Analysis of Retinoid Mediated Anti Cancer Activities

类维生素A已显示出预防和治疗癌症的前景。由于广泛的生物学反应，天然和经典的维甲酸引起许多副作用，限制了其在临床上的使用。类维生素A信号通路的破译，以及可以诱导限制性生物反应的选择性化合物的发现，重新引起了人们对开发用于治疗各种疾病的类维生素A或类维生素A相关分子（RRM）的兴趣。某些RRM可以在许多癌细胞系（包括肺癌细胞）中诱导细胞凋亡，并且已经显示在体内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还不清楚。有趣的是，蛋白质合成和/或mRNA转录是不必要的RRM介导的激活半胱天冬酶在Jurkat细胞，这表明了一种新的机制，这类特定的凋亡类维生素A的行动。我们现在已经观察到，凋亡类维生素A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，并且它们阻止TNF介导的NF κ B活化。JNK和p38已被证明以细胞类型特异性方式参与某些刺激诱导的细胞凋亡。相反，NF κ B的激活阻止细胞凋亡。我们将在这里研究RRM诱导肺癌细胞凋亡的机制。我们将研究JNK/p38激活和NF κ B抑制在类维生素A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类维生素A诱导肺癌细胞凋亡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显著增强我们开发用于治疗和预防肺癌的最佳新型疗法的能力。

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.