mitoguazone and methylglyoxal-bis(cyclopentylamidinohydrazone)

In order to better understand the development of skeletal metastases, we developed an appropriate animal model, as the natural progression of metastases in humans cannot be studied on the cellular level. In this study, we established a new animal model which developed bone metastasis in a bone grafted subcutaneously. C57BL/6 mice, which had received a bone (femur or tibia) transplanted in the dorsal subcutis, were injected with B16 melanoma cells into the left heart ventricle. Metastasis was found in approximately 70% of the extraskeletal bones. Using this model, the antimetastatic effect of a polyamine synthesis inhibitor was investigated. Inhibitors of the polyamine biosynthetic pathway have received considerable attention for their potential use in the treatment of cancer as they are responsible for the greatly increased production of the polyamines putrescine, spermidine, and spermine. A polyamine synthesis inhibitor, methylglyoxal-bis(cyclopentylamidinohydrazone) MGBCP, was investigated for its inhibitory effects on bone metastases. MGBCP (20 mg/kg) was administered intraperitoneally every day for 4 weeks and demonstrated strong inhibitory effects on bone metastases. MGBCP inhibited angiogenesis in the transplanted bone and the growth of B16 melanoma cells, thus suggesting a preventive mechanism in bone metastasis. No remarkable adverse effects of MGBCP were observed in any animal throughout the experimental period. Our results indicate that MGBCP has a strong potential for use as an anti-metastatic drug.

Topics: Animals; Antineoplastic Agents; Bone Neoplasms; Disease Models, Animal; DNA Fragmentation; Melanoma; Mice; Mice, Inbred C57BL; Mitoguazone; Neovascularization, Pathologic; Polyamines; Tumor Cells, Cultured

The antitumor effects of a polyamine biosynthetic pathway inhibitor methylglyoxal bis(cyclopentylamidinohydrazone) (MGBCP) on the human hepatocellular carcinoma SK-HEP-1 cell line have been investigated. The growth of these cultured hepatocellular carcinoma cells was inhibited by MGBCP in a dose-dependent manner. Spermidine and spermine levels were dose-dependently depressed, and morphological changes due to programmed cell death (apoptosis) were observed in these MGBCP-treated hepatocellular carcinoma cells. These results suggest that in addition to reducing the growth rates, MGBCP can induce apoptotic cell death in this human hepatocellular carcinoma cell line.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Division; DNA Fragmentation; Dose-Response Relationship, Drug; Humans; Liver Neoplasms; Mitoguazone; Polyamines; Tumor Cells, Cultured

Polyamines are considered to be important intracellular molecules for the proliferation of the cancer cells. In this study, effects of methylglyoxal bis(cyclopentylamidinohydrazone) (MGBCP), a potent inhibitor of the polyamine biosynthetic pathway, on the growth and cell cycle of T-47D human breast cancer cells were investigated. MGBCP dose-dependently inhibited the growth of T-47D cells, in which the contents of spermine, spermidine and putrescine decreased concomitantly. The gene expression of cyclin D1 was also repressed by the MGBCP treatment. The MGBCP-treated cells clearly exhibited morphological changes indicating the blebbing and chromatin condensation which are characteristic of apoptosis. Flow cytometric analysis showed hypo-diploid subpopulations due to apoptotic cells, and characteristic oligonucleosomal-sized DNA fragments were clearly observed for MGBCP-treated cells as the concentration of the drug was increased. These findings suggest that the inhibition of polyamine synthesis results in the repressions of cyclin D1 expression and cell cycle progression, eventually inducing apoptosis in these human breast cancer cells.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Cycle; Cell Division; Cyclin D1; DNA Fragmentation; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Mitoguazone; Polyamines; RNA, Messenger; Time Factors; Tumor Cells, Cultured

The anti-proliferative effect of methylglyoxal bis(cyclopentylamidino-hydrazone) (MGBCP), a multi-enzyme inhibitor of polyamine biosynthesis, on the growth of Helicobacter pylori was investigated. MGBCP inhibited the cell growth of H. pylori in a dose-dependent manner. The inhibition was partially reversed by the addition of spermidine. Synthesis of macromolecules, DNA, RNA and protein, was inhibited in the spermidine-depleted H. pylori cells. These findings suggest that MGBCP exhibits an anti-proliferative effect on H. pylori by suppression of macromolecule synthesis.

Topics: Anti-Bacterial Agents; Bacterial Proteins; DNA, Bacterial; Enzyme Inhibitors; Helicobacter Infections; Helicobacter pylori; Humans; In Vitro Techniques; Mitoguazone; Polyamines; Putrescine; RNA, Bacterial; Spermidine

Antiproliferative effects of combined treatment with methylglyoxal bis(cyclopentylamidinohydrazone) (MGBCP), a polyamine biosynthesis inhibitor, and cepharanthine, a biscoclaurine alkaloid, on methicillin- and gentamicin-resistant Staphylococcus aureus were investigated. The bactericidal effect of MGBCP on S. aureus was potentiated by the cepharanthine treatment. Cellular polyamine levels of the bacteria treated with both MGBCP and cepharanthine were much lower than those of the bacteria treated with MGBCP alone. On the contrary, the cellular MGBCP concentration was much higher in the cepharanthine-treated bacteria. Thus, cepharanthine was considered to enhance the incorporation of MGBCP into the bacteria. The combination of MGBCP and cepharanthine resulted in greater suppression of macromolecular synthesis in the bacteria that might have caused greater suppression of bacterial growth.

Topics: Alkaloids; Benzylisoquinolines; Drug Synergism; Mitoguazone; Staphylococcus aureus

Metabolic and antiproliferative effects of methylglyoxal bis(butylamidinohydrazone) (MGBB) and methylglyoxal bis(cyclopentylamidinohydrazone) (MGBCP), inhibitors for polyamine biosynthetic pathway, on Escherichia coli, Shigella sonnei, Aeromonas sobria, Aeromonas hydrophila and Vibrio cholerae were investigated. MGBB at the concentration of 100 mumol/l depleted intracellular putrescine and spermidine concentrations of E. coli to 25 and 20% of the controls, respectively, while MGBCP depressed their concentrations to 38 and 24%, respectively. In these polyamine-depleted E. coli cells the syntheses of RNA, DNA and protein decreased to 13, 54 and 29% of the control, respectively, with MGBB and to 23, 71 and 55%, respectively, with MGBCP. The minimum inhibitory concentrations (MIC) of MGBB for the growth of A. sobria, E. coli, A. hydrophila, V. cholerae and Sh. sonnei were estimated to be 50, 160, 240, 285 and 320 mumol/l, respectively, whereas those of MGBCP were slightly higher for respective bacteria.

Topics: Bacteria; Bacterial Proteins; Biogenic Polyamines; Escherichia coli; Mitoguazone

Methylglyoxal-bis(cyclopentylamidinohydrazone) (MGBCP) has been synthesized as a multienzyme inhibitor for the polyamine-synthesizing pathway. This drug inhibited S-adenosylmethionine decarboxylase (EC 4.1.1.50), spermine synthase and spermidine synthase activities, competitively with S-adenosylmethionine, spermidine, and putrescine, respectively. MGBCP inhibited the growth of human leukemia Molt 4B and K 562 cells at 10 to 100 microM concentrations. Spermidine and spermine levels were markedly depressed in these MGBCP-treated leukemic cells, and the synthesis of protein, but not of DNA or RNA, was significantly diminished. In in vivo experiments, MGBCP depleted spermidine and spermine in the P388 leukemic ascites cells, and prolonged the survival time of mice bearing P388 leukemia. The S-adenosylmethionine decarboxylase-stabilizing effect of MGBCP in mouse liver, Molt 4B and K 562 cells was much less than that of the parent inhibitor methylglyoxal-bis(guanylhydrazone). Induction of ornithine decarboxylase activity by MGBCP in the cultured leukemic cells was also much less than that by methylglyoxal-bis(guanylhydrazone).

Topics: Adenosylmethionine Decarboxylase; Animals; Antineoplastic Agents; Biogenic Polyamines; Female; Humans; Leukemia; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mitoguazone; Ornithine Decarboxylase; Spermidine Synthase; Spermine Synthase; Transferases; Tumor Cells, Cultured