5-lipoxygenase mediates docosahexaenoyl ethanolamide and N-arachidonoyl-L-alanine-induced reactive oxygen species production and inhibition of proliferation of head and neck squamous cell carcinoma cells

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Abstract Background 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. Methods and Results 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. Conclusions 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

DIFFERENTIAL EFFECTS BETWEEN CYCLOOXYGENASE-2 INHIBITORS AND siRNA ON VASCULAR ENDOTHELIAL GROWTH FACTOR PRODUCTION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA CELL LINES

Background. Several researchers have observed that cyclooxygenase-2 (COX-2) inhibitors display anticancer effects only at higher concentrations than doses that block COX-2 activity in head and neck squamous cell carcinoma (HNSCC) cells. Methods. To better understand the exact anticancer mechanism of COX-2-inhibitors, we compared the effects of pharmacologic inhibitors to those of small-interfering RNA against COX-2 on cell-growth, vascular endothelial growth factor (VEGF) production, and intracellular signaling in HNSCC cell lines. Results. We observed in HNSCC cells, that COX-2-siRNA induced an inhibitory effect on intracellular signaling, but unlike the pharmacologic inhibitors, did not affect cell proliferation. Whereas the chemical inhibitors increased VEGF synthesis even at low doses, COX-2-siRNA showed differential inhibition of VEGF production according to expression patterns of COX1 and COX-2 in tested cells. Conclusion. The majority of the anticancer effects of COX-2-inhibitors in HNSCC cells seem to result from COX-2-independent action, suggesting that COX-1 and COX-2 may contribute to VEGF synthesis in cancer cells through a prostaglandin-dependent mechanism. (C) 2010 Wiley Periodicals, Inc. Head Neck 32: 1534-1543,2010Park JW, 2006, J CANCER RES CLIN, V132, P184, DOI 10.1007/s00432-005-0060-xCharames GS, 2006, INT J ONCOL, V28, P543Palayoor ST, 2005, CLIN CANCER RES, V11, P6980, DOI 10.1158/1078-0432.CCR-05-0326Kino Y, 2005, PROSTAG LEUKOTR ESS, V73, P103, DOI 10.1016/j.plefa.2005.04.014Zhi YH, 2005, WORLD J GASTROENTERO, V11, P3724Maier TJ, 2005, FASEB J, V19, P1353, DOI 10.1096/fj.04-3274fjeDaikoku T, 2005, CANCER RES, V65, P3735Brown JR, 2005, J CLIN ONCOL, V23, P2840Honjo S, 2005, DNA CELL BIOL, V24, P141Wang Z, 2005, CURR PHARM DESIGN, V11, P1771Farivar-Mohseni H, 2004, AM J SURG, V188, P505, DOI 10.1016/j.amjsurg.2004.07.025Roh JL, 2004, CANCER RES, V64, P3230Maier TJ, 2004, BIOCHEM PHARMACOL, V67, P1469, DOI 10.1016/j.bcp.2003.12.014Shao JY, 2004, J BIOL CHEM, V279, P14287, DOI 10.1074/jbc.M313276200Kinugasa Y, 2004, CLIN EXP METASTAS, V21, P737, DOI 10.1007/s10585-005-1190-xPark SW, 2003, INT J CANCER, V107, P729, DOI 10.1002/ijc.11498Regan JW, 2003, LIFE SCI, V74, P143, DOI 10.1016/j.lfs.2003.09.031Denkert C, 2003, ONCOGENE, V22, P8653, DOI 10.1038/sj.onc.1206920Shao JY, 2003, CANCER RES, V63, P5218Soh JW, 2003, PROG EXP TUMOR RES, V37, P261Muller-Decker K, 2002, P NATL ACAD SCI USA, V99, P12483, DOI 10.1073/pnas.192323799Lee DW, 2002, ANTICANCER RES, V22, P2089Baek SJ, 2002, J PHARMACOL EXP THER, V301, P1126Elder DJE, 2002, INT J CANCER, V99, P323, DOI 10.1002/ijc.10330Sheng HM, 2001, J BIOL CHEM, V276, P18075Warner TD, 1999, P NATL ACAD SCI USA, V96, P7563EBERHART CE, 1994, GASTROENTEROLOGY, V107, P1183

Role of surgical salvage for regional recurrence in laryngeal cancer

OBJECTIVES: The aims of this study were to analyze the pattern of regional recurrence in laryngeal cancer, evaluate the role of surgical salvage, and identify factors affecting salvage outcome. METHODS: Retrospective analysis was conducted on medical records from a 16-year period. Of 463 patients diagnosed with laryngeal cancer, 25 patients with regional recurrence managed with salvage neck dissection were identified and subject to study. Isolated local recurrences and all distant metastases were excluded. RESULTS: All patients were male with a median age of 61 years. The overall rate of regional recurrence was 5.4%. Median time to regional recurrence was 13 months. Isolated regional recurrence occurred in 76% of cases, whereas locoregional recurrence occurred in 24%. A 5-year survival rate for patients undergoing neck dissection as salvage management was 61.2%. Patients with recurrence in the contralateral neck were definitely associated with poor prognosis. Although standard statistical significance was not met, trends for poorer salvage result were identified in patients with a history of local recurrence before regional recurrence, recurrence in a previously dissected neck, and recurred node size of 3 cm or above. CONCLUSIONS: Our study shows that salvage neck dissection for regional recurrence in laryngeal cancer is an acceptable approach. Surgical eradication of disease should be warranted whenever possible. Prudent planning of management is mandatory in the presence of history of local recurrence before regional recurrence, previously dissected neck, large size of recurrent node, and contralateral neck recurrence

Neoadjuvant Chemotherapy Followed by Limited Surgery in a Mouse Model of Head and Neck Cancer

Background: This study evaluated the effect of limited surgery following neoadjuvant chemotherapy compared to radical surgery in SCC VII (squamous cell cancer) tumor-bearing syngeneic C3H/HeJ mice. Materials and Methods: Mice showing a tumor response to cisplatin and 5-fluorouracil therapy were divided into three groups: radical surgery, with a 5 nun margin from the original tumor, group (A); limited surgery of 5 mm margin from the residual tumor, group (B); and very limited surgery with no margin from the residual tumor, group (C). The number of mice was 13 (group A), 12 (group B) and 12 (group C). Results: No recurrence developed except in one mouse in group C. Three mice died in group A, one in group B and one in group C from perioperative complications. By intent-to-treat analysis, the survival was not significantly different among the three groups (p=0.64), or between group A and B (p=0.33). Conclusion: The outcome of limited surgery was comparable to radical surgery after neoadjuvant chemotherapy in the mouse model of head and neck cancer

Neoadjuvant Chemotherapy Followed by Limited Surgery in a Mouse Model of Head and Neck Cancer

