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1.
Anticancer Res ; 35(1): 31-38, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25550532

ABSTRACT

BACKGROUND/AIM: Medullary thyroid carcinoma (MTC) is a tumor associated with poor prognosis since it exhibits high resistance against conventional cancer therapy. Recent studies have shown that quinazolines exhibit a pro-apoptotic effect on malignant cells. The aim of the present study was to elucidate whether MTC cells are affected by quinazolines, in particular prazosin. MATERIALS AND METHODS: Proliferation, apoptosis and cell morphology of the MTC cell line TT were analyzed by WST-1 assay, caspase 3/7 activation tests and microscopy. Fibroblasts were used as control for non-malignant cells. RESULTS: Prazosin potently inhibited the growth of TT cells, induced apoptosis and caused vacuolization, as well as needle-like filopodia. Fibroblasts were affected by prazosin in the same way as MTC cells. CONCLUSION: MTC cells are responsive to prazosin treatment similar to other malignancies. The fact that fibroblasts also respond to prazosin further highlights the importance to identify the unknown pro-apoptotic target of quinazolines.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Carcinoma, Medullary/drug therapy , Prazosin/pharmacology , Thyroid Neoplasms/drug therapy , Antihypertensive Agents/pharmacology , Cell Line, Tumor/drug effects , Drug Screening Assays, Antitumor , Humans , Receptors, Adrenergic, alpha-1/metabolism
2.
Anticancer Res ; 33(4): 1267-72, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23564764

ABSTRACT

Neuroendocrine tumors are relatively insensitive to radiation therapy, as well as chemotherapy. Thus, new approaches for alternative therapies are needed. We found that glutamate receptor antagonists are capable of suppressing tumor growth and cell activity of different peripheral malignancies. In the present article we review scientific literature in this field of science. Subtype-specific, non-competitive, metabotropic glutamate receptor-1 antagonists differently suppressed the growth and metabolic cell activity of one human medullary thyroid carcinoma cell line, as well as of four different human midgut neuroendocrine tumor cell lines. Furthermore, PCR analyses revealed that this subtype of glutamate receptor is expressed in these cell lines. These first results indicate that specific metabotropic glutamate receptor antagonists suppress the proliferation and cell activity of neuroendocrine tumor cells, which makes them possible targets in cancer therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Cell Proliferation/drug effects , Neuroendocrine Tumors/drug therapy , Neuroendocrine Tumors/metabolism , Receptors, Glutamate/chemistry , Animals , Humans , Neuroendocrine Tumors/pathology , Receptors, Glutamate/metabolism
3.
Exp Cell Res ; 317(20): 2969-80, 2011 Dec 10.
Article in English | MEDLINE | ID: mdl-21851819

ABSTRACT

Even though the erythroleukemia cell lines K562 and HEL do not express α1-adrenoceptors, some α1-adrenergic drugs influence both survival and differentiation of these cell lines. Since Ca2+ is closely related to cellular homeostasis, we examined the capacity of α1-adrenergic drugs to modulate the intracellular Ca2+ content in K562 cells. Because of morphological alterations of mitochondria following α1-adrenergic agonist treatment, we also scrutinized mitochondrial functions. In order to visualize the non-adrenoceptor binding site(s) of α1-adrenergic drugs in erythroleukemia cells, we evaluated the application of the fluorescent α1-adrenergic antagonist BODIPY® FL-Prazosin. We discovered that the α1-adrenergic agonists naphazoline, oxymetazoline and also the α1-adrenergic antagonist benoxathian are able to raise the intracellular Ca2+-content in K562 cells. Furthermore, we demonstrate that naphazoline treatment induces ROS-formation as well as an increase in Δψm in K562 cells. Using BODIPY® FL-Prazosin we were able to visualize the non-adrenoceptor binding site(s) of α1-adrenergic drugs in erythroleukemia cells. Interestingly, the SERCA-inhibitor thapsigargin appears to interfere with the binding of BODIPY® FL-Prazosin. Our data suggest that the effects of α1-adrenergic drugs on erythroleukemia cells are mediated by a thapsigargin sensitive binding site, which controls the fate of erythroleukemia cells towards differentiation, senescence and cell death through modulation of intracellular Ca2+.


Subject(s)
Adrenergic Agents/pharmacology , Calcium/metabolism , Homeostasis/drug effects , Leukemia, Erythroblastic, Acute/drug therapy , Leukemia, Erythroblastic, Acute/metabolism , Thapsigargin/pharmacology , Adrenergic alpha-1 Receptor Agonists/pharmacology , Adrenergic alpha-1 Receptor Antagonists/pharmacology , Aging/drug effects , Binding Sites/drug effects , Cell Death/drug effects , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Humans , K562 Cells , Membrane Potential, Mitochondrial/drug effects , Mitochondria/drug effects , Mitochondrial Membranes/drug effects , Mitochondrial Membranes/metabolism , Naphazoline/pharmacology , Reactive Oxygen Species/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & inhibitors , Sarcoplasmic Reticulum Calcium-Transporting ATPases/metabolism
4.
Exp Cell Res ; 317(16): 2239-51, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21781962

ABSTRACT

Preliminary data showed that α1-adrenergic antagonists induce apoptosis and a switch towards megakaryocytic differentiation in human erythroleukemia cells. To test the hypothesis whether survival and differentiation of erythroleukemia cells are under control of α1-adrenergic signalling, we examined α1-adrenoceptor expression of erythroleukemia cells and compared the in vitro effects of α-adrenergic antagonists with those of agonists. We discovered that α1-adrenergic agonists suppress both erythroid differentiation and growth of erythroleukemia cells concomitant with lipofuscin accumulation, autophagy and necrotic cell death. α1-adrenergic agonists also inhibit the in vitro growth of physiologic hematopoietic progenitors obtained from umbilical cord blood with high selectivity for the erythroid lineage. Interestingly, the observed effects could not be related to α1-adrenoceptors, even though agonists and antagonists displayed opposing effects regarding cellular growth and differentiation of erythroleukemia cells. Our data suggest that the effects of α1-adrenergic drugs are related to a non-adrenoceptor binding site, controlling the fate of erythroid progenitor cells towards differentiation and cell death. Since the observed effects are not mediated through adrenoceptors, the physiologic relevance of our data remains unclear, so far. Nevertheless, the identification of the still unknown binding site(s) might disclose new insights into regulation of erythroid differentiation and cell death.


Subject(s)
Adrenergic alpha-1 Receptor Agonists/pharmacology , Cell Death/drug effects , Cell Differentiation/drug effects , Leukemia, Erythroblastic, Acute/pathology , Adrenergic alpha-Agonists/pharmacology , Adrenergic alpha-Antagonists/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Caspase 3/metabolism , Cell Aggregation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Interactions , Erythroid Cells/cytology , Erythroid Cells/metabolism , Erythroid Precursor Cells/cytology , Erythroid Precursor Cells/drug effects , Erythroid Precursor Cells/metabolism , Fetal Blood/cytology , Gene Expression/drug effects , Gene Expression/genetics , Glycophorins/metabolism , Hemin/pharmacology , Hemoglobins/metabolism , Humans , Hydrogen-Ion Concentration/drug effects , K562 Cells , Leukemia, Erythroblastic, Acute/metabolism , Leukocyte Common Antigens/metabolism , Megakaryocyte Progenitor Cells/cytology , Megakaryocyte Progenitor Cells/drug effects , Megakaryocyte Progenitor Cells/metabolism , Megakaryocytes/cytology , Naphazoline/pharmacology , Necrosis/chemically induced , Oxathiins/pharmacology , Prazosin/pharmacology , Receptors, Adrenergic, alpha-1/genetics
5.
Head Neck ; 32(11): 1554-72, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20848447

ABSTRACT

The major excitatory neurotransmitter glutamate is also found in the periphery in an increasing number of nonexcitable cells. In line with this it became apparent that glutamate can regulate a broad array of peripheral biological responses, as well. Of particular interest is the discovery that glutamate receptor reactive reagents can influence tumor biology. However, the knowledge of glutamate signaling in peripheral tissues is still incomplete and, in the case of head and neck areas, is almost lacking. The roles of glutamate signaling pathways in these regions are manifold and include orofacial pain, periodontal bone production, skin and airway inflammation, as well as salivation. Furthermore, the interrelations between glutamate and cancers in the oral cavity, thyroid gland, and other regions are discussed. In summary, this review shall strengthen the view that glutamate receptor reagents may also be promising targets for novel therapeutic concepts suitable for a number of diseases in peripheral tissues. The contents of this review cover the following sections: Introduction; The "Glutamate System"; The Taste of Glutamate; Glutamate Signaling in Dental Regions; Glutamate Signaling in Head and Neck Areas; Glutamate Signaling in Head and Neck Cancer; A Brief Overview of Glutamate Signaling in Other Cancers; and Conclusion.


Subject(s)
Excitatory Amino Acid Antagonists/pharmacology , Head and Neck Neoplasms/metabolism , Receptors, Glutamate/physiology , Signal Transduction/physiology , Animals , Cell Proliferation/drug effects , Glutamic Acid/metabolism , Head and Neck Neoplasms/pathology , Humans , Oral Surgical Procedures , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/physiology , Salivary Glands/innervation , Salivary Glands/metabolism , Skin/metabolism , Taste/physiology , Taste Buds/metabolism , Thyroid Gland/metabolism
6.
Oncol Rep ; 17(6): 1399-404, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17487397

ABSTRACT

Five decades ago, the dicarboxylic amino acid glutamate became recognized as the major excitatory neurotransmitter in the central nervous system. In recent years, the expression of glutamate receptors was detected also in peripheral, non-neuronal tissues. Furthermore, it was found that glutamate stimulated the proliferation and migration of several peripheral tumor cells, and that glutamate receptor antagonists limited tumor growth. Most of these studies, however, used broad spectrum compounds and/or group-specific antagonists. Here we report that a selective, non-competitive metabotropic glutamate receptor-1 antagonist, CPCCOEt (7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester), significantly inhibited the proliferation and modified the morphology of two human melanoma cell lines. These effects were independent of the external glutamate level in the culture medium. In addition, CPCCOEt significantly enhanced the tumoricidal effects of cytostatic drugs. Thus, selective non-competitive metabotropic glutamate receptor antagonists may be used alone and/or with the synergistic effects of chemotherapy, thus enhancing existing therapies of melanoma and possibly other malignancies.


Subject(s)
Chromones/pharmacology , Drug Resistance, Neoplasm/drug effects , Excitatory Amino Acid Antagonists/pharmacology , Melanoma/metabolism , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Skin Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Docetaxel , Glutamic Acid/metabolism , Humans , Melanoma/ultrastructure , Skin Neoplasms/ultrastructure , Taxoids/pharmacology , Tumor Cells, Cultured
7.
Int J Oncol ; 27(3): 867-74, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16077940

ABSTRACT

Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS) and binds to a variety of receptors, which recently have also been detected in peripheral, non-excitable cells. New research suggests that this abundant amino acid might also be involved in the growth of tumor cells acting via novel receptor-mediated autocrine/paracrine signal transduction pathways. We report here that glutamate, as well as glutamate receptor reactive drugs, differentially modulate growth and morphology of human histiocytic lymphoma-derived U937 cells. These effects were different depending on the culture milieu: in glutamine-free medium the glutamate receptor agonists, kainate (KA), and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), but also the antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), significantly decreased the proliferation of U937 cells. In contrast, in cultures devoid of glutamate, glutamine and serum, the agonists significantly increased cell proliferation whereas the antagonist CNQX showed no effect. These data point to a significant role of peripheral glutamate receptors in tumor cell proliferation.


Subject(s)
Cell Proliferation/drug effects , Glutamic Acid/pharmacology , Receptors, Glutamate/physiology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Cell Shape/drug effects , Culture Media, Serum-Free/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glutamine/pharmacology , Humans , Kainic Acid/pharmacology , Lymphoma, Large B-Cell, Diffuse/pathology , Lymphoma, Large B-Cell, Diffuse/ultrastructure , Microscopy, Electron , Time Factors , U937 Cells , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
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