El-Soussi Sarra, Hanna Reine, Semaan Hanna, Khater Amanda-Rose, Abdallah Jad, Abou-Kheir Wassim, Abou-Antoun Tamara
Shool of Pharmacy, Lebanese American University, Byblos, Lebanon.
Faculty of Sciences, Lebanese University, Fanar, Lebanon.
Front Pediatr. 2021 Aug 4;9:693145. doi: 10.3389/fped.2021.693145. eCollection 2021.
Neuroblastoma is the most common extracranial nervous system tumor in children. It presents with a spectrum of clinical prognostic measures ranging from benign growths that regress spontaneously to highly malignant, treatment evasive tumors affiliated with increased mortality rates. MYCN amplification is commonly seen in high-risk neuroblastoma, rendering it highly malignant and recurrence prone. In our current study, we investigated the therapeutic potential of small molecule inducers of TRAIL, ONC201, and ONC206 in MYCN-amplified IMR-32 and non-MYCN-amplified SK-N-SH human neuroblastoma cell lines. Our results exhibit potent antitumor activity of ONC201 and ONC206 a novel inhibition of EGF-induced L1CAM and PDGFRβ phosphorylation in both cell lines. Drug treatment significantly reduced cellular proliferation, viability, migration, invasion, tumorsphere formation potential, and increased apoptosis in both cell lines. The protein expression of tumorigenic NMYC, Sox-2, Oct-4, FABP5, and HMGA1 significantly decreased 48 h post-drug treatment, whereas cleaved PARP1/caspase-3 and γH2AX increased 72 h post-drug treatment, compared with vehicle-treated cells in the MYCN-amplified IMR-32 cell line. We are the first to report this novel differential protein expression after ONC201 or ONC206 treatment in human neuroblastoma cells, demonstrating an important multitarget effect which may yield added therapeutic benefits in treating this devastating childhood cancer.
神经母细胞瘤是儿童最常见的颅外神经系统肿瘤。它呈现出一系列临床预后指标，从可自发消退的良性生长到高度恶性、难以治疗且死亡率增加的肿瘤。MYCN扩增在高危神经母细胞瘤中常见，使其具有高度恶性且易于复发。在我们当前的研究中，我们研究了TRAIL小分子诱导剂ONC201和ONC206对MYCN扩增的IMR - 32和非MYCN扩增的SK - N - SH人神经母细胞瘤细胞系的治疗潜力。我们的结果显示ONC201和ONC206具有强大的抗肿瘤活性，并且在两种细胞系中对表皮生长因子（EGF）诱导的L1细胞粘附分子（L1CAM）和血小板衍生生长因子受体β（PDGFRβ）磷酸化有新的抑制作用。药物处理显著降低了两种细胞系的细胞增殖、活力、迁移、侵袭、肿瘤球形成潜力，并增加了细胞凋亡。在MYCN扩增的IMR - 32细胞系中，与用赋形剂处理的细胞相比，药物处理48小时后，致癌性NMYC、性别决定区Y框蛋白2（Sox - 2）、八聚体结合转录因子4（Oct - 4）、脂肪酸结合蛋白5（FABP5）和高迁移率族蛋白A1（HMGA1）的蛋白表达显著降低，而药物处理72小时后，裂解的聚（ADP - 核糖）聚合酶1（PARP1）/半胱天冬酶 - 3和γH2AX增加。我们是第一个报道ONC201或ONC206处理后人神经母细胞瘤细胞中这种新的差异蛋白表达的，证明了一种重要的多靶点效应，这可能在治疗这种毁灭性的儿童癌症中产生额外的治疗益处。
