Glutamate antagonists limit tumor growth

Abstract

The management of malignancies in humans constitutes a major challenge for contemporary medicine. Despite progress in chemotherapy, bone marrow transplantation, surgical measures, and radiation technologies, and in immunological and immunomodulatory approaches, humans continue to succumb to cancer due to tumor recurrence and metastatic disease. The excitatory neurotransmitter glutamate, which regulates proliferation and migration of neuronal progenitors and immature neurons during the development of the mammalian nervous system, is present in peripheral cancers. Since both neuronal progenitors and tumor cells possess propensity to proliferate and to migrate, and since glutamate and glutamate receptors are known to modify these phenomena in the nervous system, we proceeded to investigate the possible influence of glutamate antagonists on the proliferation and migration of tumor cells. We found and recently reported that glutamate N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) antagonists inhibit the proliferation of human colon adenocarcinoma, astrocytoma, breast and lung carcinoma, and neuroblastoma cells in vitro. The antiproliferative effect of glutamate antagonists is Ca²⁺-dependent and results from decreased cell division and increased cell death. Glutamate antagonists produce morphological alterations in tumor cells, which consist of reduced membrane ruffling and pseudopodial protrusions, and decrease their motility and invasive growth. Furthermore, glutamate antagonists enhance in vitro cytostatic and cytotoxic effects of common chemotherapeutic agents used in cancer therapy. These findings demonstrate the anticancer potential of glutamate antagonists and suggest that they may be used as an adjunctive measure in the treatment of cancer.

Introduction

Glutamate is an essential amino acid and a transmitter in the mammalian nervous system [1], [2]. NMDA, AMPA, kainate, and metabotropic receptors are activated by glutamate [1], [2]. Its neurotransmitter role was discovered about 50 years ago, when Hayashi [3], [4] administered glutamate into the motor cortex of dogs and monkeys and triggered severe convulsions. At the same time, Lucas and Newhouse [5] made the observation that systemic administration of glutamate causes retinal degeneration in mice [5]. Further work linked activation of excitatory amino acid receptors to glutamate neurotoxicity and led to the concept of excitotoxicity [6], [7], [8]. Excitotoxicity was shown to mediate neuronal death in anoxic hippocampal cultures [9] and to be Ca²⁺-dependent [10], [11], [12]. Glutamate receptor subtypes in mammalian brain sensitive to the agonists NMDA, AMPA, and kainate, and the quisqualate sensitive metabotropic site were identified, and antagonists that selectively block glutamate receptors were developed [11].

A new field of research emerged from these discoveries, attempting to explore the physiological functions of glutamate [11]. At the same time, substantial evidence was generated implicating abnormal glutamate signaling and excitotoxicity in the pathogenesis of various CNS diseases [11]. Now, a few decades after the discovery of the dual role of glutamate in the CNS, there is hardly any neurological or psychiatric disease entity in the pathogenesis of which glutamate has not been implicated. Glutamate has been pathogenetically linked to human psychiatric disorders such as anxiety or depression and to neurological disorders such as epilepsy, spasticity, stroke, or traumatic brain injury [11], [12], [13]. Glutamate antagonists were demonstrated to have anxiolytic, anticonvulsant, muscle relaxant, sedative/anesthetic, and neuroprotective properties [11].