germanium and Neuroblastoma

Germanium (Ge) is commonly used in the semiconductor industry as well as health-promoting and medical field. Biologically, germanium possesses erythropoietic, anti-microbial, anti-tumor, anti-amyloidosis, and immunomodulative effects. However, toxic effects of Ge-containing compounds on kidney, muscle, neuronal cells, and nerves have been reported. Mitochondrial dysfunction was found to be involved in the pathogenesis of GeO(2)-induced nephropathy and myopathy. Since it is well known that mitochondria play a major role in apoptosis triggered by many stimuli, an effort was made to examine whether the Ge-induced neurotoxicity occurs through mitochondria-mediated apoptosis. A mouse neuroblastoma cell line, Neuro-2A, was used in the present study. After incubating with 0.1-800microM of GeO(2) for 0-72h, the cell viability of Neuro-2A cells was inhibited in a dose- and time-dependent manner. Further analysis showed that aside from the changes in the nuclear morphology responsible for apoptosis, the release of cytochrome c, the loss of mitochondrial membrane potential, the translocation of Bax, and the reduction of Bcl-2 expression were also observed in Neuro-2A cells after GeO(2) treatment. These results indicate that the mitochondria-mediated apoptosis is involved in this in vitro model of GeO(2)-induced neurotoxicity.

Topics: Acridine Orange; Analysis of Variance; Animals; Antimutagenic Agents; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Survival; Cytochromes c; Dose-Response Relationship, Drug; Ethidium; Flow Cytometry; Germanium; Immunohistochemistry; In Situ Nick-End Labeling; Membrane Potential, Mitochondrial; Mice; Mitochondria; Neuroblastoma; Proto-Oncogene Proteins c-bcl-2; Time Factors

Lethal and other biological effects of 2-aza-8-germanspiro[4,5]decane-2-propanamine-8,8-diethyl-N,N-dimethyl dichloride (NSC 192965; spirogermanium), representing a new chemical class of compound exhibiting antitumor activity, have been studied in vitro. Survival curves for NIL 8 hamster cells were exponential with greater kill occurring with increasing drug concentrations and longer exposure times. Cytotoxicity was temperature dependent. "Quiescent" cultures were significantly less sensitive to spirogermanium than were logarithmically growing cells. These lethal effects showed no phase specificity. There was no evidence of progression delay through the cycle following spirogermanium treatment. When spirogermanium was tested against a range of human cell lines, the consistency of the values for the drug concentration required to reduce survival by 50% on the exponential part of the survival curve, derived from colony-forming assays, was most marked. The survival curves, characterized by an initial shoulder, were steep and exponential with measurements possible over only a narrow concentration range since complete cell lysis occurred at levels causing a greater than 2-log kill. Cell membrane damage by spirogermanium, as judged by dye exclusion, was progressive with time and increasing drug concentrations. Protein synthesis proved most susceptible to the drug. Spirogermanium concentrations cytotoxic to tumor cells were also toxic to cultured rat neurons, confirming the clinical neurological toxicity encountered. The precise mode of action of spirogermanium remains to be established, and these data further illustrate its apparent lack of specificity.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Cycle; Cell Line; Cell Survival; Cells, Cultured; Colonic Neoplasms; Cricetinae; Female; Germanium; Humans; Mesocricetus; Neuroblastoma; Neurons; Organometallic Compounds; Ovary; Rats; Spiro Compounds