全反式维甲酸对人类多发性骨髓瘤OPM-2细胞系抗增殖作用的研究

Study on Antiproliferative Effect of All-trans Retinoic Acid on the Human Multiple Myeloma OPM-2 Cell Line

观察了全反式维甲酸(ATRA)对人类多发性骨髓瘤(MM)OPM-2细胞系作用,~3H-TdR掺入法显示ATRA使S及G_2/M期细胞标记指数下降,提示G_1→S期细胞增殖受抑制。抑制程度与其浓度呈依赖关系。当ATRA浓度在≤(1-2)×10^(-8)mol/L有时反有刺激生长的作用。外源性IL-6(rhIL-6)能刺激OPM-2细胞克隆生长,抗IL-6单克隆抗体(McAb)可抑制其生长,rhIL-6不能逆转ATRA致OPM-2细胞生长抑制,提示OPM-2细胞能自分泌IL-6。^(125)I标记IL-6测得细胞表面IL-6受体(IL-6R)密度降低及亲和性下降,RT-PCR测得IL-6RmRNA下降,但gp130 mRNA表达无改变,在培养上清液测不出IL-6活性。这进一步证明ATRA对OPM-2细胞增殖的抑制作用是通过下调IL-6R及抑制瘤细胞自分泌IL-6双重作用而实现的。本实验提出ATRA有可能作为一种新的抗增殖药物治疗MM及其它自/旁分泌IL-6依赖性生长特性的肿瘤。

We investigated the effect of all-trans retinoic acid (ATRA) on the in vitro growth of a human multiple myeloma OPM-2 cell line. ATRA decreased the labeling index and the cell fraction in S and G2/M phase suggesting a block in G1→S phase transition. ATRA inhibited the clonogenic growth in a concentration -dependent fashion, except when at a concentration less than or equal to (1-2)×10-8 mol/L, where the effect was variable and appeared to be stimulatory in some experiments. The clonogenic growth was stimulated by exogenous IL-6 (rhIL-6) and was not reversed by rhIL-6, suggesting an autocrine function of IL-6. 125I-rhIL-6 binding assay showed that ATRA reduced the binding sites and the high-affinity. RT-PCR showed the IL-6R mRNA expression was markedly reduced but not the expression of IL-6 mRNA and gp130 mRNA. However, IL-6 secretion into supernatant was abolished. These data further confirm that the anti-proliferative effect of ATRA on OPM-2 cells is caused both by the down regulation of IL-6R and the inhibition of IL-6 production. Our findings implicate the rational use of ATRA as an anti-proliferative drug in tumors which show IL-6-dependent growth characteristics.