Abstract
Curcumin, a natural polyphenol that contributes to the flavor and yellow pigment of the spice turmeric, is known for its antioxidant, anti-inflammatory, and anticarcinogenic properties. Capable of affecting the initiation, promotion, and progression of carcinogenesis through multiple mechanisms, curcumin has potential utility for both chemoprevention and chemotherapy. Previous studies demonstrated that curcumin can inhibit ornithine decarboxylase (ODC) activity in human leukemia and breast cancer cells, and pretreatment with dietary curcumin blocks carcinogen-induced ODC activity in rodent models of skin, colon, and renal cancer. The current study investigated the regulation of polyamine metabolism in human gastric and colon carcinoma cell lines in response to curcumin. Curcumin treatment significantly induced spermine oxidase (SMOX) mRNA and activity, which results in the generation of hydrogen peroxide, a source of ROS. Simultaneously, curcumin down regulated spermidine/spermine N1-acetyltransferase (SSAT) activity and the biosynthetic enzymes ODC and S-adenosylmethionine decarboxylase (SAMDC), thereby diminishing intracellular polyamine pools. Combination treatments using curcumin with the ODC inhibitor 2-difluoromethylornithine (DFMO), an agent currently in clinical chemoprevention trials, significantly enhanced inhibition of ODC activity and decreased growth of GI cancer cell lines beyond that observed with either agent alone. Similarly, combining curcumin with the polyamine analogue bis(ethyl)norspermine enhanced growth inhibition that was accompanied by enhanced accumulation of the analogue and decreased intracellular polyamine levels beyond those observed with either agent alone. Importantly, cotreatment with curcumin permitted the lowering of the effective dose of ODC inhibitor or polyamine analogue. These studies provide insight into the polyamine-related mechanisms involved in the cancer cell response to curcumin and its potential as a chemopreventive or chemotherapeutic agent in the GI tract.
Highlights
Curcumin, or diferuloylmethane (1,7-bis(4-hydroxy 3-methoxy phenyl)-1,6-heptadiene3.5-dione) (Fig 1A) accounts for the characteristic yellow-orange color and flavor of the spice turmeric
As the potential for long-term exposure to dietary factors is greatest in the gastrointestinal (GI) tract, the current study comprehensively investigates the effects of curcumin on gastric and colon cancer cell lines with regard to polyamine metabolism including the catabolic pathway
Treatment of AGS gastric cancer cells with increasing concentrations of pure curcumin for 48 hours resulted in a dose-dependent decrease in ornithine decarboxylase (ODC) activity, this decrease was not associated with altered levels of ODC mRNA (Fig 2A)
Summary
Diferuloylmethane (1,7-bis(4-hydroxy 3-methoxy phenyl)-1,6-heptadiene3.5-dione) (Fig 1A) accounts for the characteristic yellow-orange color and flavor of the spice turmeric. As a naturally occurring bioactive polyphenol, curcumin has been used for centuries in traditional medicines for relief from a wide variety of ailments. It is commonly used in cooking as a spice and food coloring, in skin care products, and as a textile dye. The purported health-promoting properties of curcumin are diverse and include antioxidant, anti-inflammatory, antiproliferative, anti-angiogenic, and antibacterial activities. This multitude of curcumin effects can likely be attributed to its capacity for modulating certain key signaling pathways with roles in multiple pathologies, including cancer [2]. In addition to chemopreventive potential, curcumin has demonstrated anticancer effects on established tumor cells, which, in contrast to non-tumorigenic cells, often undergo apoptosis and cell death upon exposure to curcumin [3]
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