VANL-100: Shaking up the Game of Glycogen Synthase Kinase-3beta Inhibition in SH-SY5Y Human Neuroblastoma Cells

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University of Guelph

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This thesis introduces VANL-100, a conjugate of alpha-lipoic acid and naringenin, as a novel inhibitor of glycogen synthase kinase-3beta (GSK3B). Immunoblotting analysis in SH-SY5Y cells evidenced this through increased GSK3B phosphorylation at serine-9. Interestingly, neither of the parent compounds of VANL-100, individually or combined without a chemical bond, achieved inhibition of GSK3B, underscoring the significance of conjugate therapy. VANL-100 was then benchmarked against CHIR99021, a gold-standard GSK3B inhibitor. Immunofluorescence illustrated that both compounds seemed to notably promote nuclear migration of beta-catenin, a key GSK3B target. Cell viability assays highlighted VANL-100 and its ability to boost neuroblastoma cell viability, whereas CHIR99021 diminished it. Critically, VANL-100 outperformed CHIR99021 in counteracting cell loss due to amyloid beta toxicity. These findings spotlight the significant potential of VANL-100 for GSK3B inhibition and advocate for its continued exploration across diverse disease models.

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Glycogen synthase kinase-3beta (GSK3B), CHIR99021, Akt, Conjugate therapy, Neuroblastoma, VANL-100, Inhibitor, Alpha-lipoic acid, Naringenin, Beta-catenin

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