Opioid analgesic-induced apoptosis and caspase-independent cell death in human lung carcinoma A549 cells

We characterized anticancer effects of opioid analgesics that are clinicall y used for cancer patients for pain relief. Treatment with 100 mu M bupreno rphine, a representative analgesic, induced cell death of human carcinomas, such as A549 (squamous epithelial cell of lung cancer), MCF-7 (breast canc er) and N417 (small cell of lung cancer), but not in KATO III (gastric canc er) cells as evaluated by alamar blue assay. Among 18 clinically utilized a nd related analgesics, buprenorphine and loperamide showed potent inhibitio n of cell viability. However, these anti-cancer effects were not affected b y opioid receptor antagonists nor by pertussis toxin. Buprenorphine-induced cell death occurred as early as 1 h after the addition, and its T-1/2 of c ell viability inhibition was 3 h. The cell death manifested the characteris tics of apoptosis, such as DNA-laddering and nuclear fragmentation, which w ere sensitive to a caspase inhibitor, Z-Asp-CH2-DCB. The nuclear fragmentat ion was independent of cell cycle phase specificity. The activity of caspas e-3-like protease which is known to be closely related to apoptotic DNA lad dering was markedly enhanced by buprenorphine. However, the inhibition of c ell viability by buprenorphine was not affected by the caspase inhibitor. T hese findings suggest that some opioid analgesics induce typical apoptotic features sensitive to the caspase inhibitor, while also inhibition of cell viability insensitive to the inhibitor.