Long Noncoding RNA HOXA11-AS Modulates the Resistance of Nasopharyngeal Carcinoma Cells to Cisplatin via miR-454-3p/c-Met.

To elucidate the mechanism of action of HOXA11-AS in modulating the cisplatin resistance of nasopharyngeal carcinoma (NPC) cells. HOXA11-AS and miR-454-3p expression in NPC tissue and cisplatin-resistant NPC cells were measured via quantitative reverse transcriptase polymerase chain reaction. NPC parental cells (C666-1 and HNE1) and cisplatin-resistant cells (C666-1/DDP and HNE1/DDP) were transfected and divided into different groups, after which the MTT method was used to determine the inhibitory concentration 50 (IC50) of cells treated with different concentrations of cisplatin. Additionally, a clone formation assay, flow cytometry and Western blotting were used to detect DDP-induced changes. Thereafter, xenograft mouse models were constructed to verify the in vitro results. Obviously elevated HOXA11-AS and reduced miR-454-3p were found in NPC tissue and cisplatin-resistant NPC cells. Compared to the control cells, cells in the si-HOXA11-AS group showed sharp decreases in cell viability and IC50, and these results were reversed in the miR-454-3p inhibitor group. Furthermore, HOXA11-AS targeted miR-454-3p, which further targeted c-Met. In comparison with cells in the control group, HNE1/DDP and C666-1/DDP cells in the si-HOXA11-AS group demonstrated fewer colonies, with an increase in the apoptotic rate, while the expression levels of c-Met, p-Akt/Akt and p-mTOR/mTOR decreased. Moreover, the si-HOXA11-AS-induced enhancement in sensitivity to cisplatin was abolished by miR-454-3p inhibitor transfection. The in vivo experiment showed that DDP in combination with si-HOXA11-AS treatment could inhibit the growth of xenograft tumors. Silencing HOXA11-AS can inhibit the c-Met/AKT/mTOR pathway by specifically upregulating miR-454-3p, thus promoting cell apoptosis and enhancing the sensitivity of cisplatin-resistant NPC cells to cisplatin.

Novel polypyridyl ruthenium complexes acting as high affinity DNA intercalators, potent transcription inhibitors and antitumor reagents.

Six novel polypyridyl ruthenium complexes with (E)-2-styryl-1H- imidazo[4,5-f][1,10]phenanthroline ligand and its analogues have been designed to enhance the DNA intercalation ability of their model compound [Ru(bpy)2(pip)]2+ (bpy = 2,2'-bipyridine, pip = 2-phenyl-1H-imidazo[4,5-f][1,10]phenanthroline). As shown in the optimized geometry of the complexes, the introduction of styryl group not only extended the conjugated area of the intercalative ligand, but also retained the excellent planarity. These two merits have been proven to be beneficial for their DNA intercalation, thus greatly improved their inhibition activity towards DNA transcription by RNA polymerase and DNA topoisomerase, two enzymes closely related to both DNA and tumor cell growth. The relationships between the substituent group structures and the biological activities have also been investigated from energetic and electronic aspects by quantum chemistry calculations. Results from cell cytotoxicity and apoptosis assay testified that the styryl substituted ruthenium complexes possessed higher antitumor activity than [Ru(bpy)2(pip)]2+, as expected. As quantified in the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, the tumor cell death is caused mostly through apoptosis for Ru2 and Ru3, while non-apoptotic processes for Ru1, Ru4 and Ru5. In vitro fluorescence evaluation revealed that all complexes located mainly in cytoplasm, but the three complexes with high antiproliferative activity could enter nucleus. All complexes have shown apparent lower cytotoxicity towards normal human colon epithelial cell CCD-841-CON than the examined tumor cell lines.

[Clinical analysis of 60 cases with radiative nasopharyngeal necrosis in nasopharyngeal carcinoma].

OBJECTIVE: To study the clinical characteristics, diagnosis, treatment and prognostic factors of patients with postradiation nasopharyngeal necrosis (PRNN) in nasopharyngeal carcinoma (NPC). METHODS: Sixty patients with PRNN were studied retrospectively, 50 males and 10 females, age ranging from 30 - 70 years of (median 51.5 years). All patients were treated with endoscopic debridement and systemic or local anti-inflammatory treatment. Kruskal-Wallis H test was used to assess the interval time between irradiation completion and necrosis onset and related factors of treatment outcome. Multivariate Cox proportional hazards regression survival analysis was performed to analyze risk factors. RESULTS: The latent period between the last irradiation and the onset of the symptom ranged from 1 to 156 months, with a median of 5 months. The median interval time was 7.0 months in 1 course group and 4.5 months in ≥2 courses group (χ2=5.527, P=0.031), and 7.5 months in T2 group and 5.0 months in ≥T3 group (χ2=4.330, P=0.037), respectively. Forty-one patients of them had nasopharyngeal infection, and the difference in curative effect between infection group and non-infection group was significantly (χ2=14.775, P<0.001). Symptoms were alleviated in all patients after endoscopic debridement and systemic or local anti-inflammatory treatment. Follow-up for all patients ranged from 2 to 46 months (median 12.5 months). Seven patients with internal carotid artery exposure died of sudden nasopharyngeal massive bleeding and fifteen patients died of tumor or systemic exhaustion; five cases were lost, and the rest were all in survival. Inter carotid artery erosion was an independent prognostic risk factor according to multivariate Cox proportional hazards regression survival analysis (P<0.05). CONCLUSIONS: Endoscopic debridement is effective in treating irradiation-related nasopharyngeal necrosis. The occurrence of nasopharyngeal necrosis is related to infection, irradiation dose and course, and T stage. Internal carotid artery erosion is a severe situation and also an independent prognostic factor for the patients. The most common causes of death were nasopharyngeal bleeding and systemic exhaustion.