ABSTRACT
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Subject(s)
Child, Preschool , Humans , Male , Chromosome Deletion , Chromosome Disorders/diagnosis , Chromosome Disorders/genetics , Hybridization, Genetic , Muscle Hypotonia/complications , Muscle Hypotonia/genetics , Nervous System Diseases/complications , Nervous System Diseases/genetics , Neurologic Examination/methods , Craniofacial Abnormalities/complications , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/genetics , Chromosome AberrationsABSTRACT
The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in the development of cancer. No in-depth studies of the involvement of this system in breast cancer (BC) have been carried out, and the action exerted by the drug aprepitant on BC cells is currently unknown. We show the involvement of this system in human BC cell lines: i) these cells express mRNA for the NK-1 receptor; ii) they overexpress NK-1 receptors; iii) the NK-1 receptor is involved in their viability; iv) SP induces their proliferation; v) NK-1 receptor antagonists block SP-induced mitogen stimulation of these cells; vi) the specific antitumor action of such antagonists on these cells occurs through the NK-1 receptor; and vii) BC cell death is due to apoptosis. We also found NK-1 receptors and SP in all human BC samples studied. The NK-1 receptor may be a promising target in the treatment of BC and NK-1 receptor antagonists could be candidates as a new antitumor drug in the treatment of BC.
Subject(s)
Antineoplastic Agents/pharmacology , Breast Neoplasms/pathology , Morpholines/pharmacology , Receptors, Neurokinin-1/metabolism , Substance P/metabolism , Aprepitant , Breast Neoplasms/drug therapy , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic/drug effects , Gene Knockdown Techniques , Humans , MCF-7 Cells , Neurokinin-1 Receptor Antagonists/pharmacology , Piperidines/pharmacology , Receptors, Neurokinin-1/genetics , Tryptophan/analogs & derivatives , Tryptophan/pharmacologyABSTRACT
Substance P and neurokinin-1 (NK-1) receptor antagonists respectively induce proliferation and growth inhibition in human melanoma cell lines. The presence of NK-1 receptors in human melanoma cell lines and samples has been reported, but the presence of NK-1 receptors has not been demonstrated in uveal melanomas. It is known that melanoma express the tachykinin 1 receptor (TAC1R) gene. This gene is overexpressed in several human cancer cell lines, but such overexpression is currently unknown in human malignant melanoma cell lines (COLO 858, MEL HO, COLO 679). In this study, we attempt to demonstrate the overexpression of the TAC1R gene in such cells. We performed an in vitro study by real-time quantitative RT-PCR for TAC1R and found that the NK-1 receptor was overexpressed in the three human melanoma cell lines studied. Using a knockdown method, we demonstrate that the NK-1 receptor is involved in the viability of the COLO 858 melanoma cell line. Immunohistochemistry was also used to demonstrate NK-1 receptors in uveal melanoma samples. We observed that NK-1 receptors were present in the 21/21 uveal melanomas. In addition, cyclosporin A inhibited the growth of the three melanoma cell lines studied in a dose-dependent manner, and after the administration of this immunosuppresive drug apoptosis was observed. This indicates at least that the antitumor action of cyclosporin A is mediated by the NK-1 receptor. Our findings suggest that the NK-1 receptor could be a promising target in the treatment of human melanomas.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis , Cyclosporine/pharmacology , Melanoma/metabolism , Neurokinin-1 Receptor Antagonists/pharmacology , Receptors, Neurokinin-1/metabolism , Uveal Neoplasms/metabolism , Adult , Aged , Cell Line, Tumor , Cell Survival , Drug Screening Assays, Antitumor , Female , Gene Expression , HEK293 Cells , Humans , Inhibitory Concentration 50 , Male , Melanoma/drug therapy , Middle Aged , Molecular Targeted Therapy , Receptors, Neurokinin-1/genetics , Uveal Neoplasms/drug therapy , Young AdultABSTRACT