Background: This study evaluated the effect of limited surgery following neoadjuvant chemotherapy compared to radical surgery in SCC VII (squamous cell cancer) tumor-bearing syngeneic C3H/HeJ mice. Materials and Methods: Mice showing a tumor response to cisplatin and 5-fluorouracil therapy were divided into three groups: radical surgery, with a 5 nun margin from the original tumor, group (A); limited surgery of 5 mm margin from the residual tumor, group (B); and very limited surgery with no margin from the residual tumor, group (C). The number of mice was 13 (group A), 12 (group B) and 12 (group C). Results: No recurrence developed except in one mouse in group C. Three mice died in group A, one in group B and one in group C from perioperative complications. By intent-to-treat analysis, the survival was not significantly different among the three groups (p=0.64), or between group A and B (p=0.33). Conclusion: The outcome of limited surgery was comparable to radical surgery after neoadjuvant chemotherapy in the mouse model of head and neck cancer.This study was supported by grants of the Cancer Research Institute, Seoul National University College of Medicine (CRI - 2002 - 9) and from the Innovative Research Institute for Cell Therapy (A062260), Republic of Korea.Vermorken JB, 2008, NEW ENGL J MED, V359, P1116Langendijk JA, 2008, J CLIN ONCOL, V26, P3770, DOI 10.1200/JCO.2007.14.6647Nicolai P, 2008, AM J RHINOL, V22, P308, DOI 10.2500/ajr.2008.22.3170Jemal A, 2008, CA-CANCER J CLIN, V58, P71, DOI 10.3322/CA.2007.0010Cho YH, 2008, HEAD NECK-J SCI SPEC, V30, P346, DOI 10.1002/hed.20713Upile T, 2007, ORAL ONCOL, V43, P321, DOI 10.1016/j.oraloncology.2006.08.002Meier JD, 2005, HEAD NECK-J SCI SPEC, V27, P952, DOI 10.1002/hed.20269McMahon J, 2003, BRIT J ORAL MAX SURG, V41, P224, DOI 10.1016/S0266-4356(03)00119-0Seikaly H, 2003, LARYNGOSCOPE, V113, P897Zackrisson B, 2003, ACTA ONCOL, V42, P443, DOI 10.1080/02841860310014886Pauloski BR, 2002, HEAD NECK-J SCI SPEC, V24, P555, DOI 10.1002/hed.10092Laccourreye O, 2002, ANN OTO RHINOL LARYN, V111, P315Taylor RJ, 2002, ARCH OTOLARYNGOL, V128, P44*GOV REP KOR, 2002, ANN REP CAUS DEATH S, P11Khurana D, 2001, HEAD NECK-J SCI SPEC, V23, P899Laccourreye O, 2001, CANCER, V92, P1504Steiner W, 2001, OTOLARYNG HEAD NECK, V124, P58, DOI 10.1067/mhn.2001.111597Pignon JP, 2000, LANCET, V355, P949Spiro RH, 1999, HEAD NECK-J SCI SPEC, V21, P408Woolgar JA, 1999, BRIT J ORAL MAX SURG, V37, P187Batsakis JG, 1999, ADV ANAT PATHOL, V6, P140Richard JM, 1998, ORAL ONCOL, V34, P224Yuen PW, 1998, AM J SURG, V175, P242OMalley BW, 1997, ARCH OTOLARYNGOL, V123, P20OSAKI T, 1994, HEAD NECK-J SCI SPEC, V16, P218GOULD EW, 1992, SEMIN SURG ONCOL, V8, P129LOREE TR, 1990, AM J SURG, V160, P410SULFARO S, 1989, CANCER, V64, P994HERMANEK P, 1987, RONTGENBLATTER, V40, P200VIKRAM B, 1984, HEAD NECK SURG, V6, P720*WHO, 1979, WHO HDB REP RES CANCLOOSER KG, 1978, HEAD NECK SURG, V1, P107GERAN RI, 1972, CANCER CHEMOTH REP, V3, P51

Preliminary results of pre-radiation neck dissection in head and neck cancer patients undergoing organ preservation treatment

CONCLUSION: Pre-RT ND in patients with HNSCC undergoing organ preservation treatment is safe, advantageous, poses no additional morbidity owing to the elective neck dissection, and may possibly improve survival outcomes. OBJECTIVE: Establish the role of pre-radiation neck dissection (pre-RT ND) in patients with head & neck squamous cell carcinoma (HNSCC) undergoing organ preservation treatment. MATERIALS AND METHODS: Fourteen patients with histologically confirmed HNSCC in stages III approximately IV with proven regional metastasis were enrolled in the organ preservation approach incorporating pre-RT ND at a tertiary referral center between May 1998 and August 2004. Site matched patients treated with organ preservation intent in the conventional fashion were used as controls. Data were collected for their diagnosis, management, treatment outcome, and follow up. RESULTS: Disease free survival was significantly better for the pre-RT ND group. There was no significant difference in overall survival, pattern of recurrence, and primary organ preservation rate between the two groups. No significant morbidity owing to neck dissection was noted in patients who underwent neck dissection. Although the delivery of radiation to the primary site was delayed for patients in the pre-RT ND group, it did not influence the major outcomes

