Inhibition of host NOX1 blocks tumor growth and enhances checkpoint inhibitor–based immunotherapy

Abstract

NADPH oxidases catalyze the production of reactive oxygen species and are involved in physio/pathological processes. NOX1 is highly expressed in colon cancer and promotes tumor growth. To investigate the efficacy of NOX1 inhibition as an anticancer strategy, tumors were grown in immunocompetent, immunodeficient, or NOX1-deficient mice and treated with the novel NOX1-selective inhibitor GKT771. GKT771 reduced tumor growth, lymph/angiogenesis, recruited proinflammatory macrophages, and natural killer T lymphocytes to the tumor microenvironment. GKT771 treatment was ineffective in immunodeficient mice bearing tumors regardless of their NOX-expressing status. Genetic ablation of host NOX1 also suppressed tumor growth. Combined treatment with the checkpoint inhibitor anti-PD1 antibody had a greater inhibitory effect on colon carcinoma growth than each compound alone. In conclusion, GKT771 suppressed tumor growth by inhibiting angiogenesis and enhancing the recruitment of immune cells. The antitumor activity of GKT771 requires an intact immune system and enhances anti-PD1 antibody activity. Based on these results, we propose blocking of NOX1 by GKT771 as a potential novel therapeutic strategy to treat colorectal cancer, particularly in combination with checkpoint inhibition.

NOX1 Inhibition Attenuates Kidney Ischemia-Reperfusion Injury via Inhibition of ROS-Mediated ERK Signaling

“…Second, further experiments with a more specific way to inhibit NOX1 expression are needed to find NOX1′s effect in IRI. GKT771, a highly selective NOX1 inhibitor [ 57 ] or NOXA1ds, a peptide NOX1 inhibitor with greater specificity and isoform selectivity [ 58 ], might reveal the specific effect of NOX1-selective inhibition. Third, our experiment was not performed on murine or human kidney epithelial cell lines.…”

The NADPH Oxidase Isoform 1 Contributes to Angiotensin II-Mediated DNA Damage in the Kidney

“…This is in line with the observation of reduced oxidative stress levels in this group. Nox1 was suggested to be involved in tumor progression, since knockout of this isoform reduced the size of fibro sarcomas, colon, and liver tumors [ 40 , 42 , 43 ]. As molecular mechanisms, the role of Nox1 in the production of inflammatory cytokines or in the promotion of angiogenesis has been discussed.…”

Immune gene prognostic signature for disease free survival of gastric cancer Translational research of an artificial intelligence survival predictive system

“…Cell proliferation was mediated by NADPH Oxidase 1 (Nox1) expression in colon carcinoma cell lines [33]. High expression of Nox1 in colon cancer accelerated the tumor growth and inhibition of Nox1 might become a new therapeutic strategy for colorectal cancer treatment [34]. Low expression of Interferon Induced Protein 44 Like (IFI44L) impaired antiviral state induced by IFN and might be potential candidate for reduction of virus replication [35].…”