Nakagawa Yu, Yanagita Ryo C, Hamada Naoko, Murakami Akira, Takahashi Hideyuki, Saito Naoaki, Nagai Hiroshi, Irie Kazuhiro
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
J Am Chem Soc. 2009 Jun 10;131(22):7573-9. doi: 10.1021/ja808447r.
Protein kinase C (PKC) is widely recognized as a therapeutic target in intractable diseases such as cancer, Alzheimer's disease (AD), and acquired immune deficiency syndrome (AIDS). While inhibition of PKC is a general therapeutic strategy for the treatment of cancer, PKC activators are potential therapeutic agents for AD and AIDS. However, concerns have been raised about their therapeutic use since PKC activators such as phorbol esters exhibit potent tumor-promoting activities. Naturally occurring bryostatin 1 (bryo-1), prostratin, and 12-deoxyphorbol 13-phenylacetate (DPP) are fascinating PKC activators without tumor-promoting activities. Bryo-1 is currently in clinical trials for the treatment of cancer and is also effective against AD. Prostratin and DPP are attractive candidates for the adjunctive treatment of human immunodeficiency virus (HIV) infection. However, their limited availability from natural sources and synthetic complexity have hampered further development as therapeutic agents. We report here easy access (22 steps) to a simple analogue (1) of the tumor-promoting aplysiatoxin (ATX) as a novel PKC activator with anticancer and anti-tumor-promoting activities. Anticancer activities of 1 against several human cancer cell lines were comparable to those of bryo-1. Moreover, 1 as well as bryo-1 significantly inhibited the Epstein-Barr virus early antigen (EBV-EA) induction by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), whereas ATX strongly induced EBV-EA. This inhibitory effect is characteristic of antitumor promoters. Compound 1 as well as bryo-1 displayed significant binding and activation of PKCdelta and induced its translocation to the nuclear membrane in CHO-K1 cells. This study provides a synthetically accessible PKC activator with bryo-1-like activities, which could be another therapeutic lead for cancer, AD, and AIDS.
蛋白激酶C（PKC）被广泛认为是癌症、阿尔茨海默病（AD）和获得性免疫缺陷综合征（AIDS）等难治性疾病的治疗靶点。虽然抑制PKC是治疗癌症的一般治疗策略，但PKC激活剂是治疗AD和AIDS的潜在治疗药物。然而，由于佛波酯等PKC激活剂具有强大的促肿瘤活性，人们对它们的治疗用途提出了担忧。天然存在的苔藓抑素1（bryo-1）、原他汀和12-脱氧佛波醇13-苯乙酸酯（DPP）是令人着迷的无促肿瘤活性的PKC激活剂。Bryo-1目前正在进行治疗癌症的临床试验，对AD也有效。原他汀和DPP是辅助治疗人类免疫缺陷病毒（HIV）感染的有吸引力的候选药物。然而，它们从天然来源获取有限且合成复杂，阻碍了其作为治疗药物的进一步开发。我们在此报告了一种易于获得（22步）的促肿瘤海兔毒素（ATX）的简单类似物（1），它是一种具有抗癌和抗促肿瘤活性的新型PKC激活剂。1对几种人类癌细胞系的抗癌活性与bryo-1相当。此外，1和bryo-1均显著抑制肿瘤启动子12-O-十四烷酰佛波醇13-乙酸酯（TPA）诱导的爱泼斯坦-巴尔病毒早期抗原（EBV-EA），而ATX强烈诱导EBV-EA。这种抑制作用是抗肿瘤启动子的特征。化合物1和bryo-1在CHO-K1细胞中均表现出对PKCδ的显著结合和激活，并诱导其转位至核膜。本研究提供了一种具有bryo-1样活性的可合成获得的PKC激活剂，它可能是癌症、AD和AIDS的另一种治疗先导物。
