Synergistic antiproliferative effects of interleukin-1 alpha and doxorubicin against the human ovarian carcinoma cell line (NIH:OVCAR-3).
Interleukin-1 alpha (IL-1 alpha) exerts antiproliferative effects on a human ovarian carcinoma cell line, NIH:OVCAR-3, which is resistant to clinically relevant concentrations of doxorubicin (DOX) and other chemotherapeutic agents. This action of IL-1 alpha depends on the presence of type I (80 kDa) receptors, although no quantitative relationship has been established between receptor occupancy and inhibition of cell growth. When NIH:OVCAR-3 cells were exposed to IL-1 alpha and DOX in combination, a mutual potentiation of the antiproliferative effects of the two agents was observed. This synergistic effect was not due to IL-1 receptor expression up-regulation by DOX, and receptor-dependent internalization of the cytokine was also unaffected. The involvement of IL-1 receptors is supported by the observation that synergism between the two agents was diminished (but not abolished) in the presence of a specific IL-1 receptor antagonist at concentrations blocking more than 75% of IL-1 alpha binding. DOX was found to significantly increase IL-1 alpha accumulation by NIH:OVCAR-3 cells after long-term (48 hr) exposure to the cytokine at 37 degrees, which might be due to increased nonspecific fluid phase uptake or to interference with cytokine degradation and/or release processes. The potent synergy of IL-1 alpha and DOX against ovarian carcinoma cells in vitro suggests that this drug combination may be effective against this disease in the clinic.
Biochemical and Molecular Pharmacology Section, National Cancer Institute, NIH, Bethesda, MD 20892.
E
E
Monti
E G
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Mimnaugh
B K
BK
Sinha
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004347:Drug Interactions; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007375:Interleukin-1 / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D007424:Intracellular Fluid / Q000378:metabolism; D007457:Iodine Radioisotopes; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017472:Receptors, Interleukin-1 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D007375:Interleukin-1; D007457:Iodine Radioisotopes; D017472:Receptors, Interleukin-1; D004317:Doxorubicin