Induction of multinucleation in oral squamous cell carcinoma tissue with mutated p53 surviving boron neutron capture therapy

Abstract

Purpose: To clarify the role of p53 in boron neutron capture therapy (BNCT) for oral squamous cell carcinoma (SCC), the effect of BNCT on oral SCC xenografts with either wild-type or mutant-type p53 was examined.Materials and methods: Oral SCC cells expressing either wild-type (SAS/neo) or mutant-type p53 (SAS/mp53) were used to produce nude mouse tumours. Tumour-bearing mice received boronophenylalanine (BPA) at a dose of 250 mg/kg and tumours were exposed to neutron irradiation.Results: After BNCT, the growth of SAS/neo and SAS/mp53 tumours was suppressed remarkably and all tumours became undetectable within two weeks. However, three of six SAS/mp53 tumours showed regrowth in two months. Histological examination of BNCT-treated tumours revealed chromosomal condensation, micronucleation, nuclear segmentation and intra- and intercelluar vacuolation. Notably, multinucleated giant cells appeared in SAS/mp53 tumours early after BNCT, suggesting mitotic catastrophe. In SAS/mp53 tumours treated with BNCT, a rapid decrease in phosphorylated cell division cycle 2 (cdc2) and a high level of cyclin B1, required for premature mitosis, were observed.Conclusion: These results indicate that BNCT suppressed oral SCC xenografts in nude mice efficiently, but cells survived in mutant-type p53 tumours. BNCT induces multinucleation which represents prestage of apoptosis or necrosis in oral SCC with mutant-type p53, but it may be also associated with the recurrence of BNCT-treated tumours.