Protection by doxycycline against doxorubicin-induced oxidative stress and apoptosis in mouse testes.
Spermatogenic cells constitute one of the body tissues that are susceptible to doxorubicin-induced oxidative stress and apoptosis. To explore whether doxorubicin toxicity to these male germ cells could be prevented by adjuvant medication, this study was designed to examine the possible ameliorating action of doxycycline, an antibiotic with anti-oxidant property, on doxorubicin-induced oxidative and apoptotic effects in mouse testes. Male mice at 5-week of age were treated with vehicles, doxorubicin alone (3 mg/kg, i.p. every other day for 3 doses), doxycycline alone (2.5 mg/kg, i.p. every other day for 3 doses), or doxycycline plus doxorubicin (each dose given 1 day post-doxycycline). After 28 days, mice treated with doxorubicin alone displayed smaller body and testicular weights, reduced sperm counts, impaired spermatogenic capability (scarcer spermatids and spermatocytes), increased oxidative stress (malondialdehyde levels), decreased anti-oxidant activity (superoxide dismutase and glutathione peroxidase), and elevated apoptotic indexes (upregulation of Bax and Bad, downregulation of Bcl-2 and Bcl-xL, release of cytochrome c from mitochondria to cytosol, activation of caspase-3, and increase of cleaved caspase-3 abundance and TUNEL positive cells), while doxycycline pretreatment could effectively prevent nearly all of these abnormalities. These results provide firm evidence that doxycycline pretreatment would offset the oxidative and apoptotic impact imposed by doxorubicin, and imply doxycycline to be a promising adjuvant agent that may attenuate the toxicity of doxorubicin on testicular tissues in clinical practice.
Cardiovascular Center, Taichung Veterans General Hospital, Taichung, Taiwan.
Yueh-Chiao
YC
Yeh
Hui-Chin
HC
Lai
Chih-Tai
CT
Ting
Wen-Lieng
WL
Lee
Li-Chuan
LC
Wang
Kuo-Yang
KY
Wang
Hui-Chun
HC
Lai
Tsun-Jui
TJ
Liu
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation; D004317:Doxorubicin / Q000009:adverse effects*; D004318:Doxycycline / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D018384:Oxidative Stress; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000166:cytology* / Q000187:drug effects*; D015854:Up-Regulation
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D004317:Doxorubicin; D045304:Cytochromes c; D053148:Caspase 3; D004318:Doxycycline