Doxorubicin blocks the increase in intracellular Ca++, part of a second messenger system in N1E-115 murine neuroblastoma cells.

Exposure of differentiated N1E-115 murine neuroblastoma cells, microinjected with the Ca(++)-sensitive photoprotein aequorin, to doxorubicin for 1 hr, but not for 2 min, produced a reversible block of the rise in intracellular free Ca++ [( Ca++]i) produced by histamine. The resting level of [Ca++]i was increased from 0.23 to 1.22 microM (P less than 0.05) by 10(-4) M histamine. After exposure to 10(-6) M doxorubicin for 1 hr, histamine increased [Ca++]i to only 0.34 microM (P less than 0.05 compared to the histamine alone value). Doxorubicin exposure for 1 hr completely blocked the increase in inositol trisphosphate caused by histamine. There was no block by doxorubicin of the release of intracellular Ca++ after microinjection of the cells with inositol 1,4,5-trisphosphate. Based on the results from studies with differentiated N1E-115 neuroblastoma cells doxorubicin may: 1) block the histamine-induced rise in [Ca++]i by decreasing synthesis of inositol polyphosphates, 2) block plasma membrane Ca++ channels that allow entry of extracellular Ca++ in response to histamine and/or 3) prevent recovery of histamine receptors after desensitization.