Analysis of Retinoid Mediated Anti Cancer Activities

类维生素a已显示出预防和治疗癌症的希望。由于广泛的生物反应，天然和经典类维生素a会引起许多副作用，限制了它们在临床中的应用。类维甲酸信号通路的破译，以及可诱导限制性生物反应的选择性化合物的发现，重新燃起了开发类维甲酸或类维甲酸相关分子（RRMs）用于治疗各种疾病的兴趣。某些RRMs可以诱导包括肺癌细胞在内的许多癌细胞系的凋亡，并且在体内已被证明对非小细胞肺癌肿瘤有效。然而，这些化合物诱导细胞凋亡的机制尚不清楚。有趣的是，在Jurkat细胞中，rrm介导的caspase激活并不需要蛋白质合成和/或mRNA转录，这表明这种特殊类型的凋亡类维甲酸具有新的作用机制。我们现在已经观察到，凋亡的类维甲酸引起肺癌细胞中Jun n -末端激酶（JNK）和p38激酶活性的显著增加，并阻止tnf介导的NFkappaB激活。JNK和p38已被证明以特定细胞类型的方式参与某些刺激诱导细胞凋亡。相反，NFkappaB的激活可以阻止细胞凋亡。我们将在此研究RRMs诱导肺癌细胞凋亡的机制。我们将研究JNK/p38激活和NFkappaB抑制在类维甲酸诱导的细胞凋亡中的作用。选择性RRMS诱导细胞凋亡的机制将在体内进一步研究。该研究的潜在结果将为肺癌细胞中诱导凋亡的类维甲酸的作用机制提供有价值的信息。重要的是，动物研究将证实类维生素a是否可以通过激活与体外观察到的相同的途径在体内诱导细胞凋亡。了解这些新型抗癌化合物的作用机制将大大提高我们开发治疗和预防肺癌的最佳新疗法的能力。

Retinoids have shown promise for the prevention and treatment of cancer. Because of broad biological responses, natural and classical retinoids cause numerous side effects that have limited their use in clinic. The deciphering of retinoid signaling pathways, together with the discovery of selective compounds that can induce a restricted biological response, has revived interest in developing retinoids or retinoid related molecules (RRMs) for the treatment of various diseases. Certain RRMs can induce apoptosis in a number of cancer cell lines, including lung cancer cells, and have been shown to be effective against non-small cell lung cancer tumors in vivo. However, the mechanism of apoptosis induced by these compounds is not well understood. Interestingly, protein synthesis and/or mRNA transcription are not necessary for the RRM-mediated activation of caspases in Jurkat cells, suggesting a novel mechanism of action for this particular class of apoptotic retinoids. We have now observed that apoptotic retinoids cause a significant increase in Jun N-terminal kinase (JNK) and p38 kinase activities in lung cancer cells and they prevent TNF-mediated activation of NFkappaB. JNK and p38 have been shown to participate in the induction of apoptosis by certain stimuli in a cell type specific manner. In contrast, the activation of NFkappaB prevents apoptosis. We will investigate here the mechanism by which RRMs induce apoptosis in lung cancer cells. We will examine the role of JNK/p38 activation and NFkappaB inhibition in retinoid- induced apoptosis. The mechanisms of apoptosis induced by selective RRMS will be further examined in vivo. The potential outcome from the proposed research will provide valuable information on the mechanism of action of apoptosis inducing retinoids in lung cancer cells. Importantly, animal studies will confirm if retinoids can induce apoptosis in vivo through the activation of the same pathways as observed in vitro. Understanding the mechanism of action of these novel anti-cancer compounds should significantly enhance our abilities to develop optimal novel therapeutics for the treatment and prevention of lung cancer.