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

Abstract

Few clinical responses have occurred in preliminary studies using the cytokines tumor necrosis factor α (TNFα) or interferon γ(IFNγ) in cancer patients. This may be related to the observation that many malignant cell lines are resistant to lysis by these cytokinesin vitro. Resistance to lysis by TNFα or IFNγ 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 TNFα and IFNγ 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 TNFα and IFNγ to determine whether such combination treatment might maximizein vitro cell lysis. Our results showed that pretreatment with IFNγ followed by exposure to TNFα in the presence of protein synthesis inhibitors increased lysis of seven of the eight cell lines above that seen with either TNFα or IFNγ and inhibitors of protein synthesis. Only the cell line C-33A was resistant to lysis by TNFα and IFNγ, when exposed to these agents both alone and in combination with protein synthesis inhibitors. Clinically, combining the cytokines TNFα and IFNγ with protein synthesis inhibitors may maximize thein vivo lytic effects of these cytokines.