Cellular uptake, retention and bioabsorption of HO-3867, a fluorinated curcumin analog with potential antitumor properties.
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.
Dayton
Alex
A
Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, USA.
Selvendiran
Karuppaiyah
K
Kuppusamy
M Lakshmi
ML
Rivera
Brian K
BK
Meduru
Sarath
S
Kálai
Tamás
T
Hideg
Kálmán
K
Kuppusamy
Periannan
P
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
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
Cancer Res. 2009 Dec 1;69(23):8958-66
19903839
J Biol Chem. 2007 Sep 28;282(39):28609-28618
17684018
Bioorg Med Chem. 2009 Apr 15;17(8):3043-52
19329324
Exp Biol Med (Maywood). 2001 Jul;226(7):620-1
11444094
Mol Cancer Ther. 2010 May;9(5):1169-79
20442315
Mol Pharm. 2007 Nov-Dec;4(6):807-18
17999464
Altern Med Rev. 2009 Sep;14(3):226-46
19803548
Cancer Sci. 2009 Sep;100(9):1719-27
19558577
Technol Cancer Res Treat. 2008 Dec;7(6):497-516
19044329
Mol Nutr Food Res. 2008 Jun;52 Suppl 1:S139-51
18551457
J Pharmacol Exp Ther. 2009 Jun;329(3):959-66
19276401
Anticancer Drugs. 2006 Mar;17(3):279-87
16520656
Cancer Chemother Pharmacol. 2008 Jan;61(1):145-55
17396264
Clin Cancer Res. 2007 Feb 15;13(4):1269-77
17317839
Biochem Pharmacol. 2008 Dec 1;76(11):1590-611
18775680
Cancer Res. 1999 Feb 1;59(3):597-601
9973206
Jpn J Cancer Res. 2000 Sep;91(9):893-8
11011116
Eur J Pharm Biopharm. 2008 Nov;70(3):770-6
18656539
Eur J Pharmacol. 2009 Dec 25;625(1-3):6-22
19836383
Cell Cycle. 2008 Aug;7(15):2409-17
18682687
Free Radic Biol Med. 2010 May 1;48(9):1228-35
20156552
Curr Med Chem. 2010;17(3):190-7
20214562
Cancer Biol Ther. 2007 Feb;6(2):178-84
17218783
Antioxid Redox Signal. 2004 Jun;6(3):587-95
15130285
Bull Cancer. 1997 Jun;84(6):665-73
9295871