Metabolism and Anticancer Activity of the Curcumin Analogue, Dimethoxycurcumin

Abstract

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 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.Curcumin (diferuloylmethane) is the active yellow pigment in turmeric, a popular plant-derived coloring spice and ingredient of many cosmetics and pharmaceuticals (see refs. 1 -5 for reviews on structural and biological aspects of curcumin). In general, curcumin has been associated with a large number of biological and cellular activities/events, including antioxidative, anti-inflammatory, anticarcinogenic, and hypocholesterolemic properties (1 -5), and a large number of studies have focused on the pathways by which curcumin acts as a chemoprotective agent (1, 2, 6, 7). Further, curcumin congeners have been reported to induce apoptosis, sensitize and overcome resistance to various agents that induce apoptosis in diverse human cancer cells (8 -16), and decrease the occurrence of cardiomyocytic apoptosis after global cardiac ischemia/reperfusion (17). In general, curcumin mediates its effects by modulating several important molecular targets, including transcription factors, enzymes, cell cycle proteins, cytokines, receptors, and cell surface adhesion molecules (reviewed in refs. 2 -4).With regard to its anticancer potential, it has been shown that curcumin congeners can inhibit proliferation and/or induce apoptosis of cancer c...

Absorption and Elimination of Dimethoxycurcumin, An Active Analogue of Curcumin

“…It has been reported that curcumin was quickly metabolized into tetrahydrocurcumin and other low activity products, and the pro-type drug could not be detected in bile, and this might be the reason of low bioavailability of curcumin. Tamvakopoulos [4] has reported that plasma stability of DMC was about 3 times higher than curcumin, but the metabolic degree of DMC has not provided. As curcumin was rapid metabolized, the lower in vivo metabolic degree of DMC further expounded it was stable enough to exert therapeutic function.…”

“…Tamvakopoulos [4] has analyzed the in vitro metabolic pathway and plasma metabolic stability of DMC, which demonstrated that metabolism of DMC was less extensive in liver microsomal systems, and the plasma metabolic stability was more stable than curcumin. However, deficient factor of consistency induces external metabolism could not completely reflect internal condition, since the latter is more complex and variable, and the quantity of pro-type drug was either indistinct.…”

Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties

“…Although both compounds were rapidly degraded in vivo, the demethoxycurcumin was more stable. It is likely that differential extent of apoptosis induced by these compounds was associated with their different metabolic profiles [58].…”

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“…On the contrary, dimethoxycurcumin showed good results probably because of the absence of free phenolic groups that prevent its conversion to glucuronide and to sulfate, resulting in better bioavailability [4]. In the last years, several studies have confirmed the potential use of curcumin for the prevention and treatment of many different diseases, especially inflammatory ones and cancer [1][2][3][4][5][6][7][8]. In particular, several studies confirmed a chemopreventive role for curcumin in tumors from different cell types (pancreas, breast, prostate, lung, mantle cell lymphoma, liver, brain, colorectal cancer, and others) [2, 7,8].…”

“…In the last few years, several curcumin analogues have been tested, but in most cases they were found to be less effective than curcumin itself. On the contrary, dimethoxycurcumin showed good results probably because of the absence of free phenolic groups that prevent its conversion to glucuronide and to sulfate, resulting in better bioavailability [4]. In the last years, several studies have confirmed the potential use of curcumin for the prevention and treatment of many different diseases, especially inflammatory ones and cancer [1][2][3][4][5][6][7][8].…”