Singhal Sharad S, Singhal Sulabh, Singhal Preeti, Singhal Jyotsana, Horne David, Awasthi Sanjay
Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA, USA.
University of California at San Diego, La Jolla, CA, USA.
Oncotarget. 2017 Apr 25;8(17):29428-29441. doi: 10.18632/oncotarget.15204.
Neuroblastoma, a rapidly growing yet treatment responsive cancer, is the third most common cancer of children and the most common solid tumor in infants. Unfortunately, neuroblastoma that has lost p53 function often has a highly treatment-resistant phenotype leading to tragic outcomes. In the context of neuroblastoma, the functions of p53 and MYCN (which is amplified in ~25% of neuroblastomas) are integrally linked because they are mutually transcriptionally regulated, and because they together regulate the catalytic activity of RNA polymerases. Didymin is a citrus-derived natural compound that kills p53 wild-type as well as drug-resistant p53-mutant neuroblastoma cells in culture. In addition, orally administered didymin causes regression of neuroblastoma xenografts in mouse models, without toxicity to non-malignant cells, neural tissues, or neural stem cells. RKIP is a Raf-inhibitory protein that regulates MYCN activation, is transcriptionally upregulated by didymin, and appears to play a key role in the anti-neuroblastoma actions of didymin. In this review, we discuss how didymin overcomes drug-resistance in p53-mutant neuroblastoma through RKIP-mediated inhibition of MYCN and its effects on GRK2, PKCs, Let-7 micro-RNA, and clathrin-dependent endocytosis by Raf-dependent and -independent mechanisms. In addition, we will discuss studies supporting potential clinical impact and translation of didymin as a low cost, safe, and effective oral agent that could change the current treatment paradigm for refractory neuroblastoma.
神经母细胞瘤是一种生长迅速但对治疗有反应的癌症，是儿童中第三常见的癌症，也是婴儿中最常见的实体瘤。不幸的是，失去p53功能的神经母细胞瘤通常具有高度耐药的表型，导致悲惨的结局。在神经母细胞瘤的背景下，p53和MYCN（在约25%的神经母细胞瘤中扩增）的功能紧密相连，因为它们相互转录调控，并且共同调节RNA聚合酶的催化活性。地迪明是一种源自柑橘的天然化合物，在培养中可杀死p53野生型以及耐药性p53突变型神经母细胞瘤细胞。此外，口服地迪明可使小鼠模型中的神经母细胞瘤异种移植物消退，对非恶性细胞、神经组织或神经干细胞无毒性。RKIP是一种Raf抑制蛋白，可调节MYCN的激活，受地迪明转录上调，并且似乎在地迪明的抗神经母细胞瘤作用中起关键作用。在本综述中，我们讨论地迪明如何通过RKIP介导的对MYCN的抑制以及其对GRK2、蛋白激酶C、Let-7微小RNA和网格蛋白依赖性内吞作用的影响，通过Raf依赖性和非依赖性机制克服p53突变型神经母细胞瘤中的耐药性。此外，我们将讨论支持地迪明作为一种低成本、安全且有效的口服药物的潜在临床影响和转化的研究，这种药物可能会改变目前难治性神经母细胞瘤的治疗模式。
