UC Davis

Cancer’s position as the second leading cause of death in the United States as well as the prevalence of treatment resistance highlights the need for new, more efficacious treatment strategies. For this reason, our lab has integrated nanotechnology with initial drug design and developed a one-component new-chemical-entity nanomedicine (ONN) strategy to improve both the potency and delivery kinetics of cancer therapeutics. Bisaminoquinolone 13 (BAQ13) is one of a series of self-delivering ONNs that has shown efficacy in lysosomal disruption and dysfunction as well as autophagy inhibition (3). To combat different types of treatment resistance we investigated BAQ13’s ability to combine with ferroptosis inducers, Paclitaxel (PTX), and radiation as well as its role in the modulation of fatty acid oxidation (FAO) and lipid toxicity. To carry out these experiments we employed methods such as viability assays (MTS and CellTiterGlo), clonogenic assays, an FAO assay kit, confocal microscopy, and western blots. As will be discussed, BAQ13 had potential in combination with ferroptosis inducer Erastin but not RSL3 with further investigation of the BAQ13 – Erastin combination potentially implicating other cell death pathways. BAQ13 also did not consistently synergize with Paclitaxel, despite multiple attempts with different dose ranges and treatment paradigms including 24- or 72-hour pretreatments. In terms of FAO, BAQ13 was observed to downregulate and potentially inhibit FAO activity at higher doses and those same higher doses led to lipid toxicity via lipid droplets, lipid bilayer disorder, and phospholipidosis. Lastly, combination of BAQ13 and radiation proved especially efficacious and synergistic in cells possessing intrinsic and acquired radioresistance and a more widespread screen revealed synergy in other cell lines. Overall, BAQ13 has the potential to be very effective in combination treatment, especially as a strategy to lessen or prevent treatment resistance.