Synergistic antiproliferative effects of interleukin-1 alpha and doxorubicin against the human ovarian carcinoma cell line (NIH:OVCAR-3).

Abstract

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.

• Authors: E Monti, E G Mimnaugh, B K Sinha
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 45 Issue 10 Pg. 2099-107 (May 25 1993) ISSN: 0006-2952 [Print] England
• PMID: 8512591 (Publication Type: Journal Article)

Chemical References

• Interleukin-1
• Iodine Radioisotopes
• Receptors, Interleukin-1
• Doxorubicin

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Division (drug effects)
• Doxorubicin (administration & dosage, pharmacology)
• Drug Interactions
• Drug Synergism
• Female
• Humans
• Interleukin-1 (administration & dosage, metabolism, pharmacokinetics)
• Intracellular Fluid (metabolism)
• Iodine Radioisotopes
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Protein Binding
• Receptors, Interleukin-1 (drug effects, metabolism, physiology)
• Tumor Cells, Cultured (drug effects)
• Up-Regulation (drug effects, physiology)