Radiation protects adriamycin-induced apoptosis.
Combined radiotherapy and chemotherapy have represented major advance in the therapeutic management of cancer therapy. Anthracycline antineoplastic agents are limited by a high incidence of severe and usually irreversible cardiac toxicity, the cause of which remains controversial. When the primary cardiomyocytes isolated from neonatal rats were preirradiated by gamma-ray, the cells were highly resistant to adriamycin-induced apoptosis. This study shows that irradiation inhibited apoptosis by enhancing Bcl-2, attenuating Bax induction, and preventing collapse of mitochondrial membrane potential (delta psi), cytochrome c release into cytoplasm and caspase-3, -6 and -9 activations. In addition, the preirradiation stimulated the activity of manganese-superoxide dismutase (Mn-SOD) and the expression of Mn-SOD mRNA and protein. Adriamycin decreased Mn-SOD activity but did not change the activity of copper/zinc (Cu/Zn)-SOD under either pre- or nonirradiated condition. Phosphothioate-linked antisense against Mn-SOD, which specifically knocked down the activity of Mn-SOD but not that of Cu/Zn-SOD, reversed irradiation-induced protective effect in adriamycin-exposed cardiomyocytes. These data suggest that the irradiation-induced expression of Mn-SOD plays an important role in irradiation-mediated protection in adriamycin-exposed rat ventricular cardiomyocytes.
Chae
Han-Jung
HJ
Department of Pharmacology and Institute of Cardiovascular Research, School of Medicine, Chonbuk National University, Jeonju, Republic of Korea.
Kim
Hyung-Ryong
HR
Lee
Wan-Goo
WG
Kwak
Yong-Keun
YK
Kim
Woo-Hyun
WH
Hong
Seong-Tshool
ST
Cho
Gwang-Hyun
GH
Kim
Jung-Soo
JS
Chae
Soo-Wan
SW
D000818:Animals; D000831:Animals, Newborn; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000528:radiation effects*; D053148:Caspase 3; D061945:Caspase Inhibitors; D018929:Cell Culture Techniques; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005720:Gamma Rays; D006352:Heart Ventricles; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011835:Radiation Protection; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D061945:Caspase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D045304:Cytochromes c; D013482:Superoxide Dismutase; C505410:Casp3 protein, rat; D053148:Caspase 3