UC Davis

High-risk neuroblastoma (NB) remains one of the most lethal pediatric malignancies, with treatment resistance representing a critical barrier to improved clinical outcomes. Autophagy-mediated drug resistance, wherein cancer cells exploit lysosomal machinery to sustain metabolic homeostasis under therapeutic stress, is a primary driver of this resistance. Bisaminoquinoline 13 (Baq13) is a self-assembling one-component new-chemical-entity nanomedicine (ONN) that induces lysosomal dysfunction and autophagy blockade with 30-fold greater antiproliferative potency than hydroxychloroquine (HCQ). To systematically evaluate Baq13's potential as a chemosensitizer in NB, this study investigated its combination with standard-of-care agents Vincristine and Cisplatin across multiple treatment schedules in SK-N-SH and BE(2)-C cell lines. Combination efficacy was assessed via MTT-based checkerboard titration matrices analyzed with the Highest Single Agent (HSA) synergy model. Additionally, qPCR was performed to assess transcriptional modulation of autophagy markers such as p62, BAX, and BAK1 to elucidate mechanistic underpinnings of the observed synergy patterns. Results demonstrated that drug synergy is highly schedule-and drug-dependent: Baq13 exhibited robust synergy with Vincristine under simultaneous co-treatment and Baq-priming paradigms, attributable to Baq13's neutralization of lysosomal acidity preventing ion-trapping sequestration of Vincristine. In contrast, minimal synergy was observed with Cisplatin, consistent with its nucleus-targeting, lysosome-independent mechanism. qPCR confirmed dose-proportional upregulation of p62, corroborating autophagy blockade as the primary sensitization mechanism. Overall, Baq13 represents a promising schedule-optimized chemosensitizer in NB, with lysosomal pH modulation as a targetable axis to overcome drug sequestration-mediated resistance.