Abstract
Therapies for head and neck squamous cell carcinoma (HNSCC) are, at best, moderately effective, underscoring the need for new therapeutic strategies. Ceramide treatment leads to cell death as a consequence of mitochondrial damage by generating oxidative stress and causing mitochondrial permeability. However, HNSCC cells are able to resist cell death through mitochondria repair via mitophagy. Through the use of the C6-ceramide nanoliposome (CNL) to deliver therapeutic levels of bioactive ceramide, we demonstrate that the effects of CNL are mitigated in drug-resistant HNSCC via an autophagic/mitophagic response. We also demonstrate that inhibitors of lysosomal function, including chloroquine (CQ), significantly augment CNL-induced death in HNSCC cell lines. Mechanistically, the combination of CQ and CNL results in dysfunctional lysosomal processing of damaged mitochondria. We further demonstrate that exogenous addition of methyl pyruvate rescues cells from CNL + CQ-dependent cell death by restoring mitochondrial functionality via the reduction of CNL- and CQ-induced generation of reactive oxygen species and mitochondria permeability. Taken together, inhibition of late-stage protective autophagy/mitophagy augments the efficacy of CNL through preventing mitochondrial repair. Moreover, the combination of inhibitors of lysosomal function with CNL may provide an efficacious treatment modality for HNSCC.
Highlights
Head and Neck Squamous Cell Carcinoma (HNSCC) is a cancer originating from squamous cells, mainly of the larynx, pharynx, and oral cavity
We examine if direct inhibitors of lysosomal function enhance the therapeutic effect of ceramide nanoliposome (CNL) in drug resistant HSNCC by circumventing autophagic resistance
We further evaluated the mechanisms by which inhibitors of late-stage autophagy/mitophagy can augment mitochondrial-dependent CNL-induced cell death
Summary
Head and Neck Squamous Cell Carcinoma (HNSCC) is a cancer originating from squamous cells, mainly of the larynx, pharynx, and oral cavity. While traditional surgical and chemoradiotherapy offer patients some benefit, these modalities cause serious adverse events and relapse still occurs [2]. Until the very recent approval of immune checkpoint inhibitors [3], Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, was the only targeted therapy approved in combination with chemoradiotherapy for first-line treatment in HNSCC. This regimen causes significant adverse events in over 80% of patients and provides minimal therapeutic benefit [2]. Second-line therapies offer a dismal 6% response [4]. There is an urgent need for new therapeutic approaches
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