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A new rexinoid, NRX194204, prevents carcinogenesis in both the lung and mammary gland
Karen Liby1, Darlene B Royce, Renee Risingsong
1Department of Pharmacology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Purpose:
We evaluated the anti-inflammatory and growth-inhibitory properties of the novel rexinoid NRX194204 (4204) in vitro and then tested its ability to prevent and/or treat experimental lung and estrogen receptor (ER)-negative breast cancer in vivo.
Experimental Design:
In cell culture studies, we measured the ability of 4204 to block the effects of lipopolysaccharide and induce apoptosis. For the lung cancer prevention studies, A/J mice were injected with the carcinogen vinyl carbamate and then fed 4204 (30-60 mg/kg diet) for 15 weeks, beginning 1 week after the administration of the carcinogen. For breast cancer prevention studies, mouse mammary tumor virus-neu mice were fed control diet or 4204 (20 mg/kg diet) for 50 weeks; for treatment, tumors at least 32 mm3 in size were allowed to form, and then mice were fed control diet or 4204 (60 mg/kg diet) for 4 weeks.
Results:
Low nanomolar concentrations of 4204 blocked the ability of lipopolysaccharide and tumor necrosis factor-alpha to induce the release of nitric oxide and interleukin 6 and the degradation of IKBalpha in RAW264.7 macrophage-like cells. In the A/J mouse model of lung cancer, 4204 significantly (P < 0.05) reduced the number and size of tumors on the surface of the lungs and reduced the total tumor volume per slide by 64% to 81% compared with the control group. In mouse mammary tumor virus-neu mice, 4204 not only delayed the development of ER-negative mammary tumors in the prevention studies but also caused marked tumor regression (92%) or growth arrest (8%) in all of the mammary tumors when used therapeutically.
Conclusions:
The combined anti-inflammatory and anticarcinogenic actions of 4204 suggest that it is a promising new rexinoid that should be considered for future clinical trials.
Insights
The novel rexinoid NRX194204 (4204) demonstrated significant anti-inflammatory and anti-cancer effects in preclinical models. This compound effectively reduced lung tumors and inhibited estrogen receptor-negative breast cancer growth, suggesting clinical potential.
Area of Science:
- Pharmacology
- Oncology
- Immunology
Background:
- Novel rexinoids are being investigated for therapeutic potential.
- Inflammation plays a role in cancer development and progression.
Purpose of the Study:
- To evaluate the anti-inflammatory and growth-inhibitory properties of NRX194204 (4204).
- To assess the efficacy of 4204 in preventing and treating experimental lung and estrogen receptor-negative breast cancer in vivo.
Main Methods:
- In vitro studies assessed 4204's ability to block lipopolysaccharide (LPS) effects and induce apoptosis.
- Lung cancer prevention involved administering 4204 to A/J mice exposed to vinyl carbamate.
- Breast cancer studies used MMTV-neu mice for prevention and treatment models with 4204.
Main Results:
- 4204 inhibited LPS-induced nitric oxide, interleukin-6 release, and IKBalpha degradation in macrophages.
- In lung cancer models, 4204 significantly reduced tumor number, size, and volume (64-81%).
- 4204 delayed breast tumor development and achieved significant regression (92%) or growth arrest (8%) in established tumors.
Conclusions:
- NRX194204 exhibits combined anti-inflammatory and anti-cancer activities.
- These findings support 4204 as a promising rexinoid candidate for clinical trials.
