Cytotoxicity, ROS-generation activity and radical-scavenging activity of curcumin and related compounds.
The cytotoxicity, ROS (reactive oxygen species)-generation activity and radical-scavenging activity of curcumin and related compounds such as eugenol, eugenol orthodimer (bis-eugenol; 3,3'-dimethoxy-5,5'-di-2-propenyl-1,1'-biphenyl-2,2'-diol) and isoeugenol were investigated. Their cytotoxicity against a human submandibular gland adenocarcinoma cell line (HSG) declined in the order curcumin > isoeugenol > bis-eugenol > eugenol. Since the hydrophobicity (log P) of curcumin, isoeugenol and eugenol is about 2.5, whereas that of bis-eugenol is 4.8, there was no relationship between cytotoxicity and log P. Generation of intracellular ROS in HSG cells was observed for curcumin alone in an assay using 5- (and -6)-carboxy-2',7'-dichlorofluorescein diacetate (CDFH-DA). The cytotoxicity of, and ROS generation by, curcumin were reduced by the addition of N-acetyl-L-cysteine (NAC) and glutathione, suggesting a possible link between cytotoxicity and ROS. The radical-scavenging (antioxidant) activity of curcumin and related compounds was determined quantitatively by the induction period method for polymerization of methyl methacrylate (MMA) initiated by peroxy radicals derived from benzoyl peroxide (BPO) under nearly anaerobic conditions. The length of the induction (inhibition) period for curcumin was significantly greater than that of the other compounds. This suggests that curcumin is an efficient scavenger of peroxy radicals. The curcumin radical possibly reacts with itself or with other radicals to yield polymeric stable products such as curcumin dimer. Such polyphenolic behavior of curcumin was considerably different from that of bis-eugenol, which, like curcumin, has two hydroxy groups, or of other compounds with one hydroxy group. The radical-scavenging activity was also investigated with 2,2-diphenyl-1-picrylhydrazyl (DPPH). Curcumin scavenged approximately one DPPH free radical, suggesting the formation of curcumin dimer. The possible formation of curcumin dimer was explored with a PM3 semiempirical molecular orbital method. A molecular mechanism of cancer prevention by curcumin is proposed, based on its high reactivity with peroxy radicals at low oxygen pressure and on ROS generation induced by curcumin radicals.
Fujisawa
Seiichiro
S
Department of Oral Diagnosis, Meikai University School of Dentistry, Saitama 350-0283, Japan. fujisawa@dent.meikai.ac.jp
Atsumi
Toshiko
T
Ishihara
Mariko
M
Kadoma
Yoshinori
Y
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D001585:Benzoyl Peroxide / Q000737:chemistry; D001713:Biphenyl Compounds / Q000737:chemistry; D045744:Cell Line, Tumor; D003474:Curcumin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D005054:Eugenol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D020366:Methylmethacrylate / Q000737:chemistry; D010851:Picrates; D017382:Reactive Oxygen Species / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013365:Submandibular Gland Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D006834:Hydrazines; D010851:Picrates; D017382:Reactive Oxygen Species; D020366:Methylmethacrylate; D005054:Eugenol; C036643:isoeugenol; C004931:1,1-diphenyl-2-picrylhydrazyl; D003474:Curcumin; D001585:Benzoyl Peroxide