Amplifying Endoplasmic Reticulum Stress With Adenosine Triphosphate–Coated Gold Nanoclusters: A Promising Approach for the Treatment of Vestibular Schwannoma

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HYPOTHESIS: We hypothesize that gold nanoclusters functionalized with adenosine triphosphate (AuNC@ATP) can inhibit schwannoma growth. BACKGROUND: There is an unmet need for an effective pharmacotherapy to treat vestibular schwannoma (VS) that does not carry the risk profile of current therapeutic modalities. Our previous research demonstrated that AuNC@ATP displays antimicrobial properties through its ability to induce a stress response, resulting in unfolded protein accumulation in the periplasm. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) can trigger ER stress, activating the unfolded protein response (UPR). ER stress has been shown to inhibit tumor growth and activate apoptotic pathways. We therefore sought to determine whether AuNC@ATP could enhance ER stress and inhibit schwannoma growth in vitro. METHODS: Rat schwannoma (S16) cells were utilized as a cellular model. The growth ability of schwannoma cells in the absence and presence of a sublethal dose of AuNC@ATP was compared to establish the inhibitory activity of this ER stress inducer. The ability of AuNC@ATP to induce ER stress was measured using thioflavin T (Th-T) fluorescence. Unfolded protein imaging was performed using TPE-MI, and apoptosis was interrogated using the Caspase-Glo 3/7 Assay. Human VS cells were isolated from tumor samples of three different VS patients. Cytoxicity of gold nanocluster treated cells was assessed using CellTox Green Dye and metabolic activity by MTT assay. RESULTS: The addition of AuNC@ATP to S16 cells for 24 hours resulted in a concentration-dependent decrease in cell viability, with a substantial loss observed at a concentration of 27.93 μM, reaching 95%. Subsequently, S16 cells were cultured in a medium containing a sublethal concentration of AuNC@ATP (6.98 μM). After 96 hours, the cell count reached 107 without AuNC@ATP compared with 105 with it. Additionally, the antitumor activity of AuNC@ATP appears to be mediated through amplified ER stress as evidenced by Th-T fluorescence and accumulation of unfolded proteins in the ER as evidenced by TPE-MI fluorescence. In addition, AuNC@ATP caused cell death of human VS cells in a concentration-dependent manner and almost totally abolished metabolic activity of treated cells. CONCLUSIONS: Our study suggests that using a nano-drug capable of inducing ER stress responses could be a promising strategy for reducing schwannoma growth.

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