己酮可可碱联合肿瘤坏死因子-α（TNF-α）或药物治疗克服人肾癌细胞对TNF-α及药物的耐药性：TNF-α mRNA下调在肿瘤细胞致敏中的作用

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.

作者信息

Mizutani Y, Bonavida B, Nio Y, Yoshida O

机构信息

Department of Urology, Faculty of Medicine, Kyoto University, Japan.

出版信息

J Urol. 1994 Jun;151(6):1697-702. doi: 10.1016/s0022-5347(17)35347-8.

DOI:10.1016/s0022-5347(17)35347-8

PMID:8189599

Abstract

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.

摘要

先前的研究表明，肿瘤细胞对肿瘤坏死因子-α（TNF-α）产生抗性的一种可能机制是TNF-α信使核糖核酸（mRNA）和/或蛋白质的表达。己酮可可碱（PTX）抑制TNF-α基因转录，并下调巨噬细胞和单核细胞中TNF-α mRNA的表达以及TNF-α蛋白的分泌。本研究调查PTX是否下调肾细胞癌（RCC）细胞中TNF-α mRNA和/或蛋白质的表达，以及PTX是否增强对TNF-α耐药的RCC细胞对TNF-α的敏感性。此外，我们探讨PTX是否通过下调TNF-α mRNA和蛋白质的表达来增强RCC细胞对除TNF-α之外的其他药物的敏感性。R4人RCC细胞系组成性表达TNF-α mRNA和蛋白质，并且对TNF-α具有抗性。当R4细胞与PTX一起孵育时，TNF-α mRNA和蛋白质的水平显著降低。己酮可可碱和TNF-α共同克服了R4细胞对TNF-α的抗性。R11人RCC细胞系不组成性表达TNF-α mRNA或蛋白质，并且对TNF-α具有抗性。R11细胞中TNF-α mRNA的表达，但不是TNF-α蛋白的产生，由TNF-α诱导。当PTX与TNF-α联合使用时，由TNF-α诱导的TNF-α mRNA水平显著降低。PTX和TNF-α的联合克服了R11细胞对TNF-α的抗性。己酮可可碱还增强了R4细胞对干扰素-α的敏感性。己酮可可碱和抗TNF-α单克隆抗体增强了R4细胞对顺二氯二氨铂（II）（CDDP）的敏感性。本研究表明，PTX与TNF-α、干扰素-α或CDDP联合使用时，克服了对RCC细胞的耐药性，并且PTX对TNF-α mRNA的下调可能与联合使用增强的细胞毒性有关。讨论了这些发现对临床治疗的意义。