Potentiation of the cyotoxic effects of natural chemopreventative agents, ellagic acid and quercetin

Fiona Saunders, Manju Oommen, Ratchadawadee Lapjitkusol, Edward Amankwatia, Lauren Kaminski, Adele Swanson, Alastair Mitchell, Heather M. Wallace

Research output: Contribution to journalAbstract

Abstract

Lung and colorectal are among the most prevalent cancers in the world. Current treatments have limited success with 5-year survival (7% and 50%, respectively). So another approach is needed. One strategy is chemoprevention (natural or chemical). The most investigated are notably non-steroidal anti-inflammatory drugs (NSAIDs). However, NSAIDs have side effects and there is growing interest in natural compounds with potentially less side effects.

Ellagic acid (EA), a polyphenol, and quercetin (QC), a flavonoid, are naturally occurring compounds, abundant in soft fruits and other foodstuffs (Ren et al., 2003). They are effective in killing cancer cells, but their mechanism of cytotoxicity is unknown. Preliminary studies suggest that inhibition of polyamine biosynthesis may be involved. Polyamine concentrations and metabolism are increased in cancer cells (Kingsnorth et al., 1984). Preventing polyamine accumulation may be one mechanism used by preventative agents to decrease cancer cell growth. Our aims were to determine the efficacy of EA and QC, alone and in combination in models of human cancer and establish their effects on polyamine metabolism.

Using non-small cell lung cancer (A549), colorectal cancer (HCT-116) and breast cancer (MDA-MB-231) cells the cytotoxicity of EA and QC was established, after 96 h of incubation. MTT, Trypan Blue and protein determination assays were used to monitor cell growth. Polyamine content was determined using HPLC. DAPI staining was used to determine whether the cell death induced was due to apoptosis.

Exposure to EA and QC alone resulted in dose-dependent cytotoxicity in all cells, measured by MTT (IC50 values; Fig. 1). We combined EA and QC by fixing the concentration of one and varying the other to test this. EA was fixed at 132 μM and QC varied from 0 to 370 μM and QC was fixed at 118 μM and EA varied from 0 to 410 μM. The combinations of EA and QC showed increased cytotoxicity compared to EA and QC alone (Fig. 1). Further studies showed that combinations were also more effective in depleting cell number, protein content and intracellular polyamine concentrations by greater than 30% (HCT-116 cells). DAPI staining gave a preliminary indication that the mechanism of cell death was apoptotic. Further investigation is required to determine which part of the polyamine pathway is a target. However, these studies indicate that modulation of polyamine metabolism may, in part, explain some of the cytotoxic effects of EA and QC in cancer cells
Original languageEnglish
Pages (from-to)21
Number of pages1
JournalToxicology
Volume262
Issue number1
Early online date1 Jul 2009
DOIs
Publication statusPublished - 28 Jul 2009

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