Curcumin mediates polyamine metabolism and sensitizes gastrointestinal cancer cells to antitumor polyamine-targeted therapies

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.

Polyamine catabolism and oxidative damage

“…In certain cancer cell types, cytotoxicity from these analogues is attributed to the production of H 2 O 2 via SMOX simultaneously with depletion of the natural PAs (50,121,122). Curcumin, a natural polyphenol and popular dietary supplement, was recently shown to increase uptake of these PA analogues, resulting in enhanced polyamine depletion and growth inhibition and allowing a substantial reduction in the required effective analogue dose (123). As curcumin possesses multiple antitumor properties, this combination with a PA analogue would target multiple anticancer pathways (124).…”

A Combinatorial Approach to Optimize the Production of Curcuminoids From Tyrosine in Escherichia coli

“…Curcuminoids are natural phenylpropanoids extracted from the plant Curcuma longa that have innumerous therapeutic properties including antioxidant (Wang et al, 2019), antiinflammatory (Dai et al, 2018), anticancer (Murray-Stewart et al, 2018;Ravindranathan et al, 2018), and cholesterollowering (Ferguson et al, 2018). They have also been reported as protective agents for several neurodegenerative diseases (Maiti and Dunbar, 2018).…”

<p>Curcumin Inhibited Podocyte Cell Apoptosis and Accelerated Cell Autophagy in Diabetic Nephropathy via Regulating Beclin1/UVRAG/Bcl2</p>

“…[19][20][21] The studies have found that curcumin inhibits cell proliferation and induces apoptosis in several tumors. [22][23][24][25] Besides, curcumin has been reported to enhance autophagy-related cell death, 26 and induce cell apoptosis through lysosomal membrane permeabilization-medicated autophagy or downregulating lncRNA. 27,28 What's more, curcumin exerts protective effects through promoting autophagy and ameliorating apoptosis in diabetic cardiomyopathy.…”