Comparison of the rexinoids Bexarotene and Pyrimidine‐Bexarotene in a preclinical model of lung carcinogenesis
Authors: Zhang Di , Leal Ana S. , Carapellucci Sarah , Zydeck Kayla , Chaaban Nicole , Sporn Michael B. , Wagner Carl E. , Liby Karen T. 
Published: November 2023

Lung cancer remains the leading cause of cancer deaths around the world. It is estimated that there will be over 150,000 deaths in the United States alone from this disease every year. With no significant improvement in 5 year survival rates over the past 30 years, effective prevention or early intervention is a promising approach to reduce the high mortality of lung cancer. Rexinoids are selective ligands for retinoid X receptors (RXR), which regulate the expression of a wide variety of genes. As transcription factors, rexinoids play important roles in proliferation, differentiation, and apoptosis, which are highly relevant in cancer. Bexarotene is the only synthetic rexinoid that has been approved by the FDA and is used for the treatment of refractory cutaneous T‐cell lymphoma. It has also been tested in various clinical trials for lung cancer and breast cancer. However, Bexarotene is not potent or selective enough for RXRs, causing limited efficacy and unacceptable toxicities. Therefore, we synthesized a series of new rexinoids and screened them for their ability to inhibit nitric oxide (NO) production in RAW264.7 macrophage‐like cells stimulated with LPS. Several of these compounds inhibited NO production at nanomolar concentrations. Based on this screening and other in vitro assays, two new rexinoids were chosen for in vivo testing. Female A/J mice were injected i.p. with vinyl carbamate (16 mg/kg). One week later, the mice were fed control diet or rexinoids in diet (40–80 mg/kg diet) for 16 weeks. Tumor number, size and histopathology were then evaluated. All of the rexinoids reduced the number and size of the lung tumors. However, Bexarotene only reduced the average number of tumors by 8–17%, while a new pyrimidine‐analog of Bexarotene—henceforth, pyrimidine‐Bexarotene—reduced the number of tumors by 24–28%. The average tumor burden on lung sections was also reduced by pyrimidine‐Bexarotene by 59% compared to the controls (from 0.47 ± 0.19 mm3 in the control group to 0.19 ± 0.05 mm3 in the treated group). In contrast, average tumor burden was 0.35 ± 0.08 mm3 in the group treated with Bexarotene, a reduction of 26%. Notably, the percentage of high grade tumors (both histological and nuclear characteristics) were significantly (p<0.05) higher in the mice fed Bexarotene (63%) than in the control group (38%), while the percentage of high grade tumors was only 34% in the pyrimidine‐Bexarotene group. Since a major side effect of rexinoids is an elevation in triglyceride levels, we measured total triclycerides in both liver and plasma. Pyrimidine‐Bexarotene reduced triclyceride levels in the liver (7.17 ug/kg tissue) compared to Bexarotene (8.23 ug/kg tissue) and plasma (3.6mg/ml vs. 4.8mg/ml, respectively; p<0.05). These studies suggest that new rexinoids can be synthesized that are superior to Bexarotene for prevention of lung cancer. Additional synthesis and testing of new rexinoids will be performed to further enhance the potency and selectivity of this promising class of drugs.