piperidines and Nasopharyngeal-Carcinoma

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

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

The poor outcomes in nasopharyngeal carcinoma (NPC) necessitate new treatments. AT7519 is a potent inhibitor of several cyclin-dependent kinases (CDKs) and is currently in the early phase of clinical development for cancer treatment. The potent anti-cancer activities of AT7519 have been reported in various cancers, but not in NPC.. The effects of AT7519 in NPC were systematically analyzed using cell culture assays and xenograft mouse models. The effects of AT7519 on molecules involved in mRNA transcription were examined.. AT7519, at a nanomolar concentration, significantly inhibits growth via arresting cells at G2/M phase, and induces apoptosis in NPC cells regardless of Epstein-Barr virus (EBV) infection and cellular origin. It also inhibits growth of a subpopulation of cells with highly proliferative and invasive features. Importantly, AT7519 acts synergistically with cisplatin and is effective against chemo-resistant NPC cells. Mechanistically, AT7519 inhibits phosphorylation of Rb, suggesting the inhibition of CDK2 in NPC. It also decreases N-myc level and RNA polymerase II phosphorylation, and inhibits transcription. Consistent with the in vitro findings, we demonstrate that AT7519 is effective as a single agent in two independent NPC xenograft mouse models. The combination of ATP7519 and cisplatin results in greater efficacy than cisplatin alone in inhibiting NPC tumor growth.. Our work is the first to report anti-NPC activities of AT7519. Our preclinical evidence suggests that AT7519 is a useful addition to overcome NPC chemo-resistance.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclin-Dependent Kinases; Drug Resistance, Neoplasm; Drug Synergism; Humans; Mice; Nasopharyngeal Carcinoma; Piperidines; Pyrazoles; Treatment Outcome; Xenograft Model Antitumor Assays

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