Figure 4.

Pathways of imatinib-induced cardiomyocyte toxicity. Imatinib, via inhibition of Abl/Arg, leads via unclear mechanisms to induction of ER stress. This activates protein kinase IRE1 which upregulates factors involved in degradation of mis-folded proteins in the ER, thereby attempting to restore homeostasis.⁵⁶ If ER stress is sustained, however, JNKs are activated leading to activation of the intrinsic apoptosis program and cell death. Both salubrinal, an inhibitor of ER stress⁵⁷, and JNK inhibition by a peptide antagonist, protected from imatinib cardiomyocyte toxicity. The role, if any, of inhibition of PDGFRs in imatinib-induced cardiotoxicity is unknown at this time.