Overcoming TNF-α and Drug Resistance of Human Renal Cell Carcinoma Cells by Treatment with Pentoxifylline in Combination with TNF-α or Drugs: The Role of TNF-α mRNA Downregulation in Tumor Cell Sensitization

Abstract

Previous studies have demonstrated that one of the possible mechanisms responsible for the resistance of tumor cells to tumor necrosis factor-α (TNF-α) is the expression of TNF-α mRNA and/or protein. Pentoxifylline (PTX) suppressed TNF-α gene transcription and downregulates the expression of TNF-α mRNA and the secretion of TNF-α protein in macrophages and monocytes. This study investigates whether PTX downregulates the expression of TNF-α mRNA and/or protein in renal cell carcinoma (RCC) cells and whether PTX enhances the sensitivity of TNF-α-resistant RCC cells to TNF-α. Further, we explored whether PTX enhances the sensitivity of RCC cells to agents other than TNF-α by downregulation of the expression of TNF-α mRNA and protein. The R4 human RCC cell line constitutively expressed TNF-α mRNA and protein and was resistant to TNF-α. When R4 cells were incubated with PTX, the level of TNF-α mRNA and protein was markedly reduced. Pentoxifylline and TNF-α together overcame the resistance of R4 cells to TNF-α. The Rll human RCC cell line did not constitutively express TNF-α mRNA or protein, and was resistant to TNF-α. The expression of TNF-α mRNA in Rll cells, but not the production of TNF-α protein, was induced by TNF-α. When PTX was used in combination with TNF-α, the level of TNF-α mRNA induced by TNF-α was markedly reduced. The combination of PTX and TNF-α overcame the resistance of Rll cells to TNF-α. Pentoxifylline also enhanced the sensitivity of R4 cells to interferon-α. Pentoxifylline and anti-TNF-α monoclonal antibody augmented the sensitivity of R4 cells to cis-diamminedichloroplatinum (II) (CDDP). This study demonstrated that PTX, in combination with TNF-α, IFN-α or CDDP, overcame the drug resistance to RCC cells and that downregulation of TNF-α mRNA by PTX may be related to the cytotoxicity enhanced by the combination. The implications of these findings for clinical therapy are discussed.