Diphenyl Difluoroketone: A Curcumin Derivative with Potent In vivo Anticancer Activity

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. [Cancer Res 2008;68(6):1962-9]

Potentiation of gemcitabine by Turmeric Force™ in pancreatic cancer cell lines

“…Studies to date have indicated that poor absorption and rapid metabolism of curcumin severely curtail its bioavailability. Because of this limitation on the therapeutic use of curcumin, structural modifications of this agent has been attempted to increase its absorption and bioavailability (20)(21)(22). However, it is too early to predict their experimental and clinical success.…”

Crystal structure of (2E,6E)-2,6-bis(2,4-dimethoxybenzylidene)- cyclohexanone, C24H26O5

“…It has asurprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemo-therapeutic activity and has been used to treat several different cancers [3][4][5]. However, although curcumin is non-toxic and has promising anti-cancer activities, preclinical and clinical studies indicate that its poor bioavailability and weak pharmacokinetic profiles derived from its structural instability under physiological conditions have seriously limited its application in anti-cancer therapies [6,7].…”

“…However, although curcumin is non-toxic and has promising anti-cancer activities, preclinical and clinical studies indicate that its poor bioavailability and weak pharmacokinetic profiles derived from its structural instability under physiological conditions have seriously limited its application in anti-cancer therapies [6,7]. In the past two decades, alot of efforts has been put into the chemical modification of curcumin to identify potential analogues with better bioavailability and antitumor activities [5,[8][9][10]. The title compound, one of monocarbonyl curcumin analogues has demonstrated excellent cytotoxic properties against several human cancer cell lines in vitro (data not shown).…”

Synthesis of N-Substituted 3,5-Bis(arylidene)-4-piperidones with High Antitumor and Antioxidant Activity

“…EF24, with ortho-fluorinated phenyl group exhibited anticancer activity in vitro when tested using breast cancer, colon cancer and ovarian epithelial cancer. [19][20][21] Its para-fluorinated derivative H-4073 was more potent than EF24 in inducing cytotoxicity to ovarian cancer cells. [21][22][23] DAP compounds have also been shown to be more readily bioavailable than the parent compound, curcumin.…”