Abstract
BackgroundHuman head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. Despite significant advances in the delivery of treatment and surgical reconstruction, there is no significant improvement of mortality rates for this disease in the past decades. Radiotherapy is the core component of the clinical combinational therapies for HNSCC. However, the tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear. Our previous study has shown that HIV PIs induce cell apoptosis via activation of endoplasmic reticulum (ER) stress. The aim of this study was to examine the role of ER stress in HIV PI-induced radiosensitivity in human HNSCC.Methodology and Principal FindingsHNSCC cell lines, SQ20B and FaDu, and the most commonly used HIV PIs, lopinavir and ritonavir (L/R), were used in this study. Clonogenic assay was used to assess the radiosensitivity. Cell viability, apoptosis and cell cycle were analyzed using Cellometer Vision CBA. The mRNA and protein levels of ER stress-related genes (eIF2α, CHOP, ATF-4, and XBP-1), as well as cell cycle related protein, cyclin D1, were detected by real time RT-PCR and Western blot analysis, respectively. The results demonstrated that L/R dose-dependently sensitized HNSCC cells to irradiation and inhibited cell growth. L/R-induced activation of ER stress was correlated to down-regulation of cyclin D1 expression and cell cycle arrest under G0/G1 phase.Conclusion and SignificanceHIV PIs sensitize HNSCC cells to radiotherapy by activation of ER stress and induction of cell cycle arrest. Our results provided evidence that HIV PIs can be potentially used in combination with radiation in the treatment of HNSCC.
Highlights
Human head and neck carcinoma includes a heterogeneous group of malignancies of the oral cavity, oropharynx, hypopharynx, larynx, lips, paranasal sinuses and salivary glands [1]
To evaluate the effect of the most commonly used HIV protease inhibitors (HIV Propidium Iodide (PI)) (L/R) on head and neck squamous cell carcinoma (HNSCC) proliferation, SQ20B and FaDu cells were treated with different concentrations of lopinavir and ritonavir (L/R) (0, 6.25, 12.5, 25 or 50 μM) for 48 h
To further determine whether HIV PIs were able to sensitize HNSCC to radiation, SQ20B and FaDu cells were pretreated with L/R
Summary
Human head and neck carcinoma includes a heterogeneous group of malignancies of the oral cavity, oropharynx, hypopharynx, larynx, lips, paranasal sinuses and salivary glands [1]. More than 90% of these cancers are squamous cell carcinomas (HNSCC). Cetuximab has been approved for combinational therapy with radiation in patients with unresectable HNSCC [6]. A major challenge of current available therapies (radiation and chemotherapy) is the rapid development of resistance. Identification of cellular/molecular mechanisms responsible for resistance and development of new therapeutic strategies to overcome the resistance would improve the efficiency of current therapies. Human head and neck squamous cell carcinoma (HNSCC) is the sixth most malignant cancer worldwide. The tumor cells have a tendency to develop radiation resistance, which is a major barrier to effective treatment. HIV protease inhibitors (HIV PIs) have been reported with radiosensitizing activities in HNSCC cells, but the underlying cellular/molecular mechanisms remain unclear.
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