piperidines and Squamous-Cell-Carcinoma-of-Head-and-Neck

Vandetanib, added to cisplatin and radiation therapy (RT) overcomes chemoradiation therapy (CRT) and epidermal growth factor receptor (EGFR) inhibitor resistance in head and neck squamous cell carcinoma (HNSCC) lines and models.. Patients with previously untreated HNSCC received vandetanib daily for 14 days (starting dose 100 mg) and then vandetanib + RT (2.2 Gy/day, 5 days/week) for 6 weeks (regimen 1) or vandetanib + RT (2 Gy/day, 5 days/week) + cisplatin (30 mg/m(2) weekly) for 7 weeks (regimen 2). The primary objective was the maximum tolerated dose (MTD) of vandetanib with RT +/- cisplatin.. Of 33 treated patients, 30 completed therapy (regimen 1, n = 12; regimen 2, n = 18). MTD in regimen 2 was 100 mg (3 dose limiting toxicities [DLTs] at 200 mg), whereas regimen 1 was stopped because of poor recruitment (1 DLT at 200 mg). Most common grade ≥3 adverse events (AEs) were dysphagia (30%), stomatitis (33%), and mucosal inflammation (27%). Five patients discontinued vandetanib because of AEs.. Vandetanib with CRT was feasible.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Female; Head and Neck Neoplasms; Humans; Male; Maximum Tolerated Dose; Middle Aged; Piperidines; Protein-Tyrosine Kinases; Quinazolines; Squamous Cell Carcinoma of Head and Neck

In the context of well-known inhibitory effects of Farrerol on the invasion of lung squamous cell carcinoma cells, the unexplored effect and regulatory mechanism of Farrerol on laryngeal squamous cell carcinoma (LSCC) emerged as the target in this study.. After treatment with Farrerol alone, or together with MitoTempo, the viability, apoptosis, cell cycle distribution, migration, and invasion of LSCC cells were measured using MTT, flow cytometry, wound-healing, and transwell assays, respectively. Meanwhile, the levels of cytochrome C (Cyt C), Cleaved caspase-3/9, Cyclin D1, E-cadherin, N-cadherin, and Vimentin in LSCC cells were evaluated by Western blot; the reactive oxygen species (ROS) formation intensity and the disruption of mitochondrial membrane potential (MMP) of LSCC cells were assessed using flow cytometry; and the effect of Farrerol on xenograft tumor formation was evaluated in animal experiment.. Farrerol (10, 20, 50 μM) inhibited the viability, proliferation, cell cycle progression, migration and invasion, but promoted apoptosis, ROS formation intensity and disruption of MMP of LSCC cells. Moreover, Farrerol up-regulated Cyt C (in the cytoplasm), Cleaved caspase-3/9 and E-cadherin levels, but down-regulated Cyclin D1, N-cadherin and Vimentin levels in LSCC cells. Additionally, we uncovered that MitoTempo reversed the promoting effects of Farrerol on ROS formation intensity, apoptosis, and Cyt C and Cleaved caspase-3/9 levels in LSCC cells, while improving the disruption of MMP in Farrerol-treated LSCC cells. Also, Farrerol lessened the volume and weight of mice tumors.. Farrerol suppressed the migration, invasion, and induced the apoptosis of LSCC cells via the mitochondria-mediated pathway.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromones; Gene Expression Regulation, Neoplastic; Humans; Laryngeal Neoplasms; Male; Membrane Potential, Mitochondrial; Mice; Mitochondria; Neoplasm Invasiveness; Organophosphorus Compounds; Piperidines; Reactive Oxygen Species; Squamous Cell Carcinoma of Head and Neck; Up-Regulation; Xenograft Model Antitumor Assays

