degradation of the factor ADA3 (alteration/deficiency in activation 3) in immortalized 76 N‐TERT cells (human mammary epithelial cells) by inhibition of stabilizing ADA3 acetylation via p300/PCAF inactivation .…”

“…In vivo activity Lung cancer Sensitization to cisplatin and erlotinib (garcinol), [28] suppression of cancer stem cells (garcinol), [29,30] increased TRAIL-based apoptosis (garcinol) [54] Upregulation of let-7c and miR-200c (garcinol), [28] suppression of Wnt/β-catenin/STAT3 and ALDH1 A1 (garcinol), [29] activation of DDIT3, induction of DR5 (garcinol), [30] suppression of c-FLIP (garcinol) [54] Inhibition of H441 LCSC mouse xenograft tumor growth (garcinol) [29] Colorectal cancer…”