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.
Oakes
S G
SG
Department of Pharmacology, Mayo Clinic and Foundation, Rochester, Minnesota.
Schlager
J J
JJ
Santone
K S
KS
Abraham
R T
RT
Powis
G
G
D000331:Aequorin / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D006633:Histamine Antagonists / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D006633:Histamine Antagonists; D000331:Aequorin; D004317:Doxorubicin; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium