Overcoming TNF-alpha and drug resistance of human renal cell carcinoma cells by treatment with pentoxifylline in combination with TNF-alpha or drugs: the role of TNF-alpha mRNA downregulation in tumor cell sensitization.
Previous studies have demonstrated that one of the possible mechanisms responsible for the resistance of tumor cells to tumor necrosis factor-alpha (TNF-alpha) is the expression of TNF-alpha mRNA and/or protein. Pentoxifylline (PTX) suppressed TNF-alpha gene transcription and downregulates the expression of TNF-alpha mRNA and the secretion of TNF-alpha protein in macrophages and monocytes. This study investigates whether PTX downregulates the expression of TNF-alpha mRNA and/or protein in renal cell carcinoma (RCC) cells and whether PTX enhances the sensitivity of TNF-alpha-resistant RCC cells to TNF-alpha. Further, we explored whether PTX enhances the sensitivity of RCC cells to agents other than TNF-alpha by downregulation of the expression of TNF-alpha mRNA and protein. The R4 human RCC cell line constitutively expressed TNF-alpha mRNA and protein and was resistant to TNF-alpha. When R4 cells were incubated with PTX, the level of TNF-alpha mRNA and protein was markedly reduced. Pentoxifylline and TNF-alpha together overcame the resistance of R4 cells to TNF-alpha. The R11 human RCC cell line did not constitutively express TNF-alpha mRNA or protein, and was resistant to TNF-alpha. The expression of TNF-alpha mRNA in R11 cells, but not the production of TNF-alpha protein, was induced by TNF-alpha. When PTX was used in combination with TNF-alpha, the level of TNF-alpha mRNA induced by TNF-alpha was markedly reduced. The combination of PTX and TNF-alpha overcame the resistance of R11 cells to TNF-alpha. Pentoxifylline also enhanced the sensitivity of R4 cells to interferon-alpha. Pentoxifylline and anti-TNF-alpha monoclonal antibody augmented the sensitivity of R4 cells to cis-diamminedichloroplatinum (II) (CDDP). This study demonstrated that PTX, in combination with TNF-alpha, IFN-alpha or CDDP, overcame the drug resistance to RCC cells and that downregulation of TNF-alpha mRNA by PTX may be related to the cytotoxicity enhanced by the combination. The implications of these findings for clinical therapy are discussed.
Mizutani
Y
Y
Department of Urology, Faculty of Medicine, Kyoto University, Japan.
Bonavida
B
B
Nio
Y
Y
Yoshida
O
O
D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D010431:Pentoxifylline / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*
D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D002945:Cisplatin; D010431:Pentoxifylline