MiRNAs that target amyloid precursor protein processing machinery in extracellular vesicles and particles derived from oral squamous cells carcinoma.

BACKGROUND: Considering that microRNAs (miRNAs), extracellular vesicles and particles (EVPs) and the amyloid precursor protein (APP) processing have been shown to be altered in oral squamous cells carcinoma (OSCC), it is possible that miRNAs that target APP processing pathways in EVPs are impacted in tumor cells. Our aim was to evaluate miRNAs that target APP itself or disintegrin and metalloproteinase domain 10 (ADAM10), which generate a trophic compound, sAPPα, in EVPs derived from OSCC cell lines, an aggressive and non-invasive, compared to normal keratinocytes. METHODS: We used two OSCC cell lines, an aggressive human oral squamous cell carcinoma cell line (SCC09) and a less aggressive cell line (CAL27) compared with a keratinocyte lineage (HaCaT). Cells were maintained in cell media, from which we isolated EVPs. EVPs were evaluated regarding their size and concentration using Nanotracking Analysis. We measured the levels of miRNAs which had as potential downstream target APP or ADAM10, specifically miR-20a-5p, miR-103a-3p, miR-424-5p, miR-92b-3p, miR-31-5p, and miR-93-5. RESULTS: There were no differences on size distributions and concentration of isolated EVPs. OSCC cell lines-derived EVPs miR-20a-5p, miR-92b-3p, and miR-93-5p were upregulated in comparison to HaCaT-derived EVPs; while miR-31-5p was reduced in EVPs obtained from CAL27 cells. CONCLUSION: Our results indicate changes in miRNAs that target APP machinery processing in EVPs derived from OSCC cell lines of different aggressiveness, which may be involved with abnormal miRNA expression in OSCC tissue and/or releasing tumor suppressor miRNA.

Cell contractility drives mechanical memory of oral squamous cell carcinoma.

Matrix stiffening is ubiquitous in solid tumors and can direct epithelial-mesenchymal transition (EMT) and cancer cell migration. Stiffened niche can even cause poorly invasive oral squamous cell carcinoma (OSCC) cell lines to acquire a less adherent, more migratory phenotype, but mechanisms and durability of this acquired "mechanical memory" are unclear. Here, we observed that contractility and its downstream signals could underlie memory acquisition; invasive SSC25 cells overexpress myosin II (vs. noninvasive Cal27 cells) consistent with OSCC. However, prolonged exposure of Cal27 cells to a stiff niche or contractile agonists up-regulated myosin and EMT markers and enabled them to migrate as fast as SCC25 cells, which persisted even when the niche softened and indicated "memory" of their prior niche. Stiffness-mediated mesenchymal phenotype acquisition required AKT signaling and was also observed in patient samples, whereas phenotype recall on soft substrates required focal adhesion kinase (FAK) activity. Phenotype durability was further observed in transcriptomic differences between preconditioned Cal27 cells cultured without or with FAK or AKT antagonists, and such transcriptional differences corresponded to discrepant patient outcomes. These data suggest that mechanical memory, mediated by contractility via distinct kinase signaling, may be necessary for OSCC to disseminate.

Mouthwash with Active Oxygen (blue®m) Reduces Postoperative Inflammation and Pain.

The aim of this case series was to evaluate the effects of blue®m mouthwash on oral surgical wounds. Eleven patients underwent bilateral preprosthetic surgery and were instructed to apply the product only to the right side of the surgery. In this way, the right side corresponds to the test side and the left side (place without applying any type of solution) to the control side. After seven days of using the product (3 times a day), the following parameters were evaluated by means of a visual analogue scale: pain, changes in taste, and acceptance by the patient. Then, the level of tissue inflammation was assessed, by the number of pixels, using ImageJ® software. The main results show that the blue®m mouthwash was widely accepted by patients, reducing their pain. The number of inflammation pixels was lower on the test side (p < 0.05), indicating improved healing. It is suggested that blue®m mouthwash positively influences tissue healing reducing pain and the postsurgical inflammatory process; however, randomized clinical trials should be done to prove this clinical observation.

The anti-tumor effects of imidazolium salts on oral squamous cell carcinoma.