Oral squamous cellular carcinoma (OSCC) is considered a life-threatening disease with detection in late stages, which forces us to opt for dangerous treatment with a combination of chemotherapy and radiotherapy. Herbal components such as piperine and quercetin are derived from edible sources, proving their anticancer potential against oral cancer cells in vitro. Encapsulation into lipid matrix-mediated nanostructured lipid carriers (NLCs) can make both drugs bio-accessible. NLCs were synthesised using the high shear homogenisation method and characterised for their physicochemical properties, followed by in vitro cellular evaluation in FaDu oral cancer cells. NLCs showed negatively charged particles smaller than 180 nm with a polydispersity index (PDI) of <0.3. Both drugs were found to encapsulate sufficiently, with >85% entrapment efficiency and an improved drug release profile compared to their pristine counterparts. Differential scanning calorimetry (DSC) thermograms showed conversion into an amorphous matrix in lyophilized NLCs, which was supported by X-ray diffraction (XRD) analysis. The cytotoxicity assay showed the IC

Topics: Alkaloids; Animals; Apoptosis; Benzodioxoles; Drug Liberation; Drug Screening Assays, Antitumor; Fatty Acids; Humans; Membrane Potential, Mitochondrial; Mouth Neoplasms; Nanoparticle Drug Delivery System; Nanostructures; Particle Size; Piperidines; Polyunsaturated Alkamides; Quercetin; Rats; Squamous Cell Carcinoma of Head and Neck; Tissue Distribution

Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (B. Blood (n = 42) and tumor tissue (n = 39) of head and neck cancer patients and healthy donors (n = 60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca. ADO-producing B. Our data demonstrate the presence of a novel ADO-producing B

Topics: Adenine; Adenosine; Agammaglobulinaemia Tyrosine Kinase; Animals; Apoptosis; B-Lymphocytes, Regulatory; Case-Control Studies; Cell Proliferation; Head and Neck Neoplasms; Humans; Male; Mice; Piperidines; Prognosis; Pyrazoles; Pyrimidines; Squamous Cell Carcinoma of Head and Neck; Tumor Cells, Cultured; Tumor Microenvironment; Xenograft Model Antitumor Assays

Epidermal growth factor receptor (EGFR) overexpression is characteristic in head and neck cancers and is associated with tumour regrowth following photodynamic therapy (PDT).. We investigated vandetanib, which selectively blocks EGFR and vascular endothelial growth factor receptor-2 (VEGFR-2), to enhance the efficacy of PDT.. We assessed the in vitro therapeutic efficacy of: 1) vandetanib; 2) PDT with the photosensitizer Chlorin e6 (Fotolon®); and 3) combined PDT + vadetanib treatment in CAL-27 oral squamous cell carcinoma (OSCC) cell line by cell viability, γH2AX foci immunostaining, cell cycle arrest and western blot. We also performed in vivo tumour regression study and immunohistochemical staining of formalin-fixed paraffin-embedded (FFPE) regressed and regrown tumour tissues.. First, we observed significantly higher cytotoxicity and residual DNA damage in vandetanib + PDT-treated CAL-27 OSCC cells than tumour cells treated with PDT alone. This is due to impaired DNA DSB repair caused by downregulation of EGFR-mediated DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activation. Next, combined vandetanib and PDT resulted in significant tumour growth delay in vivo that is linked to reduction of PDT-induced EGFR phosphorylation and cellular proliferation, along with loss of tumour vasculature. In particular, we observed significant revascularisation of the microenvironment that is associated with upregulated ERK1/2 phosphorylation in regrown tumours post-vandetanib + PDT, thereby corroborating the importance of microenvironmental modification for the observed drug-PDT synergistic interaction.. Taken together, our data suggests that vandetanib enhances the efficacy of PDT through both direct and indirect effects on the cellular DNA repair machinery and tumour microenvironment, respectively.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorophyllides; DNA Damage; DNA-Activated Protein Kinase; Down-Regulation; Drug Therapy, Combination; ErbB Receptors; Head and Neck Neoplasms; Humans; Mice; Mice, Nude; Photochemotherapy; Photosensitizing Agents; Piperidines; Porphyrins; Quinazolines; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; Vascular Endothelial Growth Factor Receptor-2

