RT Journal Article
SR Electronic
T1 Metabolism and Anticancer Activity of the Curcumin Analogue, Dimethoxycurcumin
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 1269
OP 1277
DO 10.1158/1078-0432.CCR-06-1839
VO 13
IS 4
A1 Tamvakopoulos, Constantin
A1 Dimas, Konstantinos
A1 Sofianos, Zacharias D.
A1 Hatziantoniou, Sophia
A1 Han, Zhiyong
A1 Liu, Zhong-Li
A1 Wyche, James H.
A1 Pantazis, Panayotis
YR 2007
UL http://clincancerres.aacrjournals.org/content/13/4/1269.abstract
AB Purpose: 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. Experimental Design: 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 GI50 and LC50 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.