Ncardia Belgium
47 Rue Adrienne Bolland
6041 Gosselies
Belgium
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As complex mechanisms underlie drug-induced toxicity, some compound effects will only become evident after longer incubation times. For that reason, our Multiparametric Safety Assay enables a long term analysis after compound addition. Efficient cardiac safety assessment should analyse structural as well as functional toxicity.
This multiparametric approach allows functional toxicity analysis by a combination of electrophysiology and impedance monitoring of hiPSC-derived cardiomyocytes. The structural toxicity is defined by the detection of Troponin I (a clinically relevant and established diagnostic marker for myocardial damage) release after compound addition. The Multiparametric Safety Assay provides the most comprehensive readout that generates mechanism-specific cardiotoxicity profiles, and reduces the risk of missing any cardiotoxic effect of candidate drugs.
Many novel oncology therapeutics may induce cardiotoxicity by inhibiting survival pathways which are shared by both tumors and cardiac cells. As complex mechanisms underlie drug-induced toxicity, some compound effects will only become evident after longer incubation times. Multiplexing impedance and MEA with cTnI release assay allows for a simultaneous assessment of short-term and long-term as well as structural and functional drug-induced cardiotoxicity from a single well.
Case study specifications:
|
Cell type |
Pluricyte® Cardiomyocytes |
|
Format |
48 wells |
| Technology | xCelligence CardioECR (ACEA) |
|
Assay window |
Acute (30 min) till long-term (64h) effect |
|
Assay controls |
0.1% DMSO (vehicle control) |
|
Test compounds |
Nilotinib, lapatinib, doxorubicin, and ponatinib |
|
Compound concentrations |
10 µM, 3 µM, 0.3 µM |
| Parameters |
Electrophysiology: beat rate, beat rate CoV, field potential duration, depolarization peak amplitude, proarrhythmic events Contractility: impedance amplitude (Cell Index) and peak width Troponin I release |
Results
Unlike lapatinib and nilotinib, ponatinib and doxorubicin caused a concentration- and time-dependent increase in cTnI release (right panels, represented as counts, dashed line indicates baseline cTnI levels), which correlated with reduced Cell Index (CI) values (left panels). The CI can also be affected by changes in the morphology or contractility of the cardiomyocyte monolayer as seen after addition of nitrendipine. Therefore, the CI could not be used as a direct measurement for structural cardiotoxicity.
Conclusion
Whereas addition of nilotinib and lapatinib caused a (functional) contractile/electrophysiological deficit, doxorubicin exhibited a long-term toxic effect in both MEA and impedance measurements. While lapatinib and nilotinib did not cause structural toxicity as measured by cTnI release, ponatinib and doxorubicin induced a dose- and time-dependent increase in cTnI release which correlated with reduced cell index values.
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