Inhibition of protein synthesis enhances the lytic effects of tumor necrosis factor alpha and interferon gamma in cell lines derived from gynecological malignancies

Abstract

Few clinical responses have occurred in preliminary studies using the cytokines tumor necrosis factor alpha (TNF alpha) or interferon gamma (IFN gamma) in cancer patients. This may be related to the observation that many malignant cell lines are resistant to lysis by these cytokines in vitro. Resistance to lysis by TNF alpha or IFN gamma in many cells is controlled by a protein-synthesis-dependent mechanism, such that when protein synthesis is inhibited cells become sensitive to lysis by these cytokines. Because there is some evidence that TNF alpha and IFN gamma act through different lytic mechanisms and are opposed by different resistance mechanisms, we treated a panel of eight cell lines, five derived from human cervical carcinomas (ME-180, MS751, SiHa, HT-3, and C-33A) and three derived from ovarian carcinomas (Caov-3, SK-OV-3, and NIH: OVCAR-3) with both TNF alpha and IFN gamma to determine whether such combination treatment might maximize in vitro cell lysis. Our results showed that pretreatment with IFN gamma followed by exposure to TNF alpha in the presence of protein synthesis inhibitors increased lysis of seven of the eight cell lines above that seen with either TNF alpha or IFN gamma and inhibitors of protein synthesis. Only the cell line C-33A was resistant to lysis by TNF alpha and IFN gamma, when exposed to these agents both alone and in combination with protein synthesis inhibitors. Clinically, combining the cytokines TNF alpha and IFN gamma with protein synthesis inhibitors may maximize the in vivo lytic effects of these cytokines.