Endocannabinoids have recently drawn attention as promising anti-cancer agents. We previously observed that anandamide (AEA), one of the representative endocannabinoids, effectively inhibited the proliferation of head and neck squamous cell carcinoma (HNSCC) cell lines in a receptor-independent manner. In this study, using HNSCC cell lines, we examined the anti-cancer effects and the mechanisms of action of docosahexaenoyl ethanolamide (DHEA) and N-arachidonoyl-L-alanine (NALA), which are polyunsaturated fatty acid (PUFA)-based ethanolamides like AEA.. DHEA and NALA were found to effectively inhibit HNSCC cell proliferation. These anti-proliferative effects seemed to be mediated in a cannabinoid receptor-independent manner, since the antagonist of cannabinoid receptor-1 (CB1) and vanilloid receptor-1 (VR1), two endocannabinoid receptors, did not reverse the ability of DHEA and NALA to induce cell death. Instead, we observed an increase in reactive oxygen species (ROS) production and a decrease of phosphorylated Akt as a result of DHEA and NALA treatment. Antioxidants efficiently reversed the inhibition of cell proliferation and the decrease of phosphorylated Akt induced by DHEA and NALA; inhibition of 5-lipoxygenase (5-LO), which is expected to be involved in DHEA- and NALA-degradation pathway, also partially blocked the ability of DHEA and NALA to inhibit cell proliferation and phosphorylated Akt. Interestingly, ROS production as a result of DHEA and NALA treatment was decreased by inhibition of 5-LO.. From these findings, we suggest that ROS production induced by the 5-LO pathway mediates the anti-cancer effects of DHEA and NALA on HNSCC cells. Finally, our findings suggest the possibility of a new cancer-specific therapeutic strategy, which utilizes 5-LO activity rather than inhibiting it.

Topics: Alanine; Antineoplastic Agents; Apoptosis; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Azoles; Benzoquinones; Carcinogenesis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Endocannabinoids; Head and Neck Neoplasms; Humans; Hydroxyurea; Isoindoles; Lipoxygenase Inhibitors; Organoselenium Compounds; Phosphorylation; Piperidines; Proto-Oncogene Proteins c-akt; Pyrazoles; Reactive Oxygen Species; Receptor, Cannabinoid, CB1; Signal Transduction; Squamous Cell Carcinoma of Head and Neck; TRPV Cation Channels

Metastasis is a critical event in the progression of head and neck squamous cell carcinoma (HNSCC) and closely correlates with clinical outcome. We previously showed that the farnesyl transferase inhibitor SCH66336 has antitumor activities in HNSCC by inducing the secretion of insulin-like growth factor binding protein 3 (IGFBP-3), which in turn inhibits tumor growth and angiogenesis. In our study, we found that SCH66336 at a sublethal dose for HNSCC inhibited the migration and invasion of HNSCC cells. The inhibitory effect of SCH66336 was associated with the blockade of the IGF-1 receptor (IGF-1R) pathway via suppressing IGF-1R itself and Akt expression. Consistent with previous work, induction of IGFBP-3 by SCH66336 also contributed in part to the anti-invasive effect. SCH66336 treatment also reduced the expression and activity of the urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 2 (MMP-2), both important regulators of tumor metastasis. The effect of SCH66336 on uPA activity was inhibited partly by knockdown of IGFBP-3 using small interfering RNA. The inhibitory effect of SCH66336 on migration or invasion was attenuated partly or completely by knockdown of IGFBP-3, Akt or IGF-1R expression, respectively. Our results demonstrate that the IGF-1R pathway plays a major role in the proliferation, migration and invasion of HNSCC cells, suggesting that therapeutic obstruction of the IGF-1R pathway would be a useful approach to treating patients with HNSCC.

Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Movement; Farnesyltranstransferase; Female; Head and Neck Neoplasms; Humans; Insulin-Like Growth Factor Binding Protein 3; Matrix Metalloproteinase 2; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Piperidines; Proto-Oncogene Proteins c-akt; Pyridines; Receptor, IGF Type 1; RNA Interference; RNA, Small Interfering; Squamous Cell Carcinoma of Head and Neck; Urokinase-Type Plasminogen Activator