Investigating the Therapeutic Effects of Small Molecule Imipridones In Pediatric Neuroblastoma

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dc.contributor.author El Soussi, Sarra
dc.date.accessioned 2022-04-05T11:33:29Z
dc.date.available 2022-04-05T11:33:29Z
dc.date.copyright 2020 en_US
dc.date.issued 2020-11-19
dc.identifier.uri http://hdl.handle.net/10725/13447
dc.description.abstract The small molecule inducers of TRAIL ONC201/TIC10 and its analog ONC206 exhibit anti-tumor activity by inhibiting AKT/ERK phosphorylation and causing early activation of the integrated stress response. They are reported to inhibit the DRD2 receptors and activate mitochondrial ClpP leading to apoptosis and reduced proliferation in various tumors. Neuroblastoma is the most common extra-cranial nervous system tumor in children that presents with a spectrum of clinical prognostic measures ranging from benign growths that regress spontaneously to highly malignant, treatment evasive tumors affiliated with high mortality rates. MYCN amplification renders this tumor highly malignant and recurrence prone. In our current study we report for the first time, a novel inhibition of EGF-induced L1CAM and PDGFRβ phosphorylation with either ONC201 or ONC206 treatment in human MYCN-amplified neuroblastoma IMR-32 and non-MYCN amplified SK-N-SH cell lines. Drug treatment in these cells significantly reduced cellular proliferation, viability, migration and increased apoptosis. Tumorsphere formation potential was further significantly reduced with either drug treatment in both cell lines with ONC206 exhibiting much higher potency. MYCN expression was significantly abrogated in the IMR-32 cell line with either drug treatment. The protein expression of Sox-2, Oct-4, FABP5 and HMGA1 was significantly reduced whereas cleaved PARP1 and caspase-3 and p-H2AX was increased 48 h after drug treatment 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 these cells. Our findings demonstrate an important multi-target effect of imipridones that may yield added therapeutic benefits in treating this devastating cancer. en_US
dc.language.iso en en_US
dc.subject Neuroblastoma -- Molecular aspects en_US
dc.subject Neuroblastoma -- Treatment en_US
dc.subject Cell proliferation -- Drug effects en_US
dc.subject Lebanese American University -- Dissertations en_US
dc.subject Dissertations, Academic en_US
dc.title Investigating the Therapeutic Effects of Small Molecule Imipridones In Pediatric Neuroblastoma en_US
dc.type Thesis en_US
dc.term.submitted Fall en_US
dc.author.degree MS in Pharmaceutical Development And Management en_US
dc.author.school SOP en_US
dc.author.idnumber 201806724 en_US
dc.author.commembers Abdallah, Jad
dc.author.commembers Khazen, George
dc.author.department Pharmaceutical Sciences en_US
dc.description.physdesc 1 online resource (xi, 83 leaves): col. ill. en_US
dc.author.advisor Abou-Antoun, Tamara
dc.keywords ONC201/206 en_US
dc.keywords neuroblastoma en_US
dc.keywords PDGFRβ en_US
dc.keywords L1CAM en_US
dc.keywords HMGA1 en_US
dc.keywords FABP5 en_US
dc.keywords Sox-2 en_US
dc.keywords Oct-4 en_US
dc.keywords MYCN en_US
dc.keywords y-H2AX en_US
dc.description.bibliographiccitations Bibliography: leaf 55-83. en_US
dc.author.email sarra.elsoussi@lau.edu en_US
dc.identifier.tou http://libraries.lau.edu.lb/research/laur/terms-of-use/thesis.php en_US
dc.publisher.institution Lebanese American University en_US
dc.author.affiliation Lebanese American University en_US

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