Mechanistic investigation of imatinib-induced cardiac toxicity and the involvement of c-Abl kinase.
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.
Drug Safety Research and Development, La Jolla Laboratories, Pfizer Inc., San Diego, California 92121, USA. wenyue.hu@pfizer.com
Wenyue
W
Hu
Shuyan
S
Lu
Indrawan
I
McAlpine
Joseph D
JD
Jamieson
Dong U
DU
Lee
Lisa D
LD
Marroquin
Jonathan R
JR
Heyen
Bart A
BA
Jessen
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001483:Base Sequence; D001549:Benzamides; D017931:DNA Primers; D006321:Heart / Q000187:drug effects*; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000633:toxicity*; D011494:Protein Kinases / Q000378:metabolism*; D011743:Pyrimidines / Q000633:toxicity*; D034622:RNA Interference; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011494:Protein Kinases