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

Abstract

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.

Not Only Immune Escape—The Confusing Role of the TRP Metabolic Pathway in Carcinogenesis

“…This leads to cell dormancy-a state in which cells poorly proliferate and are highly resistant to pharmacological intervention (Figure 1). Shi et al showed that blocking IDO1/Kyn/AhR pathway restores a cell cycle and induced apoptosis of TRCs [109], thus may be a proper strategy in disease relapse prevention. Additionally, TRCs release Kyn which then upregulates PD-1 expression on CD8+ Tcells by AhR activation (Figure 4) [110].…”