BACKGROUND: Imidazolium salts (IS), ionic derivatives of neutral imidazoles, have properties that can be adjusted by structural modifications to their cations and anions, which makes this particular class of compounds a promising option for developing biologically active compounds. The anti-tumor effects of the IS 1-n-butyl-3-methylimidazolium chloride (C4 MImCl), 1-n-decyl-3-methylimidazolium chloride (C10 MImCl), 1-n-hexadecyl-3-methylimidazolium chloride (C16 MImCl), 1-n-hexadecyl-2,3-dimethylimidazolium chloride (C16 M2 ImCl), 1-n-octadecyl-3-methylimidazolium chloride (C18 MImCl), 1-n-hexadecyl-3-methylimidazolium methanesulfonate (C16 MImMeS), and 1-n-hexadecyl-2,3- dimethylimidazolium methanesulfonate (C16 M2 ImMeS) on oral squamous cell carcinoma (OSCC) have been studied here. METHODS: Oral squamous cell carcinoma cells (CAL27) were incubated with increasing IS doses and then submitted to proliferation (2D), cell death (2D) and spheroid assay (3D). RESULTS: The IS anti-tumor effect was dependent on both its N-alkyl chain length and anion, whereby C16 MImCl proved to be more effective in combination for inhibiting cell proliferation and cell-cell adhesion, outperforming the methylated C16 M2 ImCl derivative and, most importantly, the gold standard-cisplatin. In addition, C16 MImCl had little effect on keratinocytes and more pronounced effects on more aggressive tumor cells. It also exhibited similar effects on inducing cell death when compared to Cisplatin. This compound spread to a greater area of the tumor sphere and produced an enhanced number of apoptotic and necrotic cells in the tumor cell line, demonstrating only a small rise in the healthy cells. CONCLUSION: These data indicate that the effect of C16 MlmCl on OSCC is promising, as it is selective for cancer cells.

Flavonoids as anticancer therapies: A systematic review of clinical trials.

Flavonoids have been proposed as potential chemotherapeutic agents because they are toxic against cancer cells but not harmful to healthy cells. This systematic review analyzed flavonoid effectiveness in human cancer chemotherapy. Overall, 22 phase II and 1 phase III clinical trials (PubMed, Scopus, and Web of Science) that used flavonoids as a single agent or combined with other therapeutics against hematopoietic/lymphoid or solid cancer published by January 2019 were selected for analysis. Flavopiridol was the most commonly used flavonoid (at a dose of 50-mg/m2 IV) for all tumor types. Aside from the relatively low rate of complete response (CR) or partial response (PR) with any administration protocol, flavonoids showed higher positive outcomes for hematopoietic and lymphoid tissues (140 patients with CR and 88 with PR among 615 patients in 11 trials) than for solid tumors (4 patients with CR and 21 with PR among 525 patients in 12 trials). However, because of the high variety in administration schedule, more studies are needed to further understand how flavonoids can promote positive outcomes for cancer patients.

Low Doses of Curcuma longa Modulates Cell Migration and Cell-Cell Adhesion.

Cell invasion and metastasis are involved in clinical failures in cancer treatment, and both events require the acquisition of a migratory behavior by tumor cells. Curcumin is a promising natural product with anti-proliferative activity, but its effects on cell migration are still unclear. We evaluated the effects of curcumin on the proliferation, apoptosis, migration, and cell-cell adhesion of keratinocyte, oral squamous cell carcinoma (OSCC), and fibroblast cell lines, as well as in a xenograft model of OSCC. Curcumin (2 µM) decreased cell proliferation in cell lines with mesenchymal characteristics, while cell death was detected only at 50 µM. We observed that highly migratory cells showed a decrease on migration speed and directionality when treated with 2 or 5 µM of curcumin (50% and 40%, respectively, p < 0.05). Using spheroids, we observed that curcumin dose dependently decreased cell-cell adhesion, especially on tumor-derived spheroids. Also, in a xenograft model with patient-derived OSCC cells, the administration of curcumin decreased tumor growth and aggressiveness when compared with untreated tumors, indicating the potential antitumor effect in oral cancer. These results suggest that lower doses of curcumin can influence several steps involved in tumorigenesis, including migration properties, suggesting a possible use in cancer therapy. Copyright © 2017 John Wiley & Sons, Ltd.