Metabolism and anticancer activity of the curcumin analogue, dimethoxycurcumin.
OBJECTIVE
The plant-derived compound curcumin has shown promising abilities as a cancer chemoprevention and chemotherapy agent in vitro and in vivo but exhibits poor bioavailability. Therefore, there is a need to investigate modified curcumin congeners for improved anticancer activity and pharmacokinetic properties.


METHODS
The synthetic curcumin analogue dimethoxycurcumin was compared with curcumin for ability to inhibit proliferation and apoptosis of human HCT116 colon cancer cells in vitro by estimating the GI(50) and LC(50) values and detecting the extent of apoptosis by flow cytometry analysis of the cell cycle. Metabolic stability and/or identification of metabolites were evaluated by recently developed mass spectrometric approaches after incubation with mouse and human liver microsomes and cancer cells in vitro. Additionally, circulating levels of dimethoxycurcumin and curcumin were determined in mice following i.p. administration.


RESULTS
Dimethoxycurcumin is significantly more potent than curcumin in inhibiting proliferation and inducing apoptosis in HCT116 cells treated for 48 h. Nearly 100% of curcumin but <30% of dimethoxycurcumin was degraded in cells treated for 48 h, and incubation with liver microsomes confirmed the limited metabolism of dimethoxycurcumin. Both compounds were rapidly degraded in vivo but dimethoxycurcumin was more stable.


CONCLUSIONS
Compared with curcumin, dimethoxycurcumin is (a) more stable in cultured cells, (b) more potent in the ability to kill cancer cells by apoptosis, (c) less extensively metabolized in microsomal systems, and (d) more stable in vivo. It is likely that the differential extent of apoptosis induced by curcumin and dimethoxycurcumin in vitro is associated with the metabolite profiling and/or the extent of stability.
Tamvakopoulos
Constantin
C
Division of Pharmacology-Pharmacotechnology, Foundation for Biomedical Research, Academy of Athens, Greece. ctamvakop@bioacademy.gr
Dimas
Konstantinos
K
Sofianos
Zacharias D
ZD
Hatziantoniou
Sophia
S
Han
Zhiyong
Z
Liu
Zhong-Li
ZL
Wyche
James H
JH
Pantazis
Panayotis
P
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005260:Female; D005434:Flow Cytometry; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism
D000970:Antineoplastic Agents; C521105:dimethoxycurcumin; D003474:Curcumin