A Novel Therapeutic Mechanism of Imipridones ONC201/ONC206 in MYCN-Amplified Neuroblastoma Cells via Differential Expression of Tumorigenic Proteins
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Frontiers Media S.A.
Abstract
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 via 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. © Copyright © 2021 El-Soussi, Hanna, Semaan, Khater, Abdallah, Abou-Kheir and Abou-Antoun.
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Cancer stem cells, Fabp5, Hmga1, L1cam, Mycn-amplified neuroblastoma, Onc201/onc206, Pdgfrβ, Γ-h2ax, Antineoplastic agent, Caspase 3, Epidermal growth factor, Fabp5 protein, Fatty acid binding protein, High mobility group a1a protein, Histone h2ax, L1 cell adhesion molecule, Mitomycin, Mycn protein, N myc proto oncogene protein, Nerve cell adhesion molecule l1, Nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1, Octamer transcription factor 4, Onc 201, Onc 206, Platelet derived growth factor beta receptor, Protein, Protein inhibitor, Transcription factor sox2, Tumor necrosis factor related apoptosis inducing ligand, Unclassified drug, Antineoplastic activity, Apoptosis, Article, Cancer stem cell, Cell invasion, Cell migration, Cell proliferation, Cell viability, Comparative study, Controlled study, Down regulation, Drug mechanism, Enzyme inhibition, Gene amplification, Gene expression, Human, Human cell, Imr-32 cell line, Neuroblastoma, Neuroblastoma cell line, Protein expression, Protein phosphorylation, Sh-sy5y cell line, Single drug dose, Sk-n-sh cell line, Therapy effect, Treatment duration