title: Cellular uptake, retention and bioabsorption of HO-3867, a fluorinated curcumin analog with potential antitumor properties.
abstract: Curcumin, a naturally-occurring compound found in the rhizome of Curcuma longa plant, is known for its antitumor activities. However, its clinical efficacy is limited due to poor bioabsorption. A new class of synthetic analogs of curcumin, namely diarylidenylpiperidone (DAP), has been developed with substantially higher anticancer activity than curcumin. However, its cellular uptake and bioabsorption have not been evaluated. In this study we have determined the absorption of a representative DAP compound, HO-3867, using optical and electron paramagnetic resonance spectrometry. The cellular uptake of HO-3867 was measured in a variety of cancer cell lines. HO-3867 was taken in cells within 15 minutes of exposure and its uptake was more than 100-fold higher than curcumin. HO-3867 was also retained in cells in an active form for 72 hours and possibly longer. HO-3867 was substantially cytotoxic to all the cancer cells tested. However, there was no direct correlation between cellular uptake and cytotoxicity suggesting that the cytotoxic mechanisms could be cell-type specific. When administered to rats by intraperitoneal injection, significantly high levels of HO-3867 were found in the liver, kidney, stomach, and blood after 3 hours. Also, significant accumulation of HO-3867 was found in murine tumor xenografts with a dose-dependent inhibition of tumor growth. The results suggest that the curcumin analog has substantially higher bioabsorption when compared to curcumin.
authors.affiliation: Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Dayton
authors.forename: Karuppaiyah
authors.initials: K
authors.lastname: Selvendiran
authors.forename: M Lakshmi
authors.initials: ML
authors.lastname: Kuppusamy
authors.forename: Brian K
authors.initials: BK
authors.lastname: Rivera
authors.forename: Sarath
authors.initials: S
authors.lastname: Meduru
authors.forename: Tamás
authors.initials: T
authors.lastname: Kálai
authors.forename: Kálmán
authors.initials: K
authors.lastname: Hideg
authors.forename: Periannan
authors.initials: P
authors.lastname: Kuppusamy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003474:Curcumin / Q000627:therapeutic use*; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D054879:Halogenation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010881:Piperidones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C541427:(3,5-bis((4-fluorophenyl)methylidene)-1-((1-hydroxy-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrol-3-yl)methyl)piperidin-4-one); D000970:Antineoplastic Agents; D010881:Piperidones; D003474:Curcumin
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