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Updated: May 29, 2025
Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Oklahoma nitrone-007 is an effective anticancer therapeutic agent targeting inflammatory and immune metabolism
Sugantha Priya Elayapillai1, Anjalika Gandhi1, Samrita Dogra1
1Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Abstract:
Advanced-stage endometrial cancer patients typically receive a combination of platinum and paclitaxel chemotherapy. However, limited treatment options are available for those with recurrent disease, and there is a need to identify alternative treatment options for the advanced setting. Our goal was to evaluate the preclinical efficacy and mechanism of action of the anticancer drug Oklahoma Nitrone-007 (OKN-007) alone and in combination with carboplatin and paclitaxel in endometrial cancer. The effect of OKN-007 on the metabolic viability of endometrial cancer cells in both two- and three-dimensional (2D and 3D) cultures, as well as on clonogenic growth, in vitro was assessed. We also evaluated OKN-007 in vivo using an intraperitoneal xenograft model and targeted gene expression profiling to determine the molecular mechanism and gene expression programs altered by OKN-007. Our results showed that endometrial cancer cells were generally sensitive to OKN-007 in both 2D and 3D cultures. OKN-007 displayed a reduction in 3D spheroid and clonogenic growth. Subsequent targeted gene expression profiling revealed that OKN-007 significantly downregulated the immunosuppressive immunometabolic regulatory enzyme indolamine 2,3-dioxygenase 1 (IDO1) (-11.27-fold change) and modulated upstream inflammatory pathways that regulate IDO1 expression (interferon-gamma [IFN-γ], Janus kinase/signal transducer and activator of transcription [JAK-STAT], transforming growth factor beta [TGF-β], and nuclear factor-kappa B [NF-κB]), downstream IDO1 effector pathways (mammalian target of rapamycin [mTOR] and aryl hydrocarbon receptor [AhR]), and altered T cell signaling pathways. OKN-007 treatment reduced IDO1, sulfatase 2 (SULF2), and TGF-β protein expression in vivo and inhibited TGF-β, NF-κB, and AhR-mediated nuclear signaling in vitro. These findings indicate that OKN-007 surmounts proinflammatory, immunosuppressive, and protumorigenic pathways and is a promising approach for the effective treatment of endometrial cancer. SIGNIFICANCE STATEMENT: Women with advanced and recurrent endometrial cancer have limited therapeutic options. Oklahoma Nitrone-007 (OKN-007), which has minimal toxicity and is currently being evaluated in early-phase clinical trials for the treatment of cancer, is a potential new strategy for the treatment of endometrial cancer.
Insights
Oklahoma Nitrone-007 (OKN-007) shows promise for treating endometrial cancer by reducing tumor growth and downregulating immunosuppressive pathways. This novel drug offers a potential new strategy for patients with advanced or recurrent disease, demonstrating minimal toxicity in preclinical studies.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Advanced-stage endometrial cancer patients often receive platinum and paclitaxel chemotherapy.
- Limited treatment options exist for recurrent endometrial cancer, necessitating alternative strategies.
- There is a critical need for novel therapeutic approaches in advanced endometrial cancer.
Purpose of the Study:
- To evaluate the preclinical efficacy of Oklahoma Nitrone-007 (OKN-007) in endometrial cancer.
- To determine the mechanism of action of OKN-007, alone and in combination therapy.
- To assess OKN-007's impact on metabolic viability, clonogenic growth, and gene expression profiles.
Main Methods:
- Assessed OKN-007's effect on endometrial cancer cell metabolic viability in 2D and 3D cultures.
- Evaluated OKN-007's impact on clonogenic growth in vitro.
- Utilized an intraperitoneal xenograft model and targeted gene expression profiling in vivo.
Main Results:
- Endometrial cancer cells demonstrated sensitivity to OKN-007 in both 2D and 3D cultures.
- OKN-007 significantly downregulated the immunosuppressive enzyme indolamine 2,3-dioxygenase 1 (IDO1).
- OKN-007 modulated inflammatory, IDO1 effector, and T cell signaling pathways, reducing tumor-promoting factors.
Conclusions:
- OKN-007 effectively overcomes proinflammatory, immunosuppressive, and protumorigenic pathways in endometrial cancer.
- OKN-007 exhibits preclinical efficacy and a promising mechanism of action for endometrial cancer treatment.
- OKN-007 represents a potential new therapeutic strategy with minimal toxicity for advanced and recurrent endometrial cancer.
