piperidines and Nasopharyngeal-Neoplasms

To investigate the capacity for ZD6474, a small molecule tyrosine kinase inhibitor, to enhance anti-tumor and anti-metastasis effects of radiation on human nasopharyngeal carcinoma (NPC).. NPC cell lines and xenograft models were evaluated following treatment with ZD6474 and radiation alone and in combination compared with untreated control mice.. Treatment with ZD6474 enhanced the anti-proliferative effect of radiation on NPC cell lines as detected by cell proliferation and apoptosis assays. ZD6474 also induced a significant increase in the radiosensitivity of NPC cells, with radiation enhancement ratios (RERs) ranging from 1.2 to 1.6. Despite the cytotoxicity exhibited by NPC cells following radiotherapy, the invasion and migration of NPC cells was found to be unaffected. In contrast, treatment with ZD6474 strongly inhibited the invasion and migration of NPC cells. When the administration of radiation and ZD6474 was investigated in vitro, the ability of ZD6474 to inhibit activation of the pro-survival signaling pathways induced by radiation was demonstrated. In vivo, ZD6474 significantly enhanced the anti-metastasis effects of radiation, while treatment with radiation and ZD6474 was found to be well tolerated and resulted in a strong inhibition of tumor growth.. Our results suggest the combination of radiation and ZD6474 represents a promising strategy for the treatment of human NPC.

Topics: Animals; Apoptosis; Carcinoma; Chemotherapy, Adjuvant; Humans; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Neoplasm Metastasis; Piperidines; Protein Kinase Inhibitors; Quinazolines

Nasopharyngeal cancer is a malignancy developing from the nasopharynx epithelium due to smoking and nitrosamine-containing foods. Nasopharyngeal cancer is highly endemic to Southeast Asia. Eugenol and piperine have shown many anticancer activities on numerous cancer types, like colon, lung, liver, and breast cancer. In this study, we amalgamated eugenol and piperine loaded with a polyhydroxy butyrate/polyethylene glycol nanocomposite (Eu-Pi/PHB-PEG-NC) for better anticancer results against nasopharyngeal cancer (C666-1) cells. In the current study, nasopharyngeal cancer cell lines C666-1 were utilized to appraise the cytotoxic potential of Eug-Pip-PEG-NC on cell propagation, programmed cell death, and relocation. Eu-Pi/PHB-PEG-NC inhibits cellular proliferation on C666-1 cells in a dose-dependent manner, and when compared with 20 µg/ml, 15 µg/ml of loaded mixture evidently restrained the passage aptitude of C666-1 cells, this was attended with a downregulated expression of mitochondrial membrane potential. Treatment with 15 µg/ml Eu-Pi/PHB-PEG-NC suggestively amplified cell apoptosis in the C666-1 cells. Furthermore, its cleaved caspase-3, 8, and 9 and Bax gene expression was augmented and Bcl-2 gene expression was diminished after Eu-Pi/PHB-PEG-NC treatment. Additionally, our data established that the collective effect of Eu-Pi/PHB-PEG-NC loaded micelles inhibited the expansion of C666-1 cells augmented apoptosis connected with the intrusion of PI3K/Akt/mTOR signaling pathway.

Topics: Alkaloids; Apoptosis; Benzodioxoles; Cell Line, Tumor; Drug Carriers; Elafin; Eugenol; Humans; Nanocomposites; Nasopharyngeal Neoplasms; Piperidines; Polyethylene Glycols; Polyhydroxyalkanoates; Polyunsaturated Alkamides; Prohibitins; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases

Advanced nasopharyngeal carcinoma (NPC) has a poor prognosis, with an unfavorable response to palliative chemotherapy. Unfortunately, there are few effective therapeutic regimens. Therefore, we require novel treatment strategies with enhanced efficacy. The present study aimed to investigate the antitumor efficacy of APG-1252-M1, a dual inhibitor of BCL-2/BCL-XL, as a single agent and combined with gemcitabine. We applied various apoptotic assays and used subcutaneous transplanted NPC model to assess the in vitro and in vivo antitumor activity. Moreover, phospho-tyrosine kinase array was used to investigate the combined therapy's potential synergistic mechanism. In addition, further validation was performed using immunohistochemistry and western blotting. In vitro, we observed that APG-1252-M1 had moderate antitumor activity toward NPC cells; however, it markedly improved gemcitabine's ability to promote NPC cell apoptosis and suppress invasion, migration, and proliferation. Specifically, APG-1252 plus gemcitabine exhibited even remarkable antitumor activity in vivo. Mechanistically, the drug combination synergistically suppressed NPC by activating caspase-dependent pathways, blocking the phospho (p)-JAK-2/STAT3/MCL-1 signaling pathway, and inhibiting epithelial-mesenchymal transition. In conclusion, the results indicated that the combination of APG-1252 and gemcitabine has synergistic anticancer activities against NPC, providing a promising treatment modality for patients with NPC.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; bcl-X Protein; Caspases; Cell Line, Tumor; Cell Movement; Cell Proliferation; Deoxycytidine; Drug Synergism; Epithelial-Mesenchymal Transition; Gemcitabine; Humans; Janus Kinase 2; Models, Biological; Myeloid Cell Leukemia Sequence 1 Protein; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Piperidines; Signal Transduction; Small Molecule Libraries; STAT3 Transcription Factor

We explored the effect of hepatocyte growth factor (HGF)/Met signaling pathway on nasopharyngeal carcinoma (NPC) cells in vitro and in vivo, and investigated the ability of Met tyrosine kinase inhibitor (TKI) to block HGF-induced biological signaling.. Met TKI inhibitor PF-2341066 alone, or in combination with cisplatin, was investigated for its ability to block HGF-induced signaling and biological effects in vitro and in vivo. HGF/Met expression and activation of signaling in NPC cells were detected by using Western blot and immunohistochemistry. Biological evaluation, including wound healing, cell proliferation, and invasion of NPC cells, was also examined, and the correlation between HGF/Met expression of primary and metastatic tumor in NPC patients and clinical prognosis were also analyzed.. Met TKI inhibitor, PF-2341066, inhibited growth of NPC cells in vivo with half maximal inhibitory concentration of 0.79±0.21 μmol/L, and suppressed invasion and migration of NPC cells; also, the inhibition of PF-2341066 was synergized with cisplatin treatment. Compared with the control group, Met TKI inhibited metastasis of transplanted NPC in nude mice (the number of live metastases [mean ± SD]: 5.8±2.2 versus 11.8±2.2, P=0.03; the number of lung metastases: 2.3±1.5 versus 5.3±0.9, P=0.06). HGF was widely expressed in both primary and metastatic lesions while Met expression of metastatic lesions was higher than that of primary lesions (primary lesions: 24.7%; liver metastases: 40%; lung metastases: 29%; lymph node metastases: 29%, P<0.05), and overall survival of NPC patients with higher expression of Met was shorter (P=0.13).. Our results demonstrated that HGF/Met signaling promoted NPC growth, further resulting in metastasis and poor prognosis. Met TKI, PF-2341066, showed potent antitumor activity in vivo and in vitro which was enhanced by combination with cisplatin. Our study implied that HGF/Met signaling was the potential therapeutic target in NPC, and blockage of the signaling could prevent growth and metastasis of NPC and derive clinical benefit.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cisplatin; Crizotinib; Dose-Response Relationship, Drug; Drug Synergism; Hepatocyte Growth Factor; Humans; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Signal Transduction; Xenograft Model Antitumor Assays

Early therapeutic effects of anti-angiogenic agent ZD6474 upon nasopharyngeal carcinoma (NPC) in nude mouse were monitored by using intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). Mice bearing NPC underwent IVIM DWI at baseline and after 1, 3, and 7 days of treatment with ZD6474 or vehicle (n = 12 per group). Parameters of apparent diffusion coefficient (ADC), true diffusion coefficient (D), perfusion fraction (f), and blood pseudodiffusion coefficient (D*) at different time points were compared between the two groups or within the treated group. In the treated group, the perfusion-related parameters f and D* of the tumors decreased significantly on day 1 while the diffusion-related parameters ADC and D were significantly higher beginning on day 3 compared with the control group. The decreases in f on day 1 and D* on day 3 were moderately correlated with the smaller tumor size change on day 7. Moderate correlations were established between MVD and f and D* as well as between increased TUNEL or decreased Ki-67 index and ADC and D. This study supports that IVIM DWI is sensitive to detect the ZD6474-induced changes in NPC in nude mouse and the f parameter could predict early response to anti-angiogenic treatment.

Topics: Animals; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Diffusion Magnetic Resonance Imaging; Humans; Image Processing, Computer-Assisted; Ki-67 Antigen; Mice; Mice, Nude; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Piperidines; Quinazolines; Radiography; Transplantation, Heterologous

The radiation recall reaction (RRR) is an inflammatory reaction that occurs in previously irradiated areas. The phenomenon is probably due to an idiosyncratic hypersensitivity reaction, in which a second agent can recall the inflammatory reaction.. This case report documents a cold-weather-induced radiation recall dermatitis (RRD). We observed a severe RRD in a patient after chemoradiotherapy treatment with cisplatin for a nasopharyngeal carcinoma, precipitated by cold temperatures, which developed 9 days after completion of therapy. In the medical literature, RRD following extreme cold temperatures seems to be a peculiar event.. Until further information on the interaction is available, future studies on combined chemotherapy with cisplatin should be carefully monitored and any side effects clearly documented. This case suggests that environmental conditions may play a contributing role in the development of RRD. This case also implies that neither fraction size nor total radiation dose is a determining factor in the development of the dermatologic reaction.

