Abstract
Abstract
Non-small lung cancer (NSCLC) is a leading cause of cancer mortality worldwide. Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have dramatically improved life expectancy for NSCLC patients, concerns about TKI-induced cardiotoxicities increased. AC0010, a novel third-generation TKI, was developed to overcome acquired EGFR-T790M mutation-induced drug resistance. However, the cardiotoxicity of AC0010 remains blurry. To evaluate the efficacy and cardiotoxicity of AC0010, we designed a novel multifunctional biosensor by integrating microelectrodes (MEs) and interdigital electrodes (IDEs) to comprehensively evaluate cells’ viability, electrophysiological activity, and morphologic change (beating for cardiomyocytes). The multifunctional biosensor can monitor AC0010-induced NSCLC inhibition and cardiotoxicity in a quantitatively, label-free, noninvasive, and real-time way. AC0010 was found to significantly inhibit NCI-H1975 (EGFR-L858R/T790M mutation) while weak inhibition was found for A549 (wild-type EGFR). Negligible inhibition was found in the viabilities of HFF-1 (normal fibroblasts) and cardiomyocytes. With the multifunctional biosensor, we found that 10 μM AC0010 significantly affected cardiomyocytes’ extracellular field potential (EFP) and mechanical beating. The amplitude of EFP continuously decreased after AC0010 treatment while the interval decreased first and then increased. We analyzed the change of systole time (ST) and diastole time (DT) within a beating interval and found DT and DT/beating interval rate decreased within one hour after AC0010 treatment, probably indicating insufficient relaxation for cardiomyocytes, which may further aggravate the dysfunction. Here we found that AC0010 significantly inhibit EGFR-mutant NSCLC cells and impair cardiomyocytes’ function at low concentrations (10 μM). It is the first study to evaluate the risk of AC0010-induced cardiotoxicity. In addition, the novel multifunctional biosensors can comprehensively evaluate the anti-tumor efficacy and cardiotoxicity of drugs and candidate compounds.
Publisher
Research Square Platform LLC