Opioid analgesic-induced apoptosis and caspase-independent cell death in human lung carcinoma A549 cells.
We characterized anticancer effects of opioid analgesics that are clinically used for cancer patients for pain relief. Treatment with 100 microM buprenorphine, a representative analgesic, induced cell death of human carcinomas, such as A549 (squamous epithelial cell of lung cancer), MCF-7 (breast cancer) and N417 (small cell of lung cancer), but not in KATO III (gastric cancer) cells as evaluated by alamar blue assay. Among 18 clinically utilized and related analgesics, buprenorphine and loperamide showed potent inhibition of cell viability. However, these anti-cancer effects were not affected by opioid receptor antagonists nor by pertussis toxin. Buprenorphine-induced cell death occurred as early as 1 h after the addition, and its T1/2 of cell viability inhibition was 3 h. The cell death manifested the characteristics of apoptosis, such as DNA-laddering and nuclear fragmentation, which were sensitive to a caspase inhibitor, Z-Asp-CH2-DCB. The nuclear fragmentation was independent of cell cycle phase specificity. The activity of caspase-3-like protease which is known to be closely related to apoptotic DNA laddering was markedly enhanced by buprenorphine. However, the inhibition of cell viability by buprenorphine was not affected by the caspase inhibitor. These 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.
Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, Nagasaki 852-8521, Japan.
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A
Yoshida
S
S
Tokuyama
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T
Iwamura
H
H
Ueda
D000701:Analgesics, Opioid / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000201:enzymology / Q000473:pathology; D002047:Buprenorphine / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology*; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008139:Loperamide / Q000494:pharmacology; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D015394:Molecular Structure; D013274:Stomach Neoplasms / Q000201:enzymology / Q000473:pathology; D014407:Tumor Cells, Cultured
D000701:Analgesics, Opioid; D002047:Buprenorphine; D008139:Loperamide; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1