GILZ EXHIBITS D PROTECTION OF CARDIOMYCTES FROM TYROSINE KINASE INHIBITORS

Adrian Ramirez , Joshua Strom, Qin Chen, PhD

GILZ EXHIBITS D PROTECTION OF CARDIOMYCTES FROM TYROSINE KINASE INHIBITORS

Tyrosine kinase inhibitors have emerged as important therapeutic agents in the treatment of several cancers. An unfortunate, and potentially limiting, side effect of this class of drugs is the potential to cause serious cardiac toxicity. Glucocorticoid induced leucine zipper (GILZ) offers a novel protein that reduced the cardiotoxic effects of the chemotherapeutic agent doxorubicin.  GILZ reduces the cardiotoxic effects of the chemotherapeutic agent doxorubicin. Extrapolated from that known protection, GILZ represents a novel approach to attenuating cardiotoxicity associated with tyrosine kinase inhibitors.  GILZ was over-expressed in H9C2 mammalian cardiomyocytes and tested against naïve H9C2 cells.  H9C2 cells were treated with the tyrosine kinase inhibitors dasatinib, imatinib, sunitinib, or sorafenib and cell viability was assessed 24 hours later using an MTT assay.  Imatinib, sorafenib and sunitinib showed significant cytotoxic effects to naïve H9C2 cells beginning at a concentration of 10µM.  Cytotoxic effects of dasatinib were significant at 25 and 50µM concentrations. Cells over-expressing GILZ showed reduced cytotoxicity for all four drugs over all doses.  We assessed cell apoptosis via caspase-3 activation in naïve H9C2 and GILZ over-expressing cells at various time points after independent treatment with 25µM of the four tyrosine kinase inhibitors.  Naïve H9C2 cells showed maximum caspase-3 activity at 32 hours after treatment with sorafenib or dasatinib.  Imatinib and sunitinib showed no significant caspase-3 activation.  Cells over-expressing GILZ exhibited decreased caspase-3 activity at all times tested after treatment with sorafenib or dasatinib.  These tests support that GILZ exhibits protection to tyrosine kinase inhibitor induced toxicity.

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