Blockade of IDO-kynurenine-AhR pathway promotes cell apoptosis in carboxyamidotriazole-induced tumor cell dormancy-apoptosis oscillation

Background: Some cancer cells may reshape their genetic make-up, adopt a special metabolism mode and undergo dormancy to endure drug attacks. Blocking survival signals in dormant cancer cells that survive a certain anticancer therapy and eradicating them while dormant may help prevent tumor recurrence and metastasis.Methods: Two colorectal cancer cell lines C26 and HCT116 were treated with carboxyamidotriazole. Sulforhodamine B assay and Ki67 staining were conducted to detect the cells proliferation response. Cell cycle distribution was measured with BrdU staining. Then treated with CAI, DMF, 1-MT or a combination and analyzed the apoptosis. The in vivo anti-tumor effects of each monotherapy or combination therapy were assessed according to their capability to slow tumor growth and extend the life span of tumor-bearing mice. Results: The colorectal cancer cells slow growth to escape the pressure of the anti-tumor drug CAI. Blocking the IDO-kynurenine-AhR pathway could promote CRC cells apoptosis in CAI-induced tumor cell dormancy-apoptosis oscillation, facilitating their eradication.Conclusion: The combination of 1-MT or DMF with CAI may prompt dormant cancer cell to enter an apoptotic state, which is triggered by STAT1 nuclear translocation but obscured by the dormancy-permissive metabolic fitness signals when the tumor cells are exposed to CAI alone.