Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines.
Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines.
复制标题
DOI：
--
复制
发表时间：
1995-10
期刊：
影响因子：
11.2
通讯作者：
N. Borsellino;A. Belldegrun;B. Bonavida
中科院分区：
文献类型：
--
作者：
N. Borsellino;A. Belldegrun;B. Bonavida
晚期前列腺癌患者的激素治疗通常会产生最初有益的反应，但接受治疗的患者会出现激素抵抗性疾病，目前尚无可用的治疗方法。最近的研究表明，白细胞介素 6 (IL-6) 是骨髓瘤、肾细胞癌和某些 T 细胞淋巴瘤的生长因子。此外，IL-6 已被证明可以阻断 p53、转化生长因子 β 和某些癌症化疗化合物诱导的细胞凋亡。本研究的目的是确定 IL-6 是否是两种人类前列腺癌细胞系的生长因子，以及它是否可以保护肿瘤细胞免受药物诱导的细胞死亡。本研究使用了两种激素非依赖性前列腺细胞系，即 PC-3 和 DU145，它们已被证明对顺式二氯铂 (CDDP)、依托泊苷 (VP-16) 和阿霉素 (ADR) 具有相对耐药性。两种细胞系均表达 IL-6 mRNA 并组成型分泌 IL-6。向细胞系中添加抗IL-6抗血清导致细胞生长显着抑制直至第2天，并且当在第2天添加额外的抗体时，抑制持续4天。抗IL-6抗血清与CDDP或VP-16的共同添加导致两种细胞系中细胞毒性的协同作用，而抗体与ADR或苏拉明的组合仅导致相加效应。顺序治疗显示需要抗IL-6抗体才能实现协同作用，而任一顺序的预处理都导致与抗IL-6和CDDP的协同作用，但不与VP-16产生协同作用。 CDDP处理肿瘤细胞下调IL-6 mRNA表达和IL-6分泌。目前的研究结果表明，IL-6 是 DU145 和 PC-3 前列腺系的自分泌/旁分泌生长因子。此外，这种细胞因子的分泌可以保护肿瘤细胞免受 CDDP 和 VP-16 的细胞毒性作用，并且其中和作用使细胞对细胞毒性敏感。总体而言，研究表明，能够下调或抑制肿瘤保护因子的药物可能会克服耐药性。
Hormonal treatment of advanced prostatic cancer patients generally results in an initially beneficial response, but the treated patients develop hormonally resistant disease in which no curative therapy is currently available. Recent studies have revealed that interleukin 6 (IL-6) is a growth factor for myeloma, renal cell carcinoma, and certain T-cell lymphomas. Further, IL-6 has been shown to block apoptosis induced by p53, transforming growth factor beta, and certain cancer chemotherapeutic compounds. The objective of the present study was to determine whether IL-6 is a growth factor for two human prostate cancer lines and whether it protects the tumor cells from drug-induced cell death. Two hormone-independent prostate cell lines were used in this study, namely PC-3 and DU145, and these have been shown to be relatively resistant to cis-diamminedichloroplatinum (CDDP), etoposide (VP-16), and adriamycin (ADR). Both cell lines express IL-6 mRNA and secrete IL-6 constitutively. The addition of anti-IL-6 antiserum to the cell lines resulted in a significant inhibition of cell growth up to day 2, and when additional antibody was added at day 2 the inhibition persisted for 4 days. The coaddition of anti-IL-6 antiserum and CDDP or VP-16 resulted in synergy in cytotoxicity in both cell lines, whereas the combination of antibody and ADR or suramin resulted only in additive effects. Sequential treatment revealed that anti-IL-6 antibody was required to achieve synergy, whereas either sequence of pretreatment resulted in synergy with anti-IL-6 and CDDP but not with VP-16. CDDP treatment of tumor cells down-regulated IL-6 mRNA expression and IL-6 secretion. The present findings demonstrate that IL-6 is an autocrine/paracrine growth factor for DU145 and PC-3 prostate lines. Additionally, the secretion of this cytokine protects the tumor cells against the cytotoxic effect of CDDP and VP-16 and its neutralization sensitizes the cells to cytotoxicity. Overall, the studies suggest that agents that can down-regulate or inhibit protective factors in tumors may overcome drug resistance.