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Pulmonary carcinoma is a major cause of cancer-related death worldwide. Because the prognosis remains poor, the development of novel therapeutic approaches is highly desirable. In this study, we investigated the effect of Tamibarotene (Am80), a retinoic acid derivative, on the growth of human lung adenocarcinoma cell line A549. Our ultimate goal in this study is to provide pulmonary carcinoma therapy with a new approach. First, we treated A549 cells with Am80 to clarify the effect of cell-growth inhibition. Am80 significantly reduced the viability of A549 cells in a dose-and time-dependent manner. The IC 50 value, which was determined using CellTiter-Glo Luminescent Cell Viability assay, of Am80 and all-trans retinoic acid (ATRA) against A549 cells at 6 d was 49.1 8.1 µM and 92.3 8.0 µM, respectively. Furthermore, Am80 reduced the anchorage-independent cell-growth ability of A549 cells. However, it was not an apoptosis-mediated mechanism. These results suggest that Am80 can be used as an effective, novel cell-growth inhibitor in lung adenocarcinoma.Key words Tamibarotene (Am80); cell-growth inhibition; pulmonary carcinoma; retinoid Pulmonary carcinoma is a major cause of cancer-related death worldwide.1) Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all pulmonary carcinoma cases. This cancer is categorized into histological subtypes of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.2) Because the prognosis of NSCLC remains poor, the development of novel therapeutic approaches is highly desirable.3) Lung adenocarcinoma, accounting for approximately 40% of all pulmonary carcinomas, is currently one of the most common histological types and its incidence has gradually increased in recent years in many countries. 4)Conventional chemotherapeutic regimens against most solid tumors have reached an efficacy plateau and display significant toxicity. In the last decade, the targeted inhibition of oncogenic driver mutations with molecular therapies, of which the epidermal growth factor receptor (EGFR) and the anaplastic lymphoma kinase (ALK) are the most studied targets, has brought dramatic improvements in the overall survival in defined subsets of patients.5) Unfortunately, in many cases, patients develop resistance to these agents via secondary mutations and alternative mechanisms. 6)In this study, we focused on a retinoic acid derivative as a cell-growth inhibitor in lung adenocarcinoma. Retinoids can inhibit the growth and modulate the differentiation of a variety of tumor cell types in vitro and in vivo.7) A novel synthetic retinoid, Tamibarotene (Am80), has been developed and applied as acute promyelocytic leukemia treatment. Am80 offers higher differentiation-inducing property and is approximately ten times more potent than all-trans retinoic acid (ATRA) as an in vitro inducer of differentiation in NB-4 and HL-60 leukemia cells. 8,9) In addition, Am80 is chemically more resistant to light, heat, and oxidation and has higher receptor selectivity compared with ATRA. Am80 is a...

Pulmonary emphysema is a disease in which lung alveoli are irreversibly damaged, thus compromising lung function. Our previous study revealed that all-trans-retinoic acid (ATRA) induces the differentiation of human lung alveolar epithelial type 2 progenitor cells and repairs the alveoli of emphysema model mice. ATRA also reportedly has the ability to activate peroxisome proliferator-activated receptor (PPAR) β/δ. A selective PPARβ/δ ligand has been reported to induce the differentiation of human keratinocytes during wound repair. Here, we demonstrate that treatment using a high-affinity PPARβ/δ agonist, GW0742, reverses the lung tissue damage induced by elastase in emphysema-model mice and improves respiratory function. Mice treated with elastase, which collapsed their alveoli, were then treated with either 10% dimethyl sulfoxide (DMSO) in saline (control group) or GW0742 (1.0 mg/kg twice a week) by pulmonary administration. Treatment with GW0742 for 2 weeks increased the in vivo expression of surfactant proteins A and D, which are known alveolar type II epithelial cell markers. GW0742 treatment also shortened the average distance between alveolar walls in the lungs of emphysema model mice, compared with a control group treated with 10% DMSO in saline. Treatment with GW0742 for 3 weeks also improved tissue elastance (cm H 2 O/mL), as well as the ratio of the forced expiratory volume in the first 0.05 s to the forced vital capacity (FEV 0.05/ FVC). In each of these experiments, GW0742 treatment reversed the damage caused by elastase. In conclusion, PPARβ/δ agonists are potential therapeutic agents for pulmonary emphysema.

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Chronic obstructive pulmonary disease (COPD) is an intractable pulmonary disease that causes widespread and irreversible alveolar collapse. Although COPD occurs worldwide, only symptomatic therapy is currently available. Our objective is the development of therapeutic agents to eradicate COPD. Therefore, we focused on 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid (Am80), which is a derivative of all- retinoic acid. We evaluated the effects of Am80 on alveolar repair in a novel COPD model of adiponectin-deficient mice. This mouse model has more symptoms similar to human COPD than the classic elastase-induced emphysema mouse model. Lung volume, computed tomography (CT) values, low-attenuation area ratios, and bone and fat mass were measured by CT. However, the administration of Am80 did not affect these results. To examine the degree of destruction in the alveoli, the mean linear intercept of the alveolar walls was calculated, and assessment of this value confirmed that there was a significant difference between the control (46.3 ± 2.3 m) and 0.5 mg/kg Am80-treated group (34.4 ± 1.7m). All mice survived the treatment, which lasted for more than 6 months, and we did not observe any abnormalities in autopsies performed at 80 weeks of age. These results suggested that Am80 was effective as a novel therapeutic compound for the treatment of COPD.