Doxycycline suppresses doxorubicin-induced oxidative stress and cellular apoptosis in mouse hearts.
Cardiac toxicity remains a serious yet unsolved complication of doxorubicin. This study was designed to examine whether doxycycline, a tetracycline-derived synthetic antibiotic with potential cytoprotective properties, could ameliorate this complication of doxorubicin. Male mice at 4-week of age were administrated with vehicle, doxorubicin (3mg/kg intraperitoneally every other day at 3 doses), doxycycline (2.5mg/kg intraperitoneally every other day for 3 doses), or doxycycline plus doxorubicin (each dose given 1day post doxycycline). After 28days, left ventricular geometric and systolic parameters were measured by transthoracic echocardiography, and hearts were harvested for extensive analyses regarding oxidative stress and cellular apoptosis. At 28days, hearts of doxorubicin-treated mice were characterized by less weight compared with controls, also with remodeling and depressed systolic function of the left ventricle. Biochemical analyses disclosed that content of malondialdehyde was increased and activity of antioxidant enzymes, including superoxide dismutase and glutathione peroxidase, was decreased in these hearts. Both mitochondrion-dependent and endoplasmic reticulum stress-induced apoptotic pathways were also activated in the hearts of doxorubicin-treated mice as reflected by decreased Bcl-2/Bcl-(XL) and elevated Bax/Bad, p53/Apaf-1, endoplasmic reticulum glucose-related protein 78, C/EBP homologous protein, cytochrome c release from mitochondria, caspases-9/-3 cleavage, and cardiomyocyte apoptosis. In contrast, all the above left ventricular remodeling, systolic depressing, oxidative and pro-apoptotic actions of doxorubicin could be significantly alleviated by doxycycline pretreatment. Thus, doxycycline extensively counteracts multiple oxidative and apoptotic actions of doxorubicin in heart, hence may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application.
Lai
Hui-Chin
HC
Cardiovascular Center and Department of Anesthesiology, Taichung Veterans General Hospital, Taichung, Taiwan.
Yeh
Yueh-Chiao
YC
Ting
Chih-Tai
CT
Lee
Wen-Lieng
WL
Lee
Hsiao-Wei
HW
Wang
Li-Chuan
LC
Wang
Kuo-Yang
KY
Lai
Hui-Chun
HC
Wu
Angie
A
Liu
Tsun-Jui
TJ
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000633:toxicity*; D004318:Doxycycline / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D013482:Superoxide Dismutase / Q000187:drug effects / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D008315:Malondialdehyde; D004317:Doxorubicin; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D004318:Doxycycline