SummaryInterleukin 6 (IL-6) is a major growth factor for tumor plasma cells involved in human multiple myeloma (MM). In particular, human myeloma cell lines (HMCL), whose growth is completely dependent on addition of exogenous IL-6, can be obtained reproducibly from every patient with terminal disease. Four cytokines, ciliary neurotropic factor (CNTF), IL-11, leukemia inhibitory factor (LIF), and oncostatin M (OM), use the same transducer chain (signal transducer gpD0) as IL-6 and share numerous biological activities with this IL. We found that these four cytokines stimulated proliferation and supported the long-term growth of two out of four IL-6-dependent HMCL obtained in our laboratory. Half-maximal proliferation was obtained with cytokine concentrations ranging from 0.4 to 1.2 ng/ml for IL-11, LIF, and OM. CNTF worked at high concentrations only (90 ng/ml), but addition of soluble CNTF receptor increased sensitivity to CNTF 30-fold. The growth-promoting effect of these four cytokines was abrogated by antigp130 antibodies, contrary to results for anti-IL-6 receptor or anti-IL-6 antibodies. No detectable changes in the morphology and phenotype were found when myeloma cells were cultured with one of these four cytokines instead of IL-6. Concordant with their IL-6-dependent growth, the four HMCL expressed membrane IL-6R and gpD0 detected by FACS | analysis. LIF-binding chain gene (LIFR) was expressed only in the two HMCL responsive to LIF and OM.

JSI-124 (cucurbitacin I) is a selective inhibitor of Janus kinase/signal transducer and activator of transcription 3(JAK/STAT3) and has been shown to exert anti-proliferative and anti-tumor properties both in vitro and in vivo. As STAT3 activation has been implicated in the development of glioma, we investigated the therapeutic efficacy of JSI-124 on glioblastoma multiforme (GBM) by interfering with STAT3 pathway. In present study, two GBM cell lines, U251 and A172 cells, were treated with JSI-124. The results showed that the cell growth was inhibited significantly in a dose-and time-dependent manner. Further investigation illustrated that the levels of phosphorylated-STAT3 were decreased in GBM cells treated by JSI-124, concomitant with apoptosis augment and cell cycle arrest. Specially, JSI-124 induced G(2)/M accumulation via downregulation of cyclin B1 and cdc2 expression. Together these results suggested that inhibition of STAT3 by JSI-124 is a potential strategy for the development of the new glioblastoma multiforme therapeutics.

Gliomas are the most common type of primary tumor in the human central nervous system. STAT3, a signal transducer and activator of transcription 3, is over expressed in gliomas. Its involvement in tumorgenesis can be attributed to its ability to induce cell proliferation and inhibit apoptosis. Double-stranded decoy oligodeoxynucleotides (ODNs) which correspond closely to the STAT3 response element within the c-fos promoter are a potential tool for inhibiting a variety of tumor cell growth. To investigate its therapeutic potential in malignant gliomas, a 15-mer double-stranded decoy ODN mimicking STAT3-specific cis-elements was transfected into two glioma cell lines, U251 and A172. The STAT3 decoy ODN treatment specifically blocked STAT3 signaling and subsequently inhibited U251 and A172 cell proliferation by inducing apoptosis and cell-cycle arrest. The ODN treatment also decreased transcription and translation of downstream STAT3 target genes including c-myc, cyclin D1 and bcl-xl in both cell lines. Thus, targeted blockade of the STAT3 signaling pathway with a decoy ODN is a potential anti-glioma therapeutic approach.

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