Topics: Aged; Antineoplastic Agents; Butyrophenones; Carcinoma, Squamous Cell; Chemoradiotherapy; Cisplatin; Cold Temperature; Drug Therapy, Combination; Female; Humans; Methylprednisolone; Nasopharyngeal Neoplasms; Neoplasm Staging; Piperidines; Radiodermatitis

ZD6474 is a vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. The present study was undertaken to investigate the direct antiproliferative effect of ZD6474 on human nasopharyngeal carcinoma (NPC) in vitro and the antitumor activity on NPC xenografts in vivo. Results indicated that ZD6474 treatment inhibited EGFR phosphorylation and led to a dose- and time-dependent decrease in NPC cell (CNE-1, CNE-2 and C666-1) proliferation. Further investigation demonstrated G0/G1 cell cycle arrest in all 3 cell lines, which was associated with an upregulation of p21 and/or p27, and downregulation of CDK4, CDK6 and CDK2. ZD6474 treatment also induced apoptosis in CNE-1 and CNE-2 cells. The apoptosis mechanisms involved reduction of Bcl-2 and/or Bcl-XL, induction of Bak and/or Bax, and activation of caspases-3, -9 and/or -8. The in vivo antitumor activity was evaluated in CNE-2 and C666-1 xenografted nude mice. Administration of ZD6474 (25-100 mg/kg/day, once-daily, p.o.) produced a dose-dependent inhibition of tumor growth and prolonged survival in both models. This study suggests that ZD6474 exerts direct antiproliferative effects on NPC cell lines in vitro by inducing G0/G1 arrest and apoptosis, and potent antitumor effects on NPC xenografts in vivo. It indicates that ZD6474 may offer a new and effective treatment for human NPC.

Topics: Animals; Apoptosis; Cell Cycle; Cell Line, Tumor; ErbB Receptors; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nasopharyngeal Neoplasms; Piperidines; Protein Kinase Inhibitors; Quinazolines; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Survival Rate; Xenograft Model Antitumor Assays

The carcinogenic effectiveness in rats of three cyclic nitrosamines administered at two doses separated by a factor of five has been studied. All three compounds showed a response at the lower dose quite different from that at the higher dose. One, 2,6-dimethyl-dinitrosopiperazine, was only a little less effective at the lower dose than at the higher dose, giving 100% nasal turbinate tumors, but only 33% esophageal tumors, compared with 100% esophageal tumors at the higher dose. 3,4-Dichloronitrosopiperidine gave 100% incidence of esophageal tumors at the higher dose. At the lower dose, survival of the rats was very much better, some living 80 weeks, and, in addition to the esophagus, there were tumors of several organs including forestomach, tongue, and nasal turbinates. On the other hand, 2,6-dimethylnitrosomorpholine was a very much weaker carcinogen at the lower than at the higher dose, only six animals dying with tumors, compared with 100% incidence at the higher dose. However, the pattern of mortality of rats given the lower dose of dimethylnitrosomorpholine was similar to that of rats given the lower dose of dichloronitrosopiperidine.

Topics: Animals; Carcinogens; Dose-Response Relationship, Drug; Esophageal Neoplasms; Morpholines; Nasopharyngeal Neoplasms; Nitrosamines; Piperazines; Piperidines; Rats; Turbinates

The carcinogenic potencies of 3,4-dichloro- and 3,4-dibromonitrosopiperdine were compared with that of nitrosopiperidine by feeding to groups of 15 male rats in drinking water. A treatment of 15 weeks with a total of 0.5 mmole of the dichloro compound led to death of all animals before 24 weeks with tumors of the tongue, pharynx, esophagus, nonglandular stomach, nasal turbinates, trachea, bronchi, and bronchioles. Treatment of 27 weeks with the dibromo compound, a total of 1.0 mmole, caused death of all the animals by 41 weeks, with the same types of tumors. One-half of the rats treated with an almost 3-fold higher daily dose of nitrosopiperidine, 3.9 mmoles total, were alive at 40 weeks, and all were not dead until 55 weeks. Most of these animals died with tumors of the tongue, pharynx, esophagus, and nonglandular stomach and with squamous cell tumors and olfactory carcinomas of the nasal cavity, but there were no tumors of the respiratory tree. Substitution of chlorine or bromine in nitrosopiperidine greatly increased the carcinogenicity of the compound.

Topics: Animals; Carcinoma, Squamous Cell; Esophageal Neoplasms; Male; Nasopharyngeal Neoplasms; Neoplasms, Experimental; Nitrosamines; Pharyngeal Neoplasms; Piperidines; Rats; Stomach Neoplasms; Tongue Neoplasms