PRESENCE OF HPV TYPE 6 IN DYSPLASIA AND CARCINOMA ARISING FROM RECURRENT RESPIRATORY PAPILLOMATOSIS

Background. We collected rare cases of recurrent respiratory papillomatosis (RRP) undergoing malignant transformation. We sought to identify human papillomavirus (HPV) subtypes in areas of papilloma, dysplasia, and carcinoma and investigate thve pattern of protein overexpression. Methods. Three patients whose disease underwent malignant transformation from RRP to carcinoma were subjected to this study, Morphologically distinct areas in the pathology specimen of each patient were diagnosed as papilloma, dysplasia. and carcinoma. Each lesion was separately obtained by laser capture microdissection and was PCR amplified for the presence of HPV. A DNA chip was used to determine the type of HPV in each area. Immunohistochemistry for p53, Ki-67, and pRb was performed. Results. HPV type 6 was present in all specimens tested positive, Expression of p53 and Ki-67 increased with increasing severity of dysplastic change. Conclusion. Although HPV type 11 is most frequently associated with malignant change of RRP. HPV type 6 may also contribute to play an equally important role in RRP carcinogenesis. (C) 2008 Wiley Periodicals, Inc. Head Neck 31: 1095-1101, 2009Gerein V, 2005, OTOLARYNG HEAD NECK, V132, P392, DOI 10.1016/j.otohns.2004.09.025FEHRMANN F, 2005, METHOD MOL BIOL, V292, P317Reidy PM, 2004, LARYNGOSCOPE, V114, P1906, DOI 10.1097/01.mlg.0000147918.81733.49Lee SA, 2003, CANCER LETT, V198, P187, DOI 10.1016/S0304-3835(03)00312-4Go C, 2003, ANN OTO RHINOL LARYN, V112, P298Lele SM, 2002, ARCH PATHOL LAB MED, V126, P1184Dedo HH, 2001, LARYNGOSCOPE, V111, P1639Gupta D, 2001, APPL IMMUNOHISTO M M, V9, P86HARTNICK CJ, 2001, CURR OPIN OTOLARYNGO, V9, P374Venuti A, 2000, J MED VIROL, V60, P396Stern Y, 2000, OTOLARYNG HEAD NECK, V122, P378Moore CE, 1999, OTOLARYNG HEAD NECK, V120, P698Rady PL, 1998, LARYNGOSCOPE, V108, P735Lin KY, 1997, LARYNGOSCOPE, V107, P942Klozar J, 1997, ACTA OTO-LARYNGOL, P100Lie ES, 1996, ACTA OTO-LARYNGOL, V116, P900Sakakura A, 1996, J LARYNGOL OTOL, V110, P75HAVRE PA, 1995, CANCER RES, V55, P4420POU AM, 1995, ANN OTO RHINOL LARYN, V104, P758DOYLE DJ, 1994, ARCH OTOLARYNGOL, V120, P1273GUILLOU L, 1991, AM J SURG PATHOL, V15, P891GERDES J, 1991, AM J PATHOL, V138, P867LINDEBERG H, 1989, ACTA OTO-LARYNGOL, V107, P141ZAROD AP, 1988, J CLIN PATHOL, V41, P280BYRNE JC, 1987, NEW ENGL J MED, V317, P873

VEGF and Ki-67 overexpression in predicting poor overall survival in adenoid cystic carcinoma

Purpose The purpose of this study was to evaluate potential prognostic factors in patients with adenoid cystic carcinoma (ACC). Materials and Methods A total of 68 patients who underwent curative surgery and had available tissue were enrolled in this study. Their medical records and pathologic slides were reviewed and immunohistochemistry for basic fibroblast growth factor, fibroblast growth factor receptor (FGFR) FGFR3, c-kit, Myb proto-oncogene protein, platelet-derived growth factor receptor beta, vascular endothelial growth factor (VEGF), and Ki-67 was performed. Univariate and multivariate analysis was performed for determination of disease-free survival (DFS) and overall survival (OS). Results In univariate analyses, primary site of nasal cavity and paranasal sinus (p=0.022) and Ki-67 expression of more than 7% (p=0.001) were statistically significant factors for poor DFS. Regarding OS, perineural invasion (p=0.032), high expression of VEGF (p=0.033), and high expression of Ki-67 (p=0.007) were poor prognostic factors. In multivariate analyses, primary site of nasal cavity and paranasal sinus (p=0.028) and high expression of Ki-67 (p=0.004) were independent risk factors for poor DFS, and high expression of VEGF (p=0.011) and Ki-67 (p=0.011) showed independent association with poor OS. Conclusion High expression of VEGF and Ki-67 were independent poor prognostic factors for OS in ACC.