H2 S is a potential pro-proliferative factor of human oral SCC cells that accelerates the progression of the SCC cell cycle; thus, H2 S plays a deleterious role in oral SCC cancer development.

Hydrogen sulfide, the third gaseous transmitter, is one of the main causes of halitosis in the oral cavity. It is generally considered as playing a deleterious role in many oral diseases including oral cancer. However, the regulatory mechanisms involved in the effects of hydrogen sulfide on oral cancer growth remain largely unknown. In the present study, we investigated the underlying mechanisms through CCK-8 assay, EdU incorporation, real-time PCR, western blot and pathway blockade assays. Our results showed that hydrogen sulfide promoted oral cancer cell proliferation through activation of the COX2, AKT and ERK1/2 pathways in a dose-dependent manner. Blocking any of the three above pathways inhibited hydrogen sulfide-induced oral cancer cell proliferation. Meanwhile, blockade of COX2 by niflumic acid downregulated NaHS-induced p-ERK and p-AKT expression. Inactivation of the AKT pathway by GSK690693 significantly decreased NaHS‑induced p-ERK1/2 expression, and inhibition of the ERK1/2 pathway by U0126 markedly increased NaHS-induced p-AKT expression. Either the AKT or ERK1/2 inhibitor did not significantly alter the COX2 expression level. Our data revealed, for the first time, that hydrogen sulfide promotes oral cancer cell proliferation through activation of the COX2/AKT/ERK1/2 axis, suggesting new potential targets to eliminate the effect of hydrogen sulfide on the development of oral cancer.

Background: Quinacrine has potential as a chemosensitizer when combined with chemotherapy, but its anti-cancer mechanisms remain unclear. The purpose of this study was to explore the capability of quinacrine to enhance the cytotoxic effects of cisplatin and the underlying mechanism involved. Methods: The potential role of quinacrine in enhancing the effects of cisplatin was investigated in Hela, SCC-VII, SACC-83 and C6 cancer cell lines with different pathologies. The inhibitory effects of quinacrine plus cisplatin on these cell lines were detected using a CCK-8 assay for viability and a TUNEL assay for apoptosis. The molecules involved in apoptotic signal translation, including cIAP-1, Bax, p53 and cleaved caspase-3, were detected by Western blot to investigate the underlying mechanism. Results: The CCK8 assay showed that quinacrine markedly enhanced the cytotoxicity of cisplatin in a dose-dependant manner in the 4 cancer cell lines. The TUNEL assay showed that treating the 4 cell lines for 24 h with cisplatin plus quinacrine significantly increased the percentage of apoptotic cells compared to treatment with single-agent treatment or untreated controls. Western blot analysis showed that quinacrine plus cisplatin significantly down-regulated cIAP-1 and up-regulated Bax and cleaved caspase-3 expression in Hela and SCC-VII cells compared with single-agent treatment. Conclusions: Quinacrine has the potential to be used as a chemotherapy adjuvant when combined with cisplatin.

The efficacy of bevacizumab plus cetuximab-based chemotherapy remains unclear in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to investigate the anticancer efficacy of a bevacizumab-cetuximab-cisplatin triple-agent combination in treating mouse HNSCC. SCC-VII tumor-bearing C3H mice were treated with bevacizumab, cetuximab and cisplatin either alone or in various combinations. In vivo results showed that the largest delay in tumor growth and the maximum increase in survival were not in the triple-agent combination therapy, but in the bevacizumab plus cisplatin therapy. TUNEL assay showed that the apoptosis indices in bevacizumab plus cisplatin group and a triple-agent combination group were 31.6 ± 12.0% and 6.9 ± 1.3%, respectively. Western blot showed that down-regulation of Bcl-2 and up-regulation of cleaved caspase-3 contributed to the anticancer effect of a triple-agent combination and bevacizumab plus cisplatin. Moreover, the maximum level of cleaved caspase-3 expression was not found in the triple-agent combination group but in the bevacizumab plus cisplatin group. Bevacizumab plus cisplatin therapy is better than bevacizumab-cetuximab-cisplatin triple therapy in the mouse HNSCC model. Our findings suggest that the bevacizumab-cetuximab-cisplatin regimen may not be suitable for treating HNSCC.

Background: The anticancer mechanism of bevacizumab beyond antiangiogenesis remains unclear. Here, we investigated whether intratumorally injected bevacizumab could serve as an effective cisplatin sensitizer in squamous cell carcinoma (SCC) in vivo. Methods: Hela and SCC-VII experimental SCC models were established to investigate the anticancer effect of bevacizumab plus cisplatin and the underlying mechanism using immunostaining, TUNEL, and Western blot assays. Results: Bevacizumab-cisplatin therapy markedly inhibited tumor growth and significantly increased survival in both Hela- and SCC-VII-bearing mice compared with single-agent treatments and the untreated control, respectively. Immunostaining of CD34 showed that intratumorally injected bevacizumab significantly reduced microvessel density in bevacizumab-cisplatin and bevacizumab-alone groups of Hela xenografts. TUNEL assay showed that bevacizumab-cisplatin significantly promoted tumor cell apoptosis compared with single-agent treatments and untreated controls in these 2 models. Western blot showed that upregulation of cleaved caspase-3 and downregulation of Bcl-2 and p-Erk expressions are part of the molecular mechanisms beyond angiogenesis which contribute to the cooperative effect of bevacizumab plus cisplatin in the 2 SCC models. Conclusions: Bevacizumab functions not only as an angiogenesis inhibitor but also as a chemosensitizer which enhances the cytotoxicity of cisplatin and promotes apoptosis of SCC cells.