BACKGROUND & AIMS: Multidrug resistance presents a major problem in hepatoblastoma (HB), and new anti-tumor strategies are desperately needed. The substance P (SP)/neurokinin-1 receptor (NK1R) complex has been discovered to be pivotal in the development of a variety of human cancers, and NK1R antagonists, such as the clinical drug aprepitant, are promising future anticancer agents. Yet, the role of the SP/NK1R complex as a potential anticancer target in HB is unknown. METHODS: Human HB cell lines HepT1, HepG2, and HuH6, human tumor samples from 17 children with HB as well as mice xenografted with human HB cell line HuH6 were analyzed regarding the SP/NK1R complex as a potential new anti-tumor target in HB. RESULTS: Therapeutic targeting with the NK1R antagonists aprepitant, L-733,060, and L-732,138 led to growth inhibition and apoptosis in HepT1, HepG2, and HuH6 cells in a dose-dependent manner. Intriguingly, HB cells predominantly expressed the truncated splice variant of NK1R. Human fibroblasts showed only dismal NK1R expression and were significantly more resistant. Stimulation of HB cells with SP, NK1R's natural ligand, caused increased growth rates and abrogated the anti-proliferative effect of NK1R antagonists. Expression analysis of 17 human HB samples confirmed the clinical relevance of NK1R. Most importantly, oral treatment of a HuH6 xenograft mouse model with 80mg/kg/day aprepitant for 24days resulted in a striking reduction of tumor growth, as evidenced by reduced tumor volume and weight, lowered tumor-specific alpha-fetoprotein (AFP) serum levels, and decreased number of Ki-67 positive cells. Furthermore, aprepitant treatment inhibited in vivo angiogenesis. CONCLUSIONS: For the first time, we describe the NK1R in its truncated splice variant as a potent target in human HB and an inhibitory effect in vivo and in vitro by NK1R antagonists. Therefore, NK1R antagonists should be considered promising new candidates for innovative therapeutic strategies against HB.
Subject(s)
Hepatoblastoma/drug therapy , Hepatoblastoma/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/metabolism , Morpholines/pharmacology , Neurokinin-1 Receptor Antagonists/pharmacology , Receptors, Neurokinin-1/metabolism , Animals , Apoptosis/drug effects , Aprepitant , Cell Line, Tumor , Cell Proliferation/drug effects , Child , Cytostatic Agents/administration & dosage , Drug Synergism , Female , Gene Expression , Hep G2 Cells , Hepatoblastoma/pathology , Humans , Liver Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Morpholines/administration & dosage , Neovascularization, Pathologic/prevention & control , Neurokinin-1 Receptor Antagonists/administration & dosage , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptors, Neurokinin-1/genetics , Substance P/metabolism , Substance P/pharmacology , Xenograft Model Antitumor AssaysABSTRACT
The last decades have seen no significant progress in extending the survival of lung cancer patients and there is an urgent need to improve current therapies. The substance P (SP)/neurokinin-1 receptor (NK-1R) system plays an important role in the development of cancer: SP and NK-1R antagonists respectively induce cell proliferation and inhibition in human cancer cell lines. No study of the involvement of this system in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells has been carried out in depth. Here, we demonstrate the involvement of the SP/NK-1R system in human H-69 (SCLC) and COR-L23 (NSCLC) cell lines: (1) they express isoforms of the NK-1R and mRNA for the NK-1R; (2) they overexpress the tachykinin 1 gene; (3) the NK-1R is involved in their viability; (4) SP induces their proliferation; (5) NK-1R antagonists (Aprepitant (Emend), L-733,060, L-732,138) inhibit the growth of both cell lines in a concentration-dependent manner; (6) the specific antitumor action of these antagonists against such cells occurs through the NK-1R; and (7) lung cancer cell death is due to apoptosis. We also demonstrate the presence of NK-1Rs and SP in all the human SCLC and NSCLC samples studied. Our findings indicate that the NK-1R may be a promising new target in the treatment of lung cancer and that NK-1R antagonists could be new candidate antitumor drugs in the treatment of SCLC and NSCLC.
Subject(s)
Antineoplastic Agents/pharmacology , Lung Neoplasms/drug therapy , Morpholines/pharmacology , Neurokinin-1 Receptor Antagonists , Piperidines/pharmacology , Substance P/antagonists & inhibitors , Tryptophan/analogs & derivatives , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Aprepitant , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Lung Neoplasms/chemistry , Lung Neoplasms/pathology , Morpholines/chemistry , Piperidines/chemistry , Receptors, Neurokinin-1/analysis , Receptors, Neurokinin-1/genetics , Structure-Activity Relationship , Substance P/analysis , Tryptophan/chemistry , Tryptophan/pharmacology , Tumor Cells, CulturedABSTRACT
Los tumores del nervio periférico son lesiones relativamente comunes que con frecuencia plantean problemas diagnósticos de marcada trascendencia. En la presente revisión se estudian de modo comparativo lesiones con nombres o con características morfológicas parecidas para poner en relieve los hallazgos diferenciales más significativos. En esta primera parte se revisan los siguientes diagnósticos: schwannoma convencional de tejidos blandos vs. neurofibroma intraneural; neurofibroma plexiforme vs. schwannoma plexiforme; schwannoma celular vs. tumor maligno de la vaina neural periférica (TMVNP); TMVNP vs. Melanoma, y TMVNP vs. sarcoma sinovial monofásico(AU)
Peripheral nerve tumours are relatively common and often pose important diagnostic problems. The present review makes a comparative study of lesions with similar names or morphological characteristics, highlighting the most significant findings. In this first part, the following diagnoses are considered: Conventional soft tissue schwannoma vs. intraneural neurofibroma; plexiform neurofibroma vs. plexiform schwannoma; cellular schwannoma vs. malignant peripheral neural sheath tumour (MPNST); MPNST vs. melanoma; and MPNST vs. monophasic synovial sarcoma(AU)
Subject(s)
Humans , Male , Female , Peripheral Nervous System Neoplasms/pathology , Melanoma/diagnosis , Melanoma/pathology , Sarcoma, Synovial/pathology , Neurofibroma, Plexiform/complications , Neurofibroma, Plexiform/diagnosis , Neurofibroma, Plexiform/pathology , Nerve Sheath Neoplasms/pathology , Neurofibroma/complications , Neurofibroma/pathology , Neurofibroma, Plexiform/ultrastructure , Neurofibroma, PlexiformABSTRACT
Melanoma, the most deadly form of skin cancer, is aggressive and resistant to current therapies. It has been previously reported that the substance P and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition, respectively, in human melanoma cell lines. Aprepitant is a selective high-affinity antagonist of the human NK-1 receptor. Until now, this drug has been used as an anxiolytic, antidepressant and antiemetic. Moreover, the antitumor action of aprepitant has been previously reported. However, the presence of NK-1 receptors in human melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas have not been previously described. The aims of this study are to show the presence of NK-1 receptors in human malignant melanomas and the antitumoral action of aprepitant against several human melanoma cell lines. Immunoblot analysis was used to determine the presence of NK-1 receptors in human melanoma cell lines, and immunohistochemistry was used to demonstrate NK-1 receptors in human melanoma samples. We performed an in vitro study of the cytotoxicity of the NK-1 receptor antagonist aprepitant on human melanoma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound MTS. The DAPI method was applied to demonstrate apoptosis. We observed that NK-1 receptors were present in all the melanoma samples studied as well as in human melanoma cell lines. We also showed that melanoma cell lines expressed mRNA for the NK-1 receptor. Moreover, after using a knockdown method, we showed that NK-1 receptors are involved in the viability of tumor cells. In this study, we also report that aprepitant, at 10-60 microM concentrations, elicits cell growth inhibition in a concentration-dependent manner in all melanoma cell lines studied, that the specific antitumor action of aprepitant occurs through the NK-1 receptor and that melanoma cell death is due to apoptosis. These findings show for the first time that the NK-1 receptor may be a promising new target and that the NK-1 receptor antagonist aprepitant could be a candidate as a new antitumor drug in the treatment of human melanoma.
Subject(s)
Melanoma/pathology , Morpholines/pharmacology , Neurokinin-1 Receptor Antagonists , Receptors, Neurokinin-1/metabolism , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Aprepitant , Cell Line , Cell Proliferation/drug effects , Humans , Melanoma/metabolism , Receptors, Neurokinin-1/physiology , Skin Neoplasms , Substance P/metabolism , Substance P/pharmacologyABSTRACT
BACKGROUND/AIMS: It has been demonstrated that substance P (SP) and neurokinin-1 (NK-1) receptor antagonist L-733,060 induces cell proliferation and inhibition, respectively, in several human cancer cell lines. At present, it is unknown whether such actions are exerted on human gastric and colon adenocarcinomas. We carried out an in vitro study of the growth-inhibitory capacity of L-733,060 against human gastric and colon adenocarcinomas. METHODS: A coulter counter was used to determine viable cell numbers followed by application of the tetrazolium compound MTS. Immunoblot analysis was used to determine the NK-1 receptors and the DAPI method was applied to demonstrate apoptosis. Immunohistochemistry was used to demonstrate NK-1 receptors in primary human gastric and colon adenocarcinomas. RESULTS: We observed the presence of several NK-1 receptor isoforms in human gastric and colon adenocarcinomas. Nanomolar concentrations of SP increased the growth of both cell lines and micromolar concentrations of L-733,060 inhibited the growth of such cell lines, with and without previous administration of SP. L-733,060 inhibited the growth of the 23132/87 and SW-403 cell lines in a dose-dependent manner. After administration of L-733,060, apoptosis was observed in both cell lines. In both human primary gastric and colon adenocarcinomas, a high density of NK-1 receptors was observed. Immunoreactivity, showing a diffuse cytoplasmic staining, was observed in the epithelial cells of normal and tumor glands and in numerous stromal elements. CONCLUSIONS: We demonstrated that NK-1 receptors were expressed in 23132/37 and SW-403 cell lines and in human primary gastric and colon adenocarcinomas, that SP is a mitogen and that the antitumor action of L-733,060 on both human cell lines occurs through the NK-1 receptor. Data also indicate that the cell death observed is produced by apoptosis. These data suggest that the NK-1 receptor is a new and promising target in the treatment of human gastrointestinal adenocarcinomas.
Subject(s)
Adenocarcinoma/chemistry , Antineoplastic Agents/pharmacology , Colonic Neoplasms/chemistry , Mitogens/pharmacology , Piperidines/pharmacology , Receptors, Neurokinin-1/analysis , Stomach Neoplasms/chemistry , Substance P/pharmacology , Adenocarcinoma/drug therapy , Apoptosis/drug effects , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Dose-Response Relationship, Drug , Humans , Immunohistochemistry , Neurokinin-1 Receptor Antagonists , Receptors, Neurokinin-1/physiology , Stomach Neoplasms/drug therapy , Stomach Neoplasms/pathologyABSTRACT
No disponible
Subject(s)
Humans , Female , Infant, Newborn , Infant, Newborn, Diseases , Heart Neoplasms/complications , Tuberous Sclerosis/complications , Rhabdomyoma/complications , Heart Neoplasms/diagnosis , Tuberous Sclerosis/diagnosis , Rhabdomyoma/diagnosis , Echocardiography, Doppler , Fatal OutcomeSubject(s)
Breast Neoplasms, Male/pathology , Carcinoma in Situ/pathology , Carcinoma, Ductal, Breast/pathology , Sarcoma/pathology , Age Factors , Aged , Breast/pathology , Breast Neoplasms, Male/epidemiology , Carcinoma in Situ/epidemiology , Female , Humans , Male , Middle Aged , Prevalence , Sarcoma/epidemiology , Sex FactorsABSTRACT
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Subject(s)
Humans , Male , Female , Adult , Middle Aged , Granular Cell Tumor/pathology , /pathology , Bronchial Neoplasms/pathology , Diagnosis, DifferentialABSTRACT
No disponible
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Gastritis, Hypertrophic/complications , Stomach Neoplasms/complications , Carcinoma/pathologyABSTRACT
No disponible
Subject(s)
Male , Middle Aged , Aged , Humans , Carcinoma, Ductal, Breast/pathology , Breast Neoplasms, Male/pathology , Biopsy , Carcinoma, Intraductal, Noninfiltrating/pathologySubject(s)
Lipoma/diagnosis , Adolescent , Adult , Age Factors , Aged , Axilla , Diagnosis, Differential , Female , Foot , Humans , Lipoma/epidemiology , Lipoma/pathology , Lipoma/surgery , Male , Sex Factors , Shoulder , Time FactorsABSTRACT
No disponible
