Abstract
V-ATPase is involved in the acidification of the microenvironment around/in solid tumors, such as oral squamous cell carcinoma (OSCC). V-ATPase is thought to induce tumor invasion and multi-drug resistance in several malignant tumors, and it also contributes to maintaining the intracellular pH under an acidic microenvironment by inducing proton extrusion into the extracellular medium. However, there is little information regarding the effects of V-ATPase inhibitors on OSCCs. In this study, the effects of a V-ATPase inhibitor, concanamycin A1 (CMA), on the proliferation and apoptosis of OSCC were investigated in vitro. We used four OSCC cell lines, MISK81-5, SAS, HSC-4 and SQUU-B. Acridine orange staining revealed that the red fluorescence was reduced in all of the low concentration CMA-treated OSCC cells, indicating that the acidification of vesicular organelles in the OSCCs was prevented by the treatment with low-concentration of CMA. CMA treatment induced apoptosis in MISK81-5, SAS and HSC-4 cells, but not in SQUU-B cells. The p-p38 expression was not altered in CMA-treated SQUU-B cells, but their levels were increased in the other cells. The Bax/Bcl-2 ratio in CMA-treated SQUU-B cells was dramatically decreased in comparison with that in the other cell lines treated with CMA. However, when the SQUU-B cells were treated with CMA and a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), the SQUU-B cells became more susceptible to the CMA-induced apoptosis. SAHA treatment led to a significantly decrease in the Bcl-2 expression in CMA-treated SQUU-B cells, resulting in a dramatically increased Bax/Bcl-2 ratio in comparison with that observed in the SQUU-B cells treated with CMA alone. These findings suggest that CMA could have an anti-tumor effect on OSCCs. In addition, combination of CMA with other agents, such as SAHA, could help improve the pro-apoptotic effects of CMA even in CMA-resistant OSCC cells.
Highlights
Induction chemotherapy for head and neck cancers reduces the number of patients requiring mandibulectomy and/or radiation therapy
Staining of vital MISK81-5, SAS, HSC-4 and SQUU-B cells with acridine orange revealed that the red fluorescence completely disappeared after treatment with 2.5 nM concanamycin A1 (CMA) for 2 hr (Fig. 1A), indicating that CMA inhibited the acidification of vesicular organelles in the oral squamous cell carcinoma (OSCC) cells
It is reasonable that the molecules responsible for the creation of a tumor-associated acidic microenvironments are regarded as targets for cancer therapy, because an acidic microenvironment is known to be involved in various biological behaviors of tumor cells, such as their proliferation [6], invasion and metastasis [7,8], angiogenesis [9] and drug resistance
Summary
Induction chemotherapy for head and neck cancers reduces the number of patients requiring mandibulectomy and/or radiation therapy. Using it in locally advanced oral cancer can lead to other benefits [1]. Induction chemotherapy has not significantly improved the survival of patients with oral squamous cell carcinoma (OSCC) [1]. Ma et al [3] reported that there was no significant difference in the overall survival, disease-free survival or locoregional recurrence between the patients treated with and without induction chemotherapy for resectable head and neck squamous cell carcinoma in a meta-analysis of randomized trials (1965– 2011). The long-term survival in patients with advanced head and neck squamous cell carcinoma is still poor [2]. The development of a new chemotherapeutic strategy is required to improve the tumor specificity for OSCC, and to overcome the resistance of such tumors to the chemotherapeutic agents, in order to increase their efficacy and/or to decrease any side effects of the drugs
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