Related Experiment Videos
Effect of some anticancer drugs on the surface membrane electrical properties of differentiated murine neuroblastoma
Abstract:
The effect of some anticancer agents that produce toxic effects on electrically excitable cells in vivo was studied in vitro with the use of differentiated N1E-115 murine neuroblastoma cells and single microelectrode electrical recording. In the presence of 10(-7) g/ml tetrodotoxin, following the release of 500-millisecond conditioning hyperpolarization, the cells exhibited Ca2+-dependent action potentials. Local application to N1E-115 neuroblastoma cells of cisplatin (cis-PDD) for 30 seconds from a drug-containing effusion pipette produced a dose-dependent reversible inhibition of the Ca2+-dependent action potential, with a 61% inhibition at 1.7 microM and 67% inhibition at 17 microM cis-PDD. trans-Dichlorodiammineplatinum(II) and platinic(IV) chloride, both of which lacked the growth inhibitory properties of cis-PDD against N1E-115 neuroblastoma cells, at concentrations of 170 and 120 microM produced only an 11 and 19% inhibition of the Ca2+-dependent action potential, respectively. Vincristine at a concentration of 1 microM reversibly inhibited the Ca2+-dependent action potential by 48%. 3'-Deamino-3'-(3''-cyano-4''-morpholinyl)doxorubicin, a more potent experimental antitumor agent than doxorubicin, at 10(-8) M inhibited the Ca2+-dependent action potential by 22%, similar to the inhibition previously reported for doxorubicin. None of the agents affected the cell transmembrane potential, which suggests a lack of an effect on the mechanisms responsible for maintaining the resting cell membrane potential difference. The effects of the agents on the Ca2+-dependent action potential might reflect a direct effect on a plasma membrane Ca2+ channel or on the lipid domain around the channels, or they might be produced by changes in intracellular Ca2+ homeostasis, among other mechanisms. It is not known whether a change in the membrane Ca2+ current is related to the antitumor effects of the agents, but such a change may contribute to the neurotoxicity of cis-PDD and vincristine and the cardiac toxicity of the anthracycline.
Insights
Anticancer drugs like cisplatin and vincristine inhibit calcium-dependent action potentials in neuroblastoma cells, potentially explaining their neurotoxicity. This study investigated drug effects on electrically excitable cells.
Area of Science:
- Neuropharmacology
- Cancer Biology
- Cell Physiology
Background:
- Electrically excitable cells, such as neurons, can be affected by anticancer agents, leading to toxic side effects.
- Understanding the in vitro effects of these agents on cellular electrophysiology is crucial for predicting in vivo toxicity.
Purpose of the Study:
- To investigate the in vitro effects of specific anticancer agents on the Ca2+-dependent action potential of neuroblastoma cells.
- To explore potential mechanisms underlying the observed cellular electrophysiological changes and their relation to drug toxicity.
Main Methods:
- Differentiated N1E-115 murine neuroblastoma cells were utilized for in vitro studies.
- Single microelectrode electrical recording techniques were employed to measure cellular electrical activity.
- Local drug application via effusion pipettes was used to assess dose-dependent effects of anticancer agents.
Main Results:
- Cisplatin (cis-PDD) demonstrated a dose-dependent, reversible inhibition of Ca2+-dependent action potentials.
- Vincristine and a novel doxorubicin analog also reversibly inhibited these action potentials.
- Platinum compounds lacking growth inhibitory properties showed minimal effects on action potentials; resting membrane potential remained unaffected.
Conclusions:
- Anticancer agents can directly impact the Ca2+-dependent action potential in neuroblastoma cells, suggesting a direct effect on Ca2+ channels or related cellular mechanisms.
- The observed inhibition of action potentials may contribute to the neurotoxicity of agents like cis-PDD and vincristine, and cardiac toxicity of anthracyclines.
- Further research is needed to correlate changes in membrane Ca2+ current with the antitumor efficacy and toxicity profiles of these agents.