Inhibitory effect of all-trans retinoic acid on the growth of freshly isolated myeloma cells via interference with interleukin-6 signal transduction [see comments]

Abstract

We showed the dose-dependent growth inhibition by alltrans retinoic acid (ATRA) of myeloma cells freshly isolated from patients. ATRA downregulated the cell surface expression of interleukin-6 receptor (IL- 6R) and/or glycoprotein (gp) 130. The growth-inhibitory activity of ATRA was well correlated with that of anti-gp 130 antibody in every sample. Furthermore, ATRA inhibited the production of IL-6 from both myeloma cells and marrow stromal cells, and recombinant IL-6 (rIL-6) could partially recover the myeloma cell growth that had been inhibited by ATRA. These data suggest that ATRA may inhibit the proliferation of myeloma cells both by the downregulation of IL-6R and gp130 expression on myeloma cells and by the inhibition of IL-6 production from myeloma and stromal cells. Prednisolone (PSL) and interferon-gamma (IFN-gamma) also inhibited the myeloma growth, while their effects were different from those of ATRA on IL-6 R and gp130 expression, IL-6 production, and morphological change. The inhibitory effect of ATRA on myeloma cell proliferation was observed in 10 of 14 samples obtained from eight patients, which suggests that ATRA may be a potent new therapeutic agent for some myeloma patients.

Retinoic acid modulates the in vivo and in vitro growth of IL-6 autocrine human myeloma cell lines via induction of apoptosis

“…Here we report that RA inhibited the proliferation of these two human myeloma cell lines, and provide evidence that this drug modulates the IL-6 autocrine circuit and triggers apoptosis of myeloma cells. RA was shown to down-regulate IL-6R expression on various cells from B lineage, such as Epstein-Barr virus (EBV)transformed lymphoblastoid cells [10], blood B cells from patients with IgM gammopathies [19] and malignant plasma cells [10,11]. In these cases, in vitro treatment with RA leads to a significant, but incomplete down-modulation of IL-6R expression in short-term cultures [10,11].…”

“…RA was shown to down-regulate IL-6R expression on various cells from B lineage, such as Epstein-Barr virus (EBV)transformed lymphoblastoid cells [10], blood B cells from patients with IgM gammopathies [19] and malignant plasma cells [10,11]. In these cases, in vitro treatment with RA leads to a significant, but incomplete down-modulation of IL-6R expression in short-term cultures [10,11]. We found that RA exerted a marked inhibitory effect on proliferation of both U266 and RPMI 8226 cells in early days after addition of the drug which was correlated with loss of viability.…”

“…Therapeutic trials with RA in myeloma patients did not show obvious clinical benefit [27]. A recent study showed that short-term in vitro effects of RA on fresh myeloma cells differed from patient to patient [11]. There was a decrease or an increase in cell proliferation and variable but partial down-modulation of IL-6R expression on plasma cells.…”

“…This drug may be of potential therapeutic interest in human haematopoietic malignancies, as examplified by its benefit in patients with acute promyelocytic leukaemias [8,9]. Myeloma may be another candidate for therapeutic use of RA, since it has been shown that this compound down-modulates the expression of the IL-6 receptor [10,11]; indeed, IL-6 is a key factor for the growth of myeloma cells, acting via a paracrine or autocrine mechanism [12][13][14][15]. The latter has been implicated in the growth of two myeloma cell lines, namely U266 and RPMI 8226.…”

Synergistic interactions between the synthetic retinoid tamibarotene and glucocorticoids in human myeloma cells

“…It is well known that IL-6 signaling plays an important role in the growth of MM, both in vitro and in vivo. (15,17,(36)(37)(38)(39) IL-6 acts as a potent survival and anti-apoptotic factor in MM through activation of multiple signaling cascades. Previous studies have shown that IL-6 induces growth and survival of human myeloma cells by way of the MAPK, (40) JAK/STAT, (31,41,42) and PI3K/Akt kinase pathways, which inhibit apoptosis and the appearance of drug resistance in MM cells.…”