Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase

Szekeres, Thomas; Gharehbaghi, Kamran; Fritzer, Monika; Woody, Michael; Srivastava, Arun; Riet, Bart Van't; Jayaram, Hiremagalur N.; Elford, Howard L.

doi:10.1007/s002800050104

Cited by 10 publications

(14 citation statements)

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“…We have shown earlier, that incubation with tiazofurin induces the expression of the CD 71 transferrin receptor [21]. The receptor expression is usually linked with the proliferation rate of the cells.…”

Section: Effect Of Benzamide Riboside On Iron Metabolismmentioning

confidence: 96%

Benzamide Riboside, a Recent Inhibitor of Inosine 5-Monophosphate Dehydrogenase Induces Transferrin Receptors in Cancer Cells

Szekeres¹,

Sedlák²,

Novotný

2002

CMC

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Benzamide riboside, a recently discovered inhibitor of IMP dehydrogenase (IMPDH) exhibits oncolytic activity. IMPDH is the key enzyme of de novo guanylate biosynthesis and was shown to be linked with proliferation. Therefore, IMPDH is a very good target for antitumor therapy. In order to be active, benzamide riboside has to be converted to BAD, an NAD analogue that binds to the NAD site on IMPDH. Inhibition of the enzyme by benzamide riboside selectively inhibits tumor cell growth and induces apoptosis in various human tumor cell lines. In this manuscript we describe the induction of the CD71 transferrin receptor in human promyelocytic leukemia HL-60 cells following treatment with benzamide riboside. The results indicate a possible involvement of the iron metabolism in the action of this new compound. Benzamide riboside might be clinically used in the treatment of leukemia and solid tumors, alone or as part of combination therapy. Since transferrin receptors are overexpressed in certain cancers, such as glioma and colon cancer, a combination therapy that includes benzamide riboside in transferrin-coupled liposomes will not only target cancer cells but also leads to suicidal action because benzamide riboside will upregulate transferrin receptors on cancer cells thereby make it accessible to dose-intensive chemotherapy. We therefore believe that benzamide riboside itself or derivatives of benzamide riboside might become an important addition for the treatment to diseases that are otherwise fatal.

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Section: Effect Of Benzamide Riboside On Iron Metabolismmentioning

confidence: 96%

Benzamide Riboside, a Recent Inhibitor of Inosine 5-Monophosphate Dehydrogenase Induces Transferrin Receptors in Cancer Cells

Szekeres¹,

Sedlák²,

Novotný

2002

CMC

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“…Trimidox (3,4,5-trihydroxybenzohydroxamidoxime) is more effective than hydroxyurea in inhibiting the growth of various tumor cell lines [124,125]. It may induce differentiation in HL-60 promyelocytic leukemic cells [125] and has antiproliferative effect on HL-60 and K562 human leukemia cell lines [123].…”

Section: Trimidox and Didoxmentioning

confidence: 99%

Evolving role of ribonucleoside reductase inhibitors in hematologic malignancies

Tsimberidou¹,

Alvarado²,

Giles³

2002

Expert Review of Anticancer Therapy

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Ribonucleotide reductases catalyze the de novo biosynthesis of deoxyribonucleosides for DNA synthesis. Increased ribonucleotide reductases activity has been associated with malignant transformation and tumor cell growth. The ribonucleotide reductases inhibitors may bind with the R1 subunit of the enzyme (Class 1) or the nonheme iron (Class 2). This review focuses on the therapeutic use of ribonucleotide reductases inhibitors in hematologic malignancies. Hydroxyurea, fludarabine and cladribine have established roles in the management of hematologic malignancies, while other ribonucleotide reductases inhibitors, such as gemcitabine, tezacitabine and heterocyclic carboxaldehyde thiosemicarbazones (e.g., triapine) are being evaluated in clinical trials.

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“…A number of compounds inhibiting this enzyme have been synthesized. Trimidox (3,4,5‐trihydroxybenzamidoxime) was shown to be one of the most potent in this series of compounds (Szekeres et al 1994a & b). Trimidox was shown to exert antiproliferative activity in HL‐60 and K562 human leukaemia cell lines (Szekeres et al 1995), prolong the life‐span of mice inoculated with L1210 mouse leukaemia cells, and enhance the effect of anticancer drugs, such as adriamycin (Fritzer‐Szekeres et al 1998) or 1‐β‐ d ‐arabinofuranosyl cytosine (Ara‐C)(Fritzer‐Szekeres et al 2002).…”

mentioning

confidence: 99%

Trimidox Induces Apoptosis via Cytochrome c Release in NALM‐6 Human B Cell Leukaemia Cells

Kanno

Uwai

Tomizawa

et al. 2006

Basic Clin Pharma Tox

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Trimidox (3,4,5-trihydroxybenzamidoxime) has been shown to reduce the activity of ribonucleotide reductase accompanied by growth inhibition and the differentiation of mammalian cells. Here we examine the induction of apoptosis by trimidox in several human leukaemia cell lines, focusing on the release of cytochrome c and the activation of caspase proteases in the human B cell line NALM-6. Induction of apoptosis by trimidox (300 mM) was detected in NALM-6, HL-60 (premyelocytic leukaemia cells), MOLT-4 (an acute lymphoblastic leukaemia cells), Jurkat (a T-cell leukaemia cells), U937 (expressing many monocyte-like characteristics), and K562 (erythroleukaemia). NALM-6 was most affected by trimidox among leukaemia cells; therefore, we employed NALM-6 cells in the subsequent experiments. The cells showed a time-dependent increase in DNA damage after trimidox (250 mM) treatment. A significant increase in the amount of cytochrome c release was detected after treatment with trimidox. Bcl-2 and Bax protein expressions were not changed by trimidox. Caspase-3 and -9 were activated by incubation with trimidox, whereas caspase-8 was not. Furthermore, trimidoxinduced apoptosis was prevented by a broad-spectrum caspase inhibitor, a caspase-3, and a caspase-9 inhibitor, but not by a caspase-8 inhibitor. Inhibition of c-Jun NH 2 -terminal kinase (JNK) by SP600125 appreciably protected cells from trimidox-induced apoptosis, but no effect inhibition of p38 mitogen-activated protein kinase (MAPK) by SB203580. In contrast, extracellular signal-regulated kinase (ERK) inhibitors U0126 and PD98059 strongly potentiated the apoptotic effect of trimidox. This report shows that the induction of apoptosis by trimidox occurs through a cytochrome c-dependent pathway, which sequentially activates caspase-3 and caspase-9.

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Biochemical and antitumor activity of trimidox, a new inhibitor of ribonucleotide reductase

Cited by 10 publications

References 0 publications

Benzamide Riboside, a Recent Inhibitor of Inosine 5-Monophosphate Dehydrogenase Induces Transferrin Receptors in Cancer Cells

Benzamide Riboside, a Recent Inhibitor of Inosine 5-Monophosphate Dehydrogenase Induces Transferrin Receptors in Cancer Cells

Evolving role of ribonucleoside reductase inhibitors in hematologic malignancies

Trimidox Induces Apoptosis via Cytochrome c Release in NALM‐6 Human B Cell Leukaemia Cells

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