The non-competitive metabotropic glutamate receptor-1 antagonist CPCCOEt inhibits the in vitro growth of human melanoma

Abstract

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 groupspecific antagonists. Here we report that a selective, noncompetitive 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.

Extracellular Calcium Modulates Actions of Orthosteric and Allosteric Ligands on Metabotropic Glutamate Receptor 1α

“…Interestingly, increasing [Ca 2ϩ ] o restored the [Ca 2ϩ ] o sensitivity of the receptor. CPCCOEt not only inhibits proliferation of melanoma cells but also reverses morphine tolerance (47,48). Thus, the findings in this study indicate that a novel drug targeting the [Ca 2ϩ ] o -binding site in mGluR1 has the potential to tune the therapeutic effect of CPCCOEt on melanoma or addiction.…”

Peripheral glutamate signaling in head and neck areas

“…143 However, in recent years it became apparent that mGluR1 signaling is critically involved in the development of melanoma, and mGluR1 antagonists were sufficient to suppress melanoma cell proliferation (also see the following text). 31,[145][146][147][148][149][150][151] Melanocytes, keratinocytes, and fibroblasts have also been described to express glutamate transporters, which underscores the view that the neuronal/glial glutamate transporters can transport glutamate in nonneural cells as well. 136,143,152 In addition, Merkel cells, which are derived from cells of the neural crest and are known to form complexes (synapselike contacts) with nerve terminals of type I mechanosensory neurons, have been found to express vesicular glutamate transporters.…”

“…Furthermore, treatment of human melanoma cells with a competitive and a noncompetitive mGluR1 antagonist (LY367385 and BAY36-7620 [(3aS,6aS)-6a-naphtalen-2-yl-methyl-5-methyliden-hexahydro-cyclopental[c]-furan-1-on]) lead to a suppression of cell proliferation, 147 which is in line with data obtained in our laboratory. 31 In our own studies, we examined the effect of the subtype-specific, noncompetitive mGluR1 antagonist CPCCOEt (7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester) on growth, metabolic cell activity, and morphology of human melanoma cell lines. CPCCOEt significantly, dose-dependently, and reversibly attenuated cell proliferation of melanomas and decreased metabolic cell activity.…”

“…Furthermore, glutamate receptor signaling has been implicated in tumor biology, and receptor antagonists have been shown to be sufficient to suppress cancer growth. 18,[23][24][25][26][27][28][29][30][31][32][33][34] With the discovery of glutamate receptors in nearly all peripheral tissues, it is reasonable to assume that glutamate receptor reactive agents can also be used in the therapeutic management of other diseases in peripheral tissues. In particular, metabotropic glutamate receptor allosteric modulators have recently been described as promising novel therapeutic agents and have attracted increasing attention within the pharmaceutical industry.…”

“…31 Furthermore, it was shown that both specific ionotropic as well as metabotropic glutamate receptors play a significant role in oral squamous cell carcinoma (OSCC). 53,54 The following review was prepared with the aim of providing a survey of the impact of peripheral glutamate receptor signaling in head and neck areas.…”