Mechanistic Investigation of Imatinib-Induced Cardiac Toxicity and the Involvement of c-Abl Kinase
| العنوان: | Mechanistic Investigation of Imatinib-Induced Cardiac Toxicity and the Involvement of c-Abl Kinase |
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| المؤلفون: | Jonathan R. Heyen, Joseph D. Jamieson, Bart Jessen, Dong U. Lee, Wenyue Hu, Shuyan Lu, Lisa D. Marroquin, Indrawan James Mcalpine |
| المصدر: | Toxicological Sciences. 129:188-199 |
| بيانات النشر: | Oxford University Press (OUP), 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | medicine.drug_class, Antineoplastic Agents, Biology, Pharmacology, Toxicology, Piperazines, Tyrosine-kinase inhibitor, hemic and lymphatic diseases, medicine, Animals, neoplasms, DNA Primers, ABL, Base Sequence, Reverse Transcriptase Polymerase Chain Reaction, Autophagy, Myeloid leukemia, Heart, Imatinib, Rats, Pyrimidines, Imatinib mesylate, Benzamides, Toxicity, Imatinib Mesylate, Unfolded protein response, Cancer research, RNA Interference, Protein Kinases, medicine.drug |
| الوصف: | The Bcr-abl tyrosine kinase inhibitor imatinib mesylate is the frontline therapy for chronic myeloid leukemia. Imatinib has been reported to cause congestive heart failure and left ventricular contractile dysfunction in patients and cardiomyopathy in rodents, findings proposed to be associated with its pharmacological activity. To investigate the specific role of Abelson oncogene 1 (c-Abl) in imatinib-induced cardiac toxicity, we performed targeted gene inhibition of c-Abl by RNA interference in neonatal cardiomyocytes (NCMs). Suppression of c-Abl did not lead to cytotoxicity or induction of endoplasmic reticulum (ER) stress. To further dis associate c-Abl from imatinib-induced cardiac toxicity, we designed imatinib structural analogs that do not have appreciable c-Abl inhibition in NCMs. The c-Abl inactive analogs induced cytotoxicity and ER stress, at similar or greater potencies and magnitudes as imatinib. Furthermore, combining c-Abl gene silencing with imatinib and analogs treatment did not significantly shift the cytotoxicity dose response curves. Imatinib and analogs were shown to accumulate in lysosomes, likely due to their physicochemical properties, and disrupt autophagy. The toxicity induced by imatinib and analogs can be rescued by bafilomycin A pretreatment, demonstrating the involvement of lysosomal accumulation in cardiac toxicity. The results from our studies strongly suggest that imatinib induces cardiomyocyte dysfunction through disruption of autophagy and induction of ER stress, independent of c-Abl inhibition. |
| تدمد: | 1096-0929 1096-6080 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f6f2a638305912c2019069c00f8972b6Test https://doi.org/10.1093/toxsci/kfs192Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f6f2a638305912c2019069c00f8972b6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10960929 10966080 |
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