dizocilpine-maleate and Neoplasms

The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However, the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs, which we refer to as the 'ground state', remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology, so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation, we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.

Topics: Animals; Cell Survival; Cells, Cultured; Mice; Molecular Structure; Neoplasms; Neurons; Pharmaceutical Preparations; Sensitivity and Specificity; Stem Cells

Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-d-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca(2+) dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

Topics: Anti-Anxiety Agents; Antineoplastic Agents; Benzodiazepines; Cell Division; Cell Movement; Cisplatin; Cyclophosphamide; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Glutamic Acid; Growth Inhibitors; HT29 Cells; Humans; Immunohistochemistry; Neoplasms; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Thiotepa; Tumor Cells, Cultured; Vinblastine

Topics: Animals; Anti-Anxiety Agents; Antineoplastic Agents; Benzodiazepines; Cell Movement; Dizocilpine Maleate; Drug Synergism; Excitatory Amino Acid Antagonists; Growth Inhibitors; Humans; Neoplasms; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate