Mechanisms of doxycycline-induced cytotoxicity on human bronchial epithelial cells.
Doxycycline (DOX), a synthetic tetracycline, may have potential utility in the management of cancers and in the treatment of chronic inflammatory diseases due to its role in growth, invasion and metastasis of many tumors, on cell proliferation and as inducer of apoptosis. Some studies established its role in the treatment of lesions induced by mustards, warfare agents causing severe damage with blistering and tissue detachment in exposed areas of the body. In the present study, the effect of Dox was investigated in a human bronchial epithelial cell line. Dox induced a time- and concentration-dependent cell proliferation inhibition, associated with a cell cycle arrest in S phase, a decrease in viability due to apoptosis and necrosis, and cell detachment. This latter was partly correlated with early activation of caspase-3 before detachment, and with mitochondrial alteration. Cell transfection with a Bcl-2 encoding vector showed a decrease both in mitochondrial depolarization and cell detachment. Dox-induced apoptosis included decrease in Bcl-2 expression, increase in Bak expression and caspase-3 and -9 activation but appeared to be p53- and Bax-independent. A better comprehension of the Dox-induced apoptotic pathway could allow to abolish its toxic effects, improving the therapeutic efficiency of Dox.
Sourdeval
Matthieu
M
Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris 7 Denis Diderot, 2 Place Jussieu, 75251 Paris Cedex 05, France. msourdeval@paris7.jussieu.fr
Lemaire
Christophe
C
Brenner
Catherine
C
Boisvieux-Ulrich
Emmanuelle
E
Marano
Francelyne
F
D000900:Anti-Bacterial Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000633:toxicity*; D004847:Epithelial Cells / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000502:physiology
D000900:Anti-Bacterial Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D020169:Caspases; D004318:Doxycycline