Abstract
Head and neck squamous cell carcinoma (HNSCC) is a highly lethal disease with high-level of epidemic both in the world and Taiwan. Previous studies support that head and neck cancer-initiating cells (HN-CICs), a subpopulation of cancer cells with enhanced stemness properties, contribute to therapy resistance and tumor recurrence. Arsenic trioxide (As2O3; ATO) has shown to be an effective anti-cancer drug targeting acute promyelocytic leukemia (APL). Combinatorial treatment with high dose of ATO and cisplatin (CDDP) exert synergistic apoptotic effects in cancer cell lines of various solid tumors, however, it may cause of significant side effect to the patients. Nevertheless, none has reported the anti-cancerous effect of ATO/CDDP targeting HN-CICs. In this study, we aim to evaluate the low dose combination of ATO with conventional chemo-drugs CDDP treatment on targeting HN-CICs. We first analyzed the inhibitory tumorigenicity of co-treatment with ATO and chemo-drugs on HN-CICs which are enriched from HNSCC cells. We observed that ATO/CDDP therapeutic regimen successfully synergized the cell death on HN-CICs with a Combination Index (CI) <1 by Chou-Talalay's analysis in vitro. Interestingly, the ATO/CDDP regimen also induced exaggerated autophagy on HN-CICs. Additionally, this drug combination strategy also empowered both preventive and therapeutic effect by in vivo xenograft assays. Finally, we provide the underlying molecular mechanisms of ATO-based therapeutic regimen on HN-CICs. Together, low dose of combinatorial ATO/CDDP regimen induced cell death as well as exacerbated autophagy via AMPK-STAT3 mediated pathway in HN-CICs.
Highlights
Head and neck cancer (HNC), a disease with a major worldwide burden
In order to evaluate the anti-cancerous efficacy of low dose combinatorial treatment with ATO/CDDP, we performed the co-treatment on head and neck cancer-initiating cells (HN-cancer initiating cells (CICs)) by combining different doses of ATO with different doses of conventional chemo-drug, CDDP
The flow cytometry analyses indicated that the cell number of Annexin V/PI positive staining under the co-treatment of ATO/CDDP was substantially higher than that of HN-CICs with single treatment (Figure 1A)
Summary
Head and neck cancer (HNC), a disease with a major worldwide burden. About 95% of HNC is squamous cell carcinoma (HNSCC) which make up the sixth most common cause of cancer death. It is responsible for 300,000 deaths annually [1]. HNSCC is considered one of the most common cancers leading to significant mortality and morbidity in Taiwan. Treatment for HNSCC usually involves therapies with surgery, radiation, or chemotherapy alone or concurrent chemotherapy/radiation. The overwhelming majority of HNSCC patients’ survival outcomes still remain poor. The 5-year overall survival rate of HNSCC’s patients is about 40–50% [2], illustrating the urgent need to develop novel therapeutic options to prolong the patients survival
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