Induction of immunogenic necroptosis by shikonin in drug‑resistant head and neck squamous cell carcinoma cells.

In recent years, immune checkpoint inhibitors such as nivolumab have been used to treat recurrent or metastatic head and neck cancer. However, some patients do not respond to nivolumab, and the treatment options for these patients are limited. Therefore, identifying compounds for developing new therapeutic strategies for intractable cancer is important. The acquired multidrug‑resistant metastatic head and neck squamous cell carcinoma cell line, R HSC‑3, expresses refractory cancer‑specific proteins such as the drug excretion transporter, ATP binding cassette subfamily G member 2, the cancer stem cell markers, CD44, SRY‑box transcription factor 9 and Notch, and the poor prognosis factor, fibroblast growth factor 9, and is a useful in vitro model for acquired multidrug resistance. In the present study, compounds that may be more effective than conventional chemotherapeutic drugs in R HSC‑3 cells were searched and the cell death mechanism was investigated. The results showed that naphthoquinones inhibited the viability of R HSC‑3 cells at low concentrations and induced necroptotic cell death. Naphthoquinone‑induced necroptotic cell death in R HSC‑3 cells induced the expression of calreticulin, an immunogenic marker. It was further found that mitochondrial‑derived reactive oxygen species mediated the oxidative stress damage by naphthoquinone‑induced necroptotic cell death in these cells. Moreover, necroptotic cell death by shikonin, a naphthoquinone, may generate immunogenic signals from multidrug‑resistant cancer cells. The present study revealed that naphthoquinones may not only induce necroptosis in refractory head and neck cancer cells but also induce tumor immunity. Therefore, naphthoquinones may represent a new avenue for the development of new therapeutic agents targeting multidrug‑resistant head and neck cancer.