Mechanisms of apoptosis in colon cancer cells induced by IDO1 inhibitor and irradiation: A metabolomic study

The study found that IDO1 inhibition combined with radiation increased apoptosis in colon cancer cells while decreasing NAD+ levels, but the clinical implications of these findings are uncertain.

Summary and findings

This study investigated the effects of IDO1 inhibition and radiation on apoptosis in colon cancer cells, specifically examining the role of NAD+. The combination treatment showed an increase in apoptosis rates and a decrease in NAD+ levels. No therapeutic claims are made.

Abstract

<title>Abstract</title> <p> Background: Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the conversion of tryptophan to kynurenine, promoting tumor progression via immune suppression and activation of the Wnt/β-catenin pathway. As the activation of kynurenine pathway also produces key metabolites such as nicotinamide adenine dinucleotide (NAD ⁺ ), its inhibition may influence tumor cell metabolism and contribute to anti-tumor effects. This study investigated the mechanisms underlying the combined effects of IDO1 inhibition and radiation (Rad) on colon cancer cells, with a focus on metabolic alterations. <h4>Methods:</h4> Colon26 murine colon cancer cells were treated with an IDO1 inhibitor, 1-methyltryptophan (1-MT), Rad (10 Gy/10 fractions), or both. Apoptosis was evaluated in cultured cells and subcutaneous tumors. Apoptosis-related proteins in cultured Colon26 cells treated with 1-MT and/or Rad were evaluated by Western blot analysis. Metabolome analysis assessed intracellular changes in metabolites including NAD ⁺ of kynurenine pathways caused by these treatments. The additional effect of β-nicotinamide mononucleotide (NMN) was evaluated. <h4>Results:</h4> Combination treatment with 1-MT and Rad increased apoptosis compared to Rad alone <italic>in vitro</italic> (7.0% vs. 5.5%, p = 0.0495) and <italic>in vivo</italic> (0.19% vs. 0.13%, p = 0.025). Western blotting showed elevations of cleaved caspase 3, 8, and 9 by dual treatments. NAD ⁺ levels decreased by additional 1-MT in radiated Colon26 cells (452 vs. 1027 nmol/g, p = 0.0495). Supplementation with NMN (500 μM) restored NAD ⁺ levels and suppressed apoptosis in cells treated with 1-MT and Rad. <h4>Conclusions:</h4> IDO1 inhibition enhanced Rad-induced apoptosis in Colon26 cell through NAD ⁺ depletion. Targeting NAD ⁺ synthesis may represent a therapeutic approach in colorectal cancer. </p>

Elsewhere in the NAD+ (Nicotinamide Adenine Dinucleotide) corpus