Thrombopoietin protects against in vitro and in vivo cardiotoxicity induced by doxorubicin.
BACKGROUND
Doxorubicin (DOX) is an important antineoplastic agent. However, the associated cardiotoxicity, possibly mediated by the production of reactive oxygen species, has remained a significant and dose-limiting clinical problem. Our hypothesis is that the hematopoietic/megakaryocytopoietic growth factor thrombopoietin (TPO) protects against DOX-induced cardiotoxicity and might involve antiapoptotic mechanism exerted on cardiomyocytes.


RESULTS
In vitro investigations on H9C2 cell line and spontaneously beating cells of primary, neonatal rat ventricle, as well as an in vivo study in a mouse model of DOX-induced acute cardiomyopathy, were performed. Our results showed that pretreatment with TPO significantly increased viability of DOX-injured H9C2 cells and beating rates of neonatal myocytes, with effects similar to those of dexrazoxane, a clinically approved cardiac protective agent. TPO ameliorated DOX-induced apoptosis of H9C2 cells as demonstrated by assays of annexin V, active caspase-3, and mitochondrial membrane potential. In the mouse model, administration of TPO (12.5 microg/kg IP for 3 alternate days) significantly reduced DOX-induced (20 mg/kg) cardiotoxicity, including low blood cell count, cardiomyocyte lesions (apoptosis, vacuolization, and myofibrillar loss), and animal mortality. Using Doppler echocardiography, we observed increased heart rate, fractional shortening, and cardiac output in animals pretreated with TPO compared with those receiving DOX alone.


CONCLUSIONS
These data have provided the first evidence that TPO is a protective agent against DOX-induced cardiac injury. We propose to further explore an integrated program, incorporating TPO with other protocols, for treatment of DOX-induced cardiotoxicity and other forms of cardiomyopathy.
Li
Karen
K
Department of Pediatrics, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Sung
Rita Yn Tz
RY
Huang
Wei Zhe
WZ
Yang
Mo
M
Pong
Nga Hin
NH
Lee
Shuk Man
SM
Chan
Wood Yee
WY
Zhao
Hailu
H
To
Man Yin
MY
Fok
Tai Fai
TF
Li
Chi Kong
CK
Wong
Yuek Oi
YO
Ng
Pak Cheung
PC
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001772:Blood Cell Count; D009202:Cardiomyopathies / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured / Q000187:drug effects / Q000648:ultrastructure; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D032446:Myoblasts / Q000187:drug effects* / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D011929:Razoxane / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D016037:Single-Blind Method; D013926:Thrombopoietin / Q000494:pharmacology / Q000627:therapeutic use*; D014463:Ultrasonography
D000903:Antibiotics, Antineoplastic; D002317:Cardiovascular Agents; D017382:Reactive Oxygen Species; D011929:Razoxane; D004317:Doxorubicin; D013926:Thrombopoietin; D051057:Proto-Oncogene Proteins c-akt