RESUMO
Oral cancer continues to be a major cause of morbidity and mortality worldwide. Treatment of oral cancer with combinatorial drugs is increasingly being performed as drugs with different molecular targets often exert synergistic effects, thereby enhancing treatment efficacy. Current combinatorial drug regimens often combine the tolerable dosages of individual drugs. However, the optimized ratio of a drug combination and sequence of drug administration could contribute toward the synergy, leading to increased efficacy and reduced dosages. This report aims to study the possible synergistic effects of three anticancer drugs, a proteasome inhibitor, bortezomib, a topoisomerase I inhibitor, Camptothecin, and a DNA intercalation drug, Doxorubicin, when used in combination for treating oral cancer. To rapidly optimize the three-drug regimen with minimal experimental efforts, a Feedback System Control optimization technique, a recent platform technique developed particularly for drug combination screening, was applied. The optimized regimen showed a therapeutic window (death rate difference between cancer cells and normal cells) close to 100%. This is the first report on the use of a combination of bortezomib, Camptothecin, and Doxorubicin in the treatment of oral cancer. Our results indicate that to have the most synergistic anticancer effect, the drugs in the optimized regimen should be dosage specific and ratio specific. Furthermore, the sequence of drug administration plays a vital role in ensuring that the combination is effective. The optimized regimen reported here has the potential to considerably increase the cure rate of oral cancer and reduce the toxicity of chemotherapy.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Camptotecina/farmacologia , Doxorrubicina/farmacologia , Neoplasias Bucais/tratamento farmacológico , Pirazinas/farmacologia , Antineoplásicos/toxicidade , Ácidos Borônicos/toxicidade , Bortezomib , Camptotecina/toxicidade , Linhagem Celular Tumoral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/toxicidade , Sinergismo Farmacológico , Humanos , Pirazinas/toxicidadeRESUMO
BACKGROUND/AIM: Perineural invasion and distant metastasis lead to a poor prognosis of adenoid cystic carcinoma and there is no effective therapy available. MicroRNAs (miRNAs) are small non-coding RNAs that regulate target gene expression, which can be biomarkers or therapeutic targets for certain cancer types. We aimed to identify miRNAs and their target genes possibly involved in metastasis of salivary gland adenoid cystic carcinoma (SACC). MATERIALS AND METHODS: Using Nanostring nCounter analysis, we examined miRNA expression in two SACC cell lines: SACC-83 and SACC-LM, with low and high lung metastasis rates, respectively. We then verified the differentially expressed miRNAs with real-time polymerase chain reaction in the cell lines and in tumor samples from patients with SACC. miRNA target-gene expression was also analyzed. RESULTS: SACC-83 showed higher gene expression of miR-130a, miR-342, and miR-205; SACC-LM showed higher gene expression of miR-99a and miR-155. In human tissue, miR-205 was highly expressed in the primary SACC, while miR-155 and miR-342 were highly expressed in recurrent SACC. Six predicted target genes of miRNA-155 and miR-99a linked to tumorigenesis were further analyzed and RNA expression of ubiquitin-like modifier activating enzyme 2 (UBA2) was higher in SACC than normal salivary gland tissue, and higher in primary compared to recurrent SACC (p<0.05). RNA expression of retinoic acid receptors (RARS) was higher in tissue from primary than recurrent SACC and normal salivary gland (p<0.05), but that in recurrent SACC was not significantly higher than normal salivary gland tissue. RNA expression of minichromosome maintenance 8 homologous recombination repair factor (MCM8) and 24-dehydrocholesterol reductase (DHCR24) was higher in primary SACC than normal salivary gland tissue (p<0.05). CONCLUSION: miR-99a, miR-155, miR-130a, miR-342, and miR-205 may play a role in metastasis of SACC. MiR-155 may be involved in SACC metastasis through UBA2 pathways, and UBA2 may function as a biomarker/mediator of SACC metastasis.
Assuntos
Carcinoma Adenoide Cístico/genética , MicroRNAs/genética , Neoplasias das Glândulas Salivares/genética , Biomarcadores Tumorais/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Expressão Gênica/genética , Humanos , Proteínas de Manutenção de Minicromossomo/genética , Proteínas do Tecido Nervoso/genética , Oxirredutases atuantes sobre Doadores de Grupo CH-CH/genética , Receptores do Ácido Retinoico/genética , Glândulas Salivares/patologiaRESUMO
This study reports a correlation between cellular morphology and the ability of adapting to vesicular stomatitis virus infection. A time-lapse approach was employed to track the individual difference between homologous cells in adapting to viral infection. The authors single-cell analysis indicates that upon viral infection, mature cells that are in spindle shape are less likely to be infected after 24 h infection. On the other hand, cells undergoing proliferation, which are in rounder shape, tend to adopt a much higher viral infection within the same amount of time. This fact suggests that cellular morphology may be an early bioindicator for viral infection. The findings in this study could potentially be applied to other viral infection models.