Tetracycline Derivatives Induce Apoptosis Selectively in Cultured Monocytes and Macrophages but not in Mesenchymal Cells

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Abstract
Evidence for a non-antibiotic activity displayed by certain tetracycline derivatives is presented. This activity is a selective cytotoxicity toward cells of the monocytic lineage (the human histiocytic lymphoma U937 cell line and the mouse macrophage line RAW264) but not toward various cells of a mesenchymal lineage (including primary ovine articular chondrocytes and meniscal cells, murine calvarial osteoblasts and MG-63 osteosarcoma cells, and primary human neonatal foreskin fibroblasts). Cells were incubated with various chemically modified tetracycline derivatives (CMTs) or doxycycline for 24 hrs at a range of concentrations between zero and 50 μg/mL in both serum-containing and serum-free culture conditions. Assessment of cell viability by means of the MTT assay demonstrated a potent dose-dependent cytotoxic effect induced by compound CMT-3 and a less potent effect induced by doxycycline, but no apparent cytotoxic effect in the presence of either CMT-2 or CMT-5. Cytospin preparations analyzed by the labeling of DNA fragments indicated the same trends and suggested that cell death was via an apoptotic mechanism. The cytotoxic potency of these tetracyclines toward cells of the monocytic lineage could be diminished but not abolished by either the presence of 10% fetal calf serum within the culture medium, or pre-treatment with phorbol esters to promote a more macrophage-like phenotype. These data provide evidence that, in addition to well-characterized antibiotic and MMPinhibitory characteristics, tetracyclines may function by a novel mechanism to induce selective apoptosis.