The antitrypanosomal and antifiliarial drug suramin is currently under investigation for treatment of advanced malignancies including prostatic cancer, adrenocortical cancer, and some lymphomas and sarcomas. Here we show that suramin is a potent inhibitor of the nuclear enzyme DNA topoisomerase II. Suramin inhibited purified yeast topoisomerase II with an IC5s of about 5 FM, as measured by decatenation or relaxation assays. Suramin did not stabilize the covalent DNA-topoisomerase II reaction intermediate ("cleavable complex"), whereas other inhibitors of this enzyme, such as amsacrine, etoposide, and the ellipticines, are known to stabilize the intermediate. In contrast, the presence of suramin strongly inhibited the cleavable-complex formation induced by amsacrine or etoposide. Accumulation of the endogenous cleavable complex was also inhibited. Suramin entered the nucleus of DC-3F Chinese hamster fibrosarcoma cells exposed to radiolabeled suramin for 24 hr as shown by both optic and electron microscopy. The suramin present in the nucleus seemed to interact with topoisomerase II, since suramin reduced the number of amsacrine-induced protein-associated DNA strand breaks in DC-3F cells and protected these cells from the cytotoxic action of amsacrine. Cells resistant to 9-hydroxyellipticine, which have been shown to have an altered topoisomerase II activity, are about 7-fold more resistant to suramin than the sensitive parental cells as shown by 72-hr growth inhibition assay. Our results suggest that DNA topoisomerase II is a target of suramin action and that this action may play a role in the cytotoxic activity of suramin.Suramin is a hexasulfated naphthylurea that has been used in the treatment of trypanosomiasis (sleeping sickness) and onchocerciasis for more than half a century (1). Mor recently, suramin was shown to prevent infection of T lymphocytes by human immunodeficiency virus in vitro (2). This led to clinical trials of the compound in AIDS patients, where it showed little therapeutic activity (3, 4). However, during these trials a complete clinical response was noted in a patient with Kaposi sarcoma and non-Hodgkin lymphoma (4), and subsequent studies showed that suramin was active in the treatment of several metastatic cancers such as renal cancer, adrenocarcinoma, lymphoma, and prostate cancer (5, 6).Suramin inhibits the binding of platelet-derived growth factor, epidermal growth factor, basic fibroblast growth factor, transforming growth factor /3, and insulin-like growth factor to their specific cell surface receptors (7-11). The drug also affects the activity of protein kinase C and inhibits phosphatidylinositol kinase and diacylglycerol kinase (12, 13). Several nuclear enzymes are also inhibited by suramin. These include DNA and RNA polymerases, terminal deoxynucleotidyltransferase, and reverse transcriptase (14-17).Suramin can induce cell differentiation in several different systems (18,19) and can inhibit tumor cell invasion (20).Here we demonstrate that suramin is a potent inhibitor of...

Unr (upstream of N-ras) is a cytoplasmic RNA-binding protein that can act as a regulator of mRNA stability and IRES-mediated translation. Unr, a member of the cold-shock domain (CSD) protein super-family, is ubiquitously expressed, with variable abundance, in different tissues or during embryonic development. Prokaryotic and eukaryotic coldshock protein expression is highly regulated at both the transcriptional and post-transcriptional levels. Here we analyzed the role of the 5'-and 3'-untranslated regions (UTR) of unr mRNA in post-transcriptional regulation of Unr expression. We show that, in vitro, unr 3'-UTR specifically destabilizes unr transcripts. Accordingly, in vivo, the half-life of unr messages deleted of noncoding regions is increased by ~3.6 fold, resulting in an enhanced steady-state level of Unr protein. We also show that the 5'-UTR exhibits IRES activity both when translated in vitro and in transiently transfected cells. This IRES activity displays cell type specificity with a higher efficiency in HeLa and HuH7 than in ES cells. Moreover, Unr IRES activity was higher in unr-/than in unr +/+ ES cells, indicating that Unr negatively regulates its own IRES activity. Our studies further reveal that Unr specifically interacts with its own mRNAs in vivo. These results suggest that a feedback control of mRNA translation is involved in regulating Unr expression.

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