Abstract
Diphenyl difluoroketone (EF24), a molecule having structural similarity to curcumin, was reported to inhibit proliferation of a variety of cancer cells in vitro. However, the efficacy and in vivo mechanism of action of EF24 in gastrointestinal cancer cells have not been investigated. Here, we assessed the in vivo therapeutic effects of EF24 on colon cancer cells. Using hexosaminidase assay, we determined that EF24 inhibits proliferation of HCT-116 and HT-29 colon and AGS gastric adenocarcinoma cells but not of mouse embryo fibroblasts. Furthermore, the cancer cells showed increased levels of activated caspase-3 and increased Bax to Bcl-2 and Bax to Bcl-xL ratios, suggesting that the cells were undergoing apoptosis. At the same time, cell cycle analysis showed that there was an increased number of cells in the G(2)-M phase. To determine the effects of EF24 in vivo, HCT-116 colon cancer xenografts were established in nude mice and EF24 was given i.p. EF24 significantly suppressed the growth of colon cancer tumor xenografts. Immunostaining for CD31 showed that there was a lower number of microvessels in the EF24-treated animals coupled with decreased cyclooxygenase-2, interleukin-8, and vascular endothelial growth factor mRNA and protein expression. Western blot analyses also showed decreased AKT and extracellular signal-regulated kinase activation in the tumors. Taken together, these data suggest that the novel curcumin-related compound EF24 is a potent antitumor agent that induces caspase-mediated apoptosis during mitosis and has significant therapeutic potential for gastrointestinal cancers.
Highlights
Colorectal carcinoma is the second leading cause of cancer mortality in the United States with f55,000 deaths in 2006 [1,2,3]
Our in vivo studies with HCT-116 colon cancer cell tumor xenografts in nude mice revealed that EF24 suppresses cancer cell proliferation and angiogenesis and induces cell cycle arrest and apoptosis, coupled with the reduction of the expression of colon cancer–promoting genes, including cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF )
EF24 significantly suppresses proliferation of colon cancer cell lines HCT-116 and HT-29 and a gastric cancer cell line (AGS) within a 24-h period, which continues to 72 h (Fig. 1B)
Summary
Colorectal carcinoma is the second leading cause of cancer mortality in the United States with f55,000 deaths in 2006 [1,2,3]. Its antitumor properties include cancer growth inhibition and apoptosis induction in a variety of cultured cancer cell lines in vitro. The use of curcumin in antiangiogenesis includes the inhibition of vascular endothelial cell proliferation in vitro and capillary tube formation and growth in vivo [14, 15]. We show results of our in vitro experiments showing that EF24 inhibits cell proliferation, prevents colony formation, and promotes G2-M arrest of colon and gastric cancer cells. Our in vivo studies with HCT-116 colon cancer cell tumor xenografts in nude mice revealed that EF24 suppresses cancer cell proliferation and angiogenesis and induces cell cycle arrest and apoptosis, coupled with the reduction of the expression of colon cancer–promoting genes, including cyclooxygenase-2 (COX-2), interleukin-8 (IL-8), and vascular endothelial growth factor (VEGF )
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