The inhibitors of cyclic AMP phosphodiesterase (papaverine and rl-(-S-butoxy-4methoxybenzyl)-2-imidazolidinone). serum-free medium, and x irradiation caused cell death and neurite formation in human neuroblastoma cells in culture (IMR-SP), whereas theophylline was ineffective. Prostaglandin (PG)E,, NeOidibutyryl adenosine S',Yqclic monophogphate (dbcAMP) induced neu rites without causing cell lethality. Inhibitore of phosphodiesterase and PGE, increased the intracellular level of CAMP by about 2-and 4fold respectively, whereas serum-free medium and x irradiation did not. The combination of PGE, and phosphodiesterase inhibitor was more effective in causing morphological differentiation and in increasing the CAMP level than the individual agent. Sodium butyrate induced cell death and neurites, probably in part by increasing the CAMP level. CAMP, guanosine S',Y-cyclic monophosphate, and adenosine had no detectable effect on the growth or morphology of neum blastoma cells in culture. Adenosine Y-monophosphate produced cell death without causing neurite formation. DbcAMP, and to a much lesser degree, 80- dium butyrate increased the tyrosine hydroxylase activity.
S6:imaiS43, 1975.
N ELEVATION OF CYCLIC AMP IN MOUSE
A neuroblastoma (NB) cells irreversibly induces many differentiated functions which are characteristic of mature neurons. These include formation of long neurites,12-14 increase in the size of soma and nucleus associated with an increase in total RNA and protein content,16 elevation of tyrosine hydroxylase,24#28 choline acetyltransferase,l@ and acetylcho-linesterase1J7 activities, inhibition of cell division, loss of tumorigenicity,l* and increase in sensitivity of adenylate cyclase to catecholarnines. We now report that the responses of human NB cells to cAMP are qualitatively similar to those of mouse